| 1. |
- Attaran, Nima, et al.
(författare)
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Antigen peptide transporters are upregulated in squamous cell carcinoma of the oral tongue and show sex‑specific associations with survival
- 2022
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Ingår i: Oncology Letters. - : Spandidos Publications. - 1792-1074 .- 1792-1082. ; 24:5
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Tidskriftsartikel (refereegranskat)abstract
- Transporter associated with antigen processing 1 (TAP1) and TAP2 serve pivotal roles in adaptive immunity. Tumor cells often show reduced antigen presentation on their surface as one mechanism to escape immune recognition. Whether downregulation of TAPs is a common mechanism of tumor immune evasion in squamous cell carcinoma of the oral tongue (SCCOT) is unclear. In the present study, samples from 78 patients with SCCOT and 17 patients with benign hyperplastic tongue lesions were analyzed for TAP1 and TAP2 expression by immunohistochemistry. The percentage of positive cells and staining intensity were scored. Associations with clinicopathological variables and survival outcome were also investigated. The results demonstrated that TAP1 and TAP2 levels were highly associated with each other in individual samples and were upregulated in SCCOT compared with benign lesions (P<0.001). The proportion of TAP1‐ or TAP2‐positive tumor cells was >80% in all but two of the tumors, whereas 25.6 and 23.0% of the tumors showed weak intensity of TAP1 and TAP2, respectively. There were no significant associations with clinicopathological variables or survival outcomes between TAP‐intermediate/strong and TAP‐weak tumors. However, in patients <70 years old and with early stage SCCOT, male patients had better outcomes than female patients (log‐rank P<0.05), and the best outcome was observed in male patients with intermediate/strong TAP expression. In conclusion, loss of TAP was not a frequent event in SCCOT and stronger TAP expression in male patients was associated with improved survival, providing further evidence for sex‐specific immune modulation in cancer.
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| 2. |
- Attaran, Nima, et al.
(författare)
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Downregulation of TAP1 in Tumor-Free Tongue Contralateral to Squamous Cell Carcinoma of the Oral Tongue, an Indicator of Better Survival.
- 2020
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Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 21:17
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Tidskriftsartikel (refereegranskat)abstract
- Oral cancers are surrounded by epithelium that histologically might seem normal, but genetically has aberrations. In patients with squamous cell carcinoma of the oral tongue (SCCOT), it is therefore important to study not only the tumor but also the clinically tumor-free contralateral tongue tissue that remains in the patient after treatment to map changes of prognostic and/or diagnostic value. The transporter associated with antigen processing (TAP) dimer is a key factor in the process of activating cytotoxic T cells. By downregulating the expression of TAP, tumor cells can escape cytotoxic T cell recognition. Biopsies from tumor and clinically tumor-free contralateral tongue tissue in 21 patients with SCCOT were analyzed together with tongue biopsies from 14 healthy individuals, which served as the control group. Dividing patients into TAP1-high and TAP1-low groups according to the median TAP1 level in tumor-free samples showed that patients with lower TAP1 mRNA levels in tumor-free samples had better overall (p = 0.003) and disease-free survival (p = 0.002). The results showing that TAP1 levels in tumor-free tongue tissue contralateral to the SCCOT correlate with survival is an important contribution to early diagnosis and follow up of SCCOT.
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| 3. |
- Boldrup, Linda, et al.
(författare)
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DeltaNp63 isoforms differentially regulate gene expression in squamous cell carcinoma : identification of Cox-2 as a novel p63 target.
- 2009
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Ingår i: The Journal of pathology. - : Wiley. - 1096-9896 .- 0022-3417.
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Tidskriftsartikel (refereegranskat)abstract
- The p53 homologue p63 produces six different isoforms that are important in development of epithelial tissues and squamous cell carcinoma of the head and neck (SCCHN). In SCCHN, the expression of p63 isoforms is highly complex, with over-expression of DeltaNp63 and p63beta isoforms in many tumours. To date, little is known about the functions of different DeltaNp63 isoforms and elucidating the distinctive properties of DeltaNp63 isoforms will help to clarify how they influence tumour biology. By gene expression profiling of SCCHN cells over-expressing the DeltaNp63 isoforms we identified different effects of the three isoforms, with DeltaNp63beta being more effective at gene induction than DeltaNp63alpha and DeltaNp63gamma, whereas DeltaNp63gamma was most effective at repressing gene expression. Thus, tumours expressing even low levels of DeltaNp63beta or DeltaNp63gamma may have distinct clinicopathological characteristics important for metastasis and therapeutic response. Induction of cyclooxygenase-2 (Cox-2) was shown by each isoform and data were confirmed by independent quantitative RT-PCR and western blotting. No direct binding of DeltaNp63 to the Cox-2 promoter could be seen, neither could any evidence for Cox-2 induction as a consequence of activated NF-kappaB pathway responses be found. As Cox-2 is known to inhibit radiotherapy responses in SCCHN patients, data indicate an additional mechanism through which DeltaNp63 acts to promote cell survival and influence therapeutic response of SCCHN. MIAME-compliant data have been deposited in the MIAME Express database (Accession No. E-MEXP-1842). Copyright (c) 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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| 4. |
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| 5. |
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| 6. |
- Boldrup, Linda, et al.
(författare)
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Evidence that circulating proteins are more promising than miRNAs for identification of patients with squamous cell carcinoma of the tongue
- 2017
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Ingår i: Oncotarget. - : IMPACT JOURNALS LLC. - 1949-2553. ; 8:61, s. 103437-103448
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Tidskriftsartikel (refereegranskat)abstract
- Despite intense research, squamous cell carcinoma of the tongue remains a devastating disease with a five-year survival of around 60%. Late detection and recurrence are the main causes for poor survival. The identification of circulating factors for early diagnosis and/or prognosis of cancer is a rapidly evolving field of interest, with the hope of finding stable and reliable markers of clinical significance. The aim of this study was to evaluate circulating miRNAs and proteins as potential factors for distinguishing patients with tongue squamous cell carcinoma from healthy controls. Array-based profiling of 372 miRNAs in plasma samples showed broad variations between different patients and did not show any evidence for their use in diagnosis of tongue cancer. Although one miRNA, miR-150, was significantly down-regulated in plasma from patients compared to controls. Surprisingly, the corresponding tumor tissue showed an up-regulation of miR-150. Among circulating proteins, 23 were identified as potential markers of squamous cell carcinoma of the tongue. These findings imply that circulating proteins are a more promising source of biomarkers for tongue squamous cell carcinomas than circulating miRNAs. The data also highlight that circulating markers are not always directly associated with tumor cell properties.
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| 7. |
- Boldrup, Linda, et al.
(författare)
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Gene expression changes in tumor free tongue tissue adjacent to tongue squamous cell carcinoma
- 2017
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 8:12, s. 19389-19402
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Tidskriftsartikel (refereegranskat)abstract
- Due to the high frequency of loco-regional recurrences, which could be explained by changes in the field surrounding the tumor, patients with squamous cell carcinoma of head and neck show poor survival. Here we identified a total of 554 genes as dysregulated in clinically tumor free tongue tissue in patients with tongue tumors when compared to healthy control tongue tissue. Among the top dysregulated genes when comparing control and tumor free tissue were those involved in apoptosis (CIDEC, MUC1, ZBTB16, PRNP, ECT2), immune response (IFI27) and differentiation (KRT36). Data suggest that these are important findings which can aid in earlier diagnosis of tumor development, a relapse or a novel squamous cell carcinoma of the tongue, in the absence of histological signs of a tumor.
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| 8. |
- Boldrup, Linda, et al.
(författare)
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Levels of MUC1 in tumours and serum of patients with different sub-types of squamous cell carcinoma of the head and neck
- 2020
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Ingår i: Oncology Letters. - : Spandidos Publications. - 1792-1074 .- 1792-1082. ; 20:2, s. 1709-1718
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Tidskriftsartikel (refereegranskat)abstract
- Mucin 1 (MUC1) is a membrane-bound and secreted glycoprotein that has a protective role in surface epithelia. We recently demonstrated that MUC1 mRNA expression was upregulated in tumour-free tongue tissues adjacent to squamous cell carcinoma of the oral tongue (SCCOT) compared with that in the tumour tissues. The present study investigated MUC1 protein in SCCOT tissue and serum from patients with squamous cell carcinoma of the head and neck (SCCHN) at different sub-sites. The results from immunohistochemistry demonstrated that all SCCOT tissues expressed MUC1; however, the protein levels were not correlated with MUC1 mRNA levels in the same tumours. Furthermore, serum MUC1 level was lower in patients with SCCOT, tonsil SCC and gingival SCC compared with that in healthy subjects; however, the difference was only significant for patients with SCCOT (P=0.0421). No correlation was seen between MUC1 level in tumour tissues and MUCI level in serum from the same patients. The absence of correlation between MUC1 protein and mRNA levels in SCCOT tissues emphasized the importance of validating genomic data in clinical samples. Although significant MUC1 downregulation was observed in the serum of patients with SCCOT, there was a large variation within the groups, suggesting that MUC1 may not be used as a biomarker for these types of tumors.
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| 9. |
- Boldrup, Linda, et al.
(författare)
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Low potential of circulating interleukin 1 receptor antagonist as a prediction marker for squamous cell carcinoma of the head and neck
- 2021
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Ingår i: Journal of Oral Pathology & Medicine. - : John Wiley & Sons. - 0904-2512 .- 1600-0714. ; 50:8, s. 785-794
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Tidskriftsartikel (refereegranskat)abstract
- Background: Circulating markers are attractive molecules for prognosis and management of cancer that allow sequential monitoring of patients during and after treatment. Based on previous protein profiling data, circulating interleukin 1 receptor antagonist (IL-1Ra) was evaluated as a potential diagnostic and prognostic marker for squamous cell carcinomas of the head and neck (SCCHN). In this study, we aimed at confirming the clinical relevance of plasma IL-1Ra in SCCHN and exploring its potential as a prediction marker for SCCHN.Methods: Plasma from 87 patients with SCCHN, control plasma from 28 healthy individuals and pre-diagnostic plasma from 44 patients with squamous cell carcinoma of the oral tongue (SCCOT) and 88 matched controls were analysed with IL-1Ra electrochemiluminescence immunoassays from mesoscale diagnostics.Results: Plasma IL-1Ra was found to be up-regulated in patients with oral tongue, gingiva and base of tongue tumours compared to healthy individuals (p < 0.01). IL-1Ra levels positively correlated with tumour size (p < 0.01) and body mass index (p = 0.013). Comparing pre-diagnostic plasma to the matched controls, similar IL1-Ra levels were seen (p = 0.05).Conclusion: The anti-inflammatory cytokine IL-1Ra could be a diagnostic marker for SCCHN, whereas its potential as a cancer prediction marker was not supported by our data.
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| 10. |
- Danielsson, Karin, et al.
(författare)
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Altered expression of miR-21, miR-125b, and miR-203 indicates a role for these microRNAs in oral lichen planus
- 2012
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Ingår i: Journal of Oral Pathology & Medicine. - : Wiley. - 0904-2512 .- 1600-0714. ; 41:1, s. 90-95
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Tidskriftsartikel (refereegranskat)abstract
- Background: Oral lichen planus (OLP), which is a chronic inflammatory disease of the oral mucosa with unknown etiology, affects about 2% of the population. MicroRNAs are small non-coding RNAs involved in normal processes such as development and differentiation as well as progression of human diseases. The aim of this study was to investigate the expression of miR-21, miR-125b, and miR-203 and to compare RNA levels of their potential targets, the tumor suppressor p53 and its relative p63, both known to be deregulated in OLP. Methods: In biopsies from 20 patients with OLP and 20 age- and sex-matched healthy controls, epithelium was laser dissected and analyzed for the expression of miR-21, miR-125b, miR-203, p53, and p63 using qRT/PCR. Results: Increased expression of miR-21 and miR-203, decreased expression of miR-125, and down-regulation of p53 and ΔNp63 RNA were seen in OLP compared to normal oral mucosa. When comparing microRNA expression to levels of p53 and p63 RNA, a significant negative correlation was seen between ΔNp63 and miR-203 and between miR-21 and p53, respectively. Conclusion: Results indicate a role for the studied microRNAs in changes seen in OLP.
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| 11. |
- Fusée, Leila, et al.
(författare)
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The p53 endoplasmic reticulum stress-response pathway evolved in humans but not in mice via PERK-regulated p53 mRNA structures
- 2023
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Ingår i: Cell Death and Differentiation. - : Springer Nature. - 1350-9047 .- 1476-5403. ; 30, s. 1072-1081
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Tidskriftsartikel (refereegranskat)abstract
- Cellular stress conditions activate p53-dependent pathways to counteract the inflicted damage. To achieve the required functional diversity, p53 is subjected to numerous post-translational modifications and the expression of isoforms. Little is yet known how p53 has evolved to respond to different stress pathways. The p53 isoform p53/47 (p47 or ΔNp53) is linked to aging and neural degeneration and is expressed in human cells via an alternative cap-independent translation initiation from the 2nd in-frame AUG at codon 40 (+118) during endoplasmic reticulum (ER) stress. Despite an AUG codon in the same location, the mouse p53 mRNA does not express the corresponding isoform in either human or mouse-derived cells. High-throughput in-cell RNA structure probing shows that p47 expression is attributed to PERK kinase-dependent structural alterations in the human p53 mRNA, independently of eIF2α. These structural changes do not take place in murine p53 mRNA. Surprisingly, PERK response elements required for the p47 expression are located downstream of the 2nd AUG. The data show that the human p53 mRNA has evolved to respond to PERK-mediated regulation of mRNA structures in order to control p47 expression. The findings highlight how p53 mRNA co-evolved with the function of the encoded protein to specify p53-activities under different cellular conditions.
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| 12. |
- Gu, Xiaolian, 1976-, et al.
(författare)
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AP001056.1, A Prognosis-Related Enhancer RNA in Squamous Cell Carcinoma of the Head and Neck
- 2019
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Ingår i: Cancers. - : MDPI. - 2072-6694. ; 11:3
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Tidskriftsartikel (refereegranskat)abstract
- A growing number of long non-coding RNAs (lncRNAs) have been linked to squamous cell carcinoma of the head and neck (SCCHN). A subclass of lncRNAs, termed enhancer RNAs (eRNAs), are derived from enhancer regions and could contribute to enhancer function. In this study, we developed an integrated data analysis approach to identify key eRNAs in SCCHN. Tissue-specific enhancer-derived RNAs and their regulated genes previously predicted using the computational pipeline PreSTIGE, were considered as putative eRNA-target pairs. The interactive web servers, TANRIC (the Atlas of Noncoding RNAs in Cancer) and cBioPortal, were used to explore the RNA levels and clinical data from the Cancer Genome Atlas (TCGA) project. Requiring that key eRNAs should show significant associations with overall survival (Kaplan-Meier log-rank test, p < 0.05) and the predicted target (correlation coefficient r > 0.4, p < 0.001), we identified five key eRNA candidates. The most significant survival-associated eRNA was AP001056.1 with ICOSLG encoding an immune checkpoint protein as its regulated target. Another 1640 genes also showed significant correlation with AP001056.1 (r > 0.4, p < 0.001), with the "immune system process" being the most significantly enriched biological process (adjusted p < 0.001). Our results suggest that AP001056.1 is a key immune-related eRNA in SCCHN with a positive impact on clinical outcome.
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| 13. |
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| 14. |
- Gu, Xiaolian, 1976-, et al.
(författare)
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Copy number variation : A prognostic marker for young patients with squamous cell carcinoma of the oral tongue
- 2019
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Ingår i: Journal of Oral Pathology & Medicine. - : John Wiley & Sons. - 0904-2512 .- 1600-0714. ; 48:1, s. 24-30
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Tidskriftsartikel (refereegranskat)abstract
- Background The incidence of squamous cell carcinoma of the oral tongue (SCCOT) is increasing in people under age 40. There is an urgent need to identify prognostic markers that help identify young SCCOT patients with poor prognosis in order to select these for individualized treatment. Materials and methods To identify genetic markers that can serve as prognostic markers for young SCCOT patients, we first investigated four young (<= 40 years) and five elderly patients (>= 50 years) using global RNA sequencing and whole-exome sequencing. Next, we combined our data with data on SCCOT from the cancer genome atlas (TCGA), giving a total of 16 young and 104 elderly, to explore the correlations between genomic variations and clinical outcomes. Results In agreement with previous studies, we found that SCCOT from young and elderly patients was transcriptomically and also genomically similar with no significant differences regarding cancer driver genes, germline predisposition genes, or the burden of somatic single nucleotide variations (SNVs). However, a disparate copy number variation (CNV) was found in young patients with distinct clinical outcome. Combined with data from TCGA, we found that the overall survival was significantly better in young patients with low-CNV (n = 5) compared to high-CNV (n = 11) burden (P = 0.044). Conclusions Copy number variation burden is a useful single prognostic marker for SCCOT from young, but not elderly, patients. CNV burden thus holds promise to form an important contribution when selecting suitable treatment protocols for young patients with SCCOT.
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| 15. |
- Gu, Xiaolian, et al.
(författare)
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Correlation between Reversal of DNA Methylation and Clinical Symptoms in Psoriatic Epidermis Following Narrow-Band UVB Phototherapy
- 2015
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Ingår i: Journal of Investigative Dermatology. - : Elsevier BV. - 0022-202X .- 1523-1747. ; 135:8, s. 2077-2083
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Tidskriftsartikel (refereegranskat)abstract
- Epigenetic modifications by DNA methylation are associated with a wide range of diseases. Previous studies. in psoriasis have concentrated on epigenetic changes in immune cells or in total skin biopsies that include stromal-associated changes. In order to improve our understanding of the role of DNA methylation in psoriasis, we sought to obtain a comprehensive DNA methylation signature specific for the epidermal component of psoriasis and to analyze methylation changes during therapy. Genome-wide DNA methylation profiling of epidermal cells from 12 patients undergoing narrow-band UVB phototherapy and 12 corresponding healthy controls revealed a distinct DNA methylation pattern in psoriasis compared with controls. A total of 3,665 methylation variable positions (MVPs) were identified with an overall hypomethylation in psoriasis patient samples. DNA methylation pattern was reversed at the end of phototherapy in patients showing excellent clinical improvement. Only 7% of phototherapy-affected MVPs (150 out of 2,108) correlate with nearby gene expression. Enrichment of MVPs in enhancers indicates tissue-specific modulation of the transcriptional regulatory machinery in psoriasis. Our study identified key epigenetic events associated with psoriasis pathogenesis and helps understand the dynamic DNA methylation landscape in the human genome.
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| 16. |
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| 17. |
- Gu, Xiaolian, 1976-, et al.
(författare)
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Early detection of squamous cell carcinoma of the oral tongue using multidimensional plasma protein analysis and interpretable machine learning
- 2023
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Ingår i: Journal of Oral Pathology & Medicine. - : John Wiley & Sons. - 0904-2512 .- 1600-0714. ; 52:7, s. 637-643
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Tidskriftsartikel (refereegranskat)abstract
- Background: Interpretable machine learning (ML) for early detection of cancer has the potential to improve risk assessment and early intervention.Methods: Data from 261 proteins related to inflammation and/or tumor processes in 123 blood samples collected from healthy persons, but of whom a sub-group later developed squamous cell carcinoma of the oral tongue (SCCOT), were analyzed. Samples from people who developed SCCOT within less than 5 years were classified as tumor-to-be and all other samples as tumor-free. The optimal ML algorithm for feature selection was identified and feature importance computed by the SHapley Additive exPlanations (SHAP) method. Five popular ML algorithms (AdaBoost, Artificial neural networks [ANNs], Decision Tree [DT], eXtreme Gradient Boosting [XGBoost], and Support Vector Machine [SVM]) were applied to establish prediction models, and decisions of the optimal models were interpreted by SHAP.Results: Using the 22 selected features, the SVM prediction model showed the best performance (sensitivity = 0.867, specificity = 0.859, balanced accuracy = 0.863, area under the receiver operating characteristic curve [ROC-AUC] = 0.924). SHAP analysis revealed that the 22 features rendered varying person-specific impacts on model decision and the top three contributors to prediction were Interleukin 10 (IL10), TNF Receptor Associated Factor 2 (TRAF2), and Kallikrein Related Peptidase 12 (KLK12).Conclusion: Using multidimensional plasma protein analysis and interpretable ML, we outline a systematic approach for early detection of SCCOT before the appearance of clinical signs.
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| 18. |
- Gu, Xiaolian, et al.
(författare)
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Effect of narrow-band ultraviolet B phototherapy on p63 and microRNA (miR-21 and miR-125b) expression in psoriatic epidermis
- 2011
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Ingår i: Acta Dermato-Venereologica. - : Medical Journals Sweden AB. - 0001-5555 .- 1651-2057. ; 91:4, s. 392-397
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Tidskriftsartikel (refereegranskat)abstract
- Psoriasis is an inflammatory skin disease in which dysregulation of p63, a member of the p53 family that is crucial for skin development and maintenance, has been demonstrated. Involvement of miR-203, miR-21 and miR-125b, small non-coding RNAs implicated in the regulation of p63 or p53, has been suggested in the patho-genesis of psoriasis. To elucidate the roles of p63 and p63-related microRNAs in psoriasis and to increase our understanding of the mechanisms of narrow-band ultraviolet B (NB-UVB) phototherapy, we studied the effects of NB-UVB treatment on the expression of these molecules. Skin biopsies from 12 psoriasis patients were collected before, during and after NB-UVB therapy. Real-time PCR and immunohistochemistry showed that p63 expression was not significantly affected, whereas NB-UVB phototherapy significantly decreased expression of miR-21 (p = 0.003) and increased miR-125b levels (p = 0.003). The results indicate that the unresolved p63 abnormality in treated epidermis may play a role in maintenance of this disease.
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| 19. |
- Gu, Xiaolian, et al.
(författare)
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Epigenetic regulation of OAS2 shows disease-specific DNA methylation profiles at individual CpG sites
- 2016
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Epigenetic modifications are essential regulators of biological processes. Decreased DNA methylation of OAS2 (2'-5'-Oligoadenylate Synthetase 2), encoding an antiviral protein, has been seen in psoriasis. To provide further insight into the epigenetic regulation of OAS2, we performed pyrosequencing to detect OAS2 DNA methylation status at 11 promoter and first exon located CpG sites in psoriasis (n = 12) and two common subtypes of squamous cell carcinoma (SCC) of the head and neck: tongue (n = 12) and tonsillar (n = 11). Compared to corresponding controls, a general hypomethylation was seen in psoriasis. In tongue and tonsillar SCC, hypomethylation was found at only two CpG sites, the same two sites that were least demethylated in psoriasis. Despite differences in the specific residues targeted for methylation/demethylation, OAS2 expression was upregulated in all conditions and correlations between methylation and expression were seen in psoriasis and tongue SCC. Distinctive methylation status at four successively located CpG sites within a genomic area of 63 bp reveals a delicately integrated epigenetic program and indicates that detailed analysis of individual CpGs provides additional information into the mechanisms of epigenetic regulation in specific disease states. Methylation analyses as clinical biomarkers need to be tailored according to disease-specific sites.
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| 20. |
- Gu, Xiaolian, 1976-, et al.
(författare)
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Evidence for etiologic field changes in tongue distant from tumor in patients with squamous cell carcinoma of the oral tongue
- 2023
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Ingår i: Journal of Pathology. - : John Wiley & Sons. - 0022-3417 .- 1096-9896. ; 259:1, s. 93-102
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Tidskriftsartikel (refereegranskat)abstract
- Oral cancer is a paradigm of Slaughter's concept of field cancerization, where tumors are thought to originate within an area of cells containing genetic alterations that predispose to cancer development. The field size is unclear but may represent a large area of tissue, and the origin of mutations is also unclear. Here, we analyzed whole exome and transcriptome features in contralateral tumor-distal tongue (i.e. distant from the tumor, not tumor-adjacent) and corresponding tumor tissues of 15 patients with squamous cell carcinoma of the oral tongue. The number of point mutations ranged from 41 to 237 in tumors and from one to 78 in tumor-distal samples. Tumor-distal samples showed mainly clock-like (associated with aging) or tobacco smoking mutational signatures. Tumors additionally showed mutations that associate with cytidine deaminase AID/APOBEC enzyme activities or a UV-like signature. Importantly, no point mutations were shared between a tumor and the matched tumor-distal sample in any patient. TP53 was the most frequently mutated gene in tumors (67%), whereas a TP53 mutation was detected in only one tumor-distal sample, and this mutation was not shared with the matched tumor. Arm-level copy number variation (CNV) was found in 12 tumors, with loss of chromosome (Chr) 8p or gain of 8q being the most frequent events. Two tumor-distal samples showed a gain of Chr8, which was associated with increased expression of Chr8-located genes in these samples, although gene ontology did not show a role for these genes in oncogenic processes. In situ hybridization revealed a mixed pattern of Chr8 gain and neutral copy number in both tumor cells and adjacent nontumor epithelium in one patient. We conclude that distant field cancerization exists but does not present as tumor-related mutational events. The data are compatible with etiologic field effects, rather than classical monoclonal field cancerization theory. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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| 21. |
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| 22. |
- Gu, Xiaolian, 1976-, et al.
(författare)
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High immune cytolytic activity in tumor-free tongue tissue confers better prognosis in patients with squamous cell carcinoma of the oral tongue
- 2019
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Ingår i: The journal of pathology. Clinical research. - : John Wiley & Sons. - 2056-4538. ; 5:4, s. 240-247
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Tidskriftsartikel (refereegranskat)abstract
- Immune cells and cytolytic activity within the tumor microenvironment are being intensively studied. Through transcriptome profiling, immune cell enumeration using the xCell tool and cytolytic activity quantification according to granzyme A (GZMA) and perforin (PRF1) mRNA levels, we investigated immunoreactivity in tumor and/or tumor‐free tongue tissue samples from 31 patients with squamous cell carcinoma of the oral tongue and 14 healthy individuals (control tongue tissues). We found significantly altered immune cell compositions (p < 0.001) and elevated cytolytic activity (p < 0.001) in tumor compared to tumor‐free samples, and altered infiltration of a subset of immune cells (e.g. CD8+ T cells, p < 0.01) as well as increased cytolytic activity (p < 0.001) in tumor‐free compared to control samples. Controlling for patient age at diagnosis and tumor stage, Cox regression analysis showed that high cytolytic activity in tumor‐free samples associated with improved disease‐free survival (hazard ratio= 4.20, 95% CI = 1.09–16.20, p = 0.037). However, the degree of cytolytic activity in tumor samples did not provide prognostic information. Taken together, our results show the presence of cancer‐related immune responses in clinically tumor‐free tongue in patients with squamous cell carcinoma of the oral tongue. Measuring cytolytic activity in tumor‐free tongue samples contralateral to tumor might thus be an effective approach to predict clinical outcome.
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| 23. |
- Gu, Xiaolian, 1976-, et al.
(författare)
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Little effect on p63 but significant effect on miR-21 and miR-125b by NB-UVB phototherapy on psoriatic lesions
- 2010
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Psoriasis is an inflammatory skin disease in which dysregulation of p63, a member of the p53 family and crucial for skin development and maintenance, has been shown. Though currently incurable, many therapies are available including narrowband ultraviolet B (NB-UVB) phototherapy. To further elucidate the role of p63 in psoriasis and increase our understanding of the mechanisms of phototherapy, we studied the effects of NB-UVB treatment on p63 expression. Expression of p53 was also studied due to its functional role in the response of skin to UV. In addition, we investigated expression of miR-203, miR-125b and miR-21, as these microRNAs are p63 and/or p53 regulators and their involvement in psoriasis pathogenesis has previously been suggested. Skin biopsies from 12 psoriasis patients were collected before, during and at the final session of phototherapy. Real time RT-PCR and immunohistochemistry showed that epidermal p63 mRNA and protein levels were not significantly affected following phototherapy, whereas a significant increase in p53 mRNA expression and protein accumulation was found. NB-UVB treatment also significantly affected expression of miR-21 and miR-125b, whereas individual clinical improvement seemed related to p53 status only. Our results indicate that even though NB-UVB phototherapy causes diverse molecular changes, induction of p53 is pivotal for successful treatment of psoriasis, and unresolved p63 abnormality in the treated epidermis of psoriasis patients further indicate a role for p63 in psoriasis.
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| 24. |
- Gu, Xiaolian, et al.
(författare)
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Oxidation Reduction is a Key Process for Successful Treatment of Psoriasis by Narrow-band UVB Phototherapy
- 2015
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Ingår i: Acta Dermato-Venereologica. - : Medical Journals Sweden AB. - 0001-5555 .- 1651-2057. ; 95:2, s. 140-146
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Tidskriftsartikel (refereegranskat)abstract
- Narrow-band UVB (NB-UVB) phototherapy is commonly used for treatment of psoriasis, though the mechanisms underlying its efficacy have not been completely elucidated. We used gene expression profiling to characterise gene expression in lesional epidermis from psoriasis patients in the middle and late stages of NB-UVB phototherapy. Increased melanogenesis gene expression was the earliest response to phototherapy. At the end of treatment, genes responding to phototherapy and correlated to treatment outcome were involved in oxidation reduction, growth and mitochondria organisation. Particularly, SPATA18, a key regulator of mitochondrial quality, was significantly down-regulated in psoriasis (p < 0.05). Poly(dA:dT) and poly(I:C) stimulation increased SPATA18 level in primary keratinocytes, indicating the importance of mitochondria quality control under innate immune induced oxidative stress. Normalised SPATA18 expression after phototherapy indicates improved mitochondrial quality control and restored cellular redox status. Our data suggest that oxidation reduction is critical for the resolution of psoriatic plaques following NB-UVB phototherapy.
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| 25. |
- Gu, Xiaolian, 1976-
(författare)
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p63 and epithelial homeostasis : studies of p63 under normal, hyper-proliferative and malignant conditions
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: The p63 gene is a member of the p53 transcription factor family and can produce six different proteins using two promoters and differential splicing. Expression of p63 is required for proper formation of epithelial tissues. Studies on the transcriptional control of specific genes involved in cell survival, proliferation, differentiation and adhesion have revealed the contributions of p63 to the continuously renewing stratified epithelium. In this thesis, the aim was to improve our understanding of the roles of p63 in epithelial homeostasis by investigating expression of p63 in normal and benign hyper-proliferative epithelia and exploring the influence of p63 deregulation on cancer progression. Materials and methods: Using quantitative real time RT-PCR and immunohistochemistry, we first examined the expression of different p63 isoforms in patients diagnosed with psoriasis - a benign hyper-proliferative and inflammatory skin disease. Afterwards, we investigated responses of p63 in psoriatic epidermis upon Narrowband-UVB (NB-UVB) phototherapy. At the same time, we studied the potential impact of p63 in carcinogenesis by searching for p63 transcriptional targets in a cell line derived from squamous cell carcinoma of the head and neck (SCCHN) - the sixth most common cancer worldwide with over-expression of the ∆Np63α protein as a common feature. p63 gene silencing and microarray were used to identify p63 regulated genes. Real time RT-PCR, western blot, immunohistochemistry, chromatin immunoprecipitation, transient transfection and reporter assays were performed to confirm specific genes as direct p63 targets. Results: Significant down-regulation of p63 mRNA levels was found in psoriatic lesions compared to patients’ own clinically normal skin. Moreover, a trend of decreased TAp63 mRNA levels was seen in patients’ normal skin compared to age- and sex-matched healthy controls. Following NB-UVB phototherapy, an effective first line therapy for psoriasis, expression of p63 was not significantly affected. However, significant changes in p53, FABP5, miR-21 and miR-125b were found. Surprisingly, location and expression levels of p63 proteins detected by immunohistochemistry were similar under all skin conditions. A direct transcriptional regulation of TRAF4 by p63 was seen in the SCCHN cell line and we further found that the localization of the TRAF4 protein was associated with histological differentiation of SCCHN cells. However, unlike its over-expression in SCCHN, similar TRAF4 mRNA expression levels were seen in psoriatic lesions as compared to healthy controls. Besides TRAF4, a total of 127 genes were identified as potentially p63 regulated in the SCCHN cell line and strikingly, about 20% of these genes are involved in cell adhesion or migration. Conclusions: Dysregulation of p63 isoforms in psoriatic epidermis, especially decreased TAp63 expression, and their resistance to NB-UVB phototherapy implicated a contribution of p63 to the psoriasis phenotype. Transcriptional regulation of genes involved in multiple biological pathways indicated that over-expression of p63 in SCCHN might account for altered cell differentiation, adhesion and migration, thus contributing to SCCHN. In conclusion, our studies have found additional mechanisms through which p63 guarded homeostasis of the established epithelium. Deregulation of p63 might play a role in distinct pathological conditions by participating in diverse cellular pathways under different microenvironments.
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| 26. |
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| 27. |
- Gu, Xiaolian, 1976-, et al.
(författare)
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TRAF4 is potently induced by TAp63 isoforms and localised according to differentiation in SCCHN
- 2007
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Ingår i: Cancer Biology & Therapy. - 1538-4047 .- 1555-8576. ; 6:12, s. 1979-1983
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Tidskriftsartikel (refereegranskat)abstract
- p63, a member of the p53 family, is overexpressed in squamous cell carcinoma of the head and neck (SCCHN) and some other tumors of epithelial origin. As a transcription factor, p63 can bind to p53-type response elements and there is some overlap between p53 family transcriptional targets. Tumor necrosis factor receptor associated factor 4 (TRAF4) is a p53 regulated gene which is overexpressed in many human carcinomas. We investigated the involvement of p63 in regulation of TRAF4 and the expression of the TRAF4 protein in SCCHN. Disrupting endogenous p63 expression resulted in downregulation of TRAF4 mRNA and protein in an SCCHN cell line. Endogenous p63 bound to the TRAF4 promoter in vivo and reporter assays showed that p63, p73 and p53 can all transactivate TRAF4, with TAp63 isoforms being the most potent activators. The level of TRAF4 activation by TAp63 was two-fold higher than by p53, and TRAF4 was ten-fold more responsive to TAp63 than another p63-target, IGFBP3. Nuclear expression of TRAF4 was seen in normal oral epithelium and highly/moderately differentiated SCCHN, whereas cytoplasmic expression of TRAF4 was seen in poorly differentiated SCCHN. These results indicate that TRAF4 is a common target of p53 family members and that localization of TRAF4 is associated with differentiation of SCCHN cells.
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| 28. |
- Gu, Xiaolian, 1976-, et al.
(författare)
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Transfer-RNA-Derived Fragments Are Potential Prognostic Factors in Patients with Squamous Cell Carcinoma of the Head and Neck
- 2020
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Ingår i: Genes. - : MDPI. - 2073-4425. ; 11:11
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Tidskriftsartikel (refereegranskat)abstract
- Transfer-RNA-derived fragments (tRFs) are a class of small non-coding RNAs that are functionally different from their parental transfer RNAs (tRNAs). tRFs can regulate gene expression by several mechanisms, and are involved in a variety of pathological processes. Here, we aimed at understanding the composition and abundance of tRFs in squamous cell carcinoma of the head and neck (SCCHN), and evaluated the potential of tRFs as prognostic markers in this cancer type. We obtained tRF expression data from The Cancer Genome Atlas (TCGA) HNSC cohort (523 patients) using MINTbase v2.0, and correlated to available TCGA clinical data. RNA-binding proteins were predicted according to the calculated Position Weight Matrix (PWM) score from the RNA-Binding Protein DataBase (RBPDB). A total of 10,158 tRFs were retrieved and a high diversity in expression levels was seen. Fifteen tRFs were found to be significantly associated with overall survival (Kaplan-Meier survival analysis, log rank test p-value < 0.01). The top prognostic marker, tRF-20-S998LO9D (p < 0.001), was further measured in tumor and tumor-free samples from 16 patients with squamous cell carcinoma of the oral tongue and 12 healthy controls, and was significantly upregulated in tumor compared to matched tumor-free tongue (p < 0.001). Results suggest that tRFs are useful prognostic markers in SCCHN
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| 29. |
- Gu, Xiaolian, 1976-, et al.
(författare)
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Variation in Plasma Levels of TRAF2 Protein During Development of Squamous Cell Carcinoma of the Oral Tongue
- 2021
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Ingår i: Frontiers in Oncology. - : Frontiers Media S.A.. - 2234-943X. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- As early detection is crucial for improvement of cancer prognosis, we searched for biomarkers in plasma from individuals who later developed squamous cell carcinoma of the oral tongue (SCCOT) as well as in patients with an already established SCCOT. Levels of 261 proteins related to inflammation and/or tumor processes were measured using the proximity extension assay (PEA) in 179 plasma samples (42 collected before diagnosis of SCCOT with 81 matched controls; 28 collected at diagnosis of SCCOT with 28 matched controls). Statistical modeling tools principal component analysis (PCA) and orthogonal partial least square - discriminant analysis (OPLS-DA) were applied to provide insights into separations between groups. PCA models failed to achieve group separation of SCCOT patients from controls based on protein levels in samples taken prior to diagnosis or at the time of diagnosis. For pre-diagnostic samples and their controls, no significant OPLS-DA model was identified. Potentials for separating pre-diagnostic samples collected up to five years before diagnosis (n = 15) from matched controls (n = 28) were seen in four proteins. For diagnostic samples and controls, the OPLS-DA model indicated that 21 proteins were important for group separation. TNF receptor associated factor 2 (TRAF2), decreased in pre-diagnostic plasma (< 5 years) but increased at diagnosis, was the only protein showing altered levels before and at diagnosis of SCCOT (p-value < 0.05). Taken together, changes in plasma protein profiles at diagnosis were evident, but not reliably detectable in pre-diagnostic samples taken before clinical signs of tumor development. Variation in protein levels during cancer development poses a challenge for the identification of biomarkers that could predict SCCOT development.
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| 30. |
- Li, Xingru, 1987-
(författare)
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Wilms' tumor gene 1 in different types of cancer
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The Wilms’ tumor gene 1 (WT1) was first reported as a tumor suppressor gene in Wilms’ tumor. However, later studies have shown the oncogenic properties of WT1 in a variety of tumors. It was recently proposed that WT1 was a chameleon gene, due to its dual functions in tumorigenesis. We aimed to investigate the clinical significance of WT1 as biomarker in acute myeloid leukemia (AML) and clear cell renal cell carcinoma (ccRCC) and to elucidate the function of WT1 as an oncogene in squamous cell carcinoma of head and neck (SCCHN).In AML, it was suggested that WT1 expression was an applicable marker of minimal residual disease (MRD). In adult patients with AML, we found a good correlation between WT1 expression levels normalized to two control genes, β-actin and ABL. Outcome could be predicted by a reduction in WT1 expression in bone marrow (≥ 1-log) detected less than 1 month after diagnosis, when β-actin was used as control. Also, irrespective of the control gene used, outcome could be predicted by a reduction in WT1 expression in peripheral blood (≥ 2-log) detected between 1 and 6 months after treatment initiation.Previous studies in RCC demonstrated that WT1 acted as a tumor suppressor. Thus, we tested whether single nucleotide polymorphisms (SNPs) or mutations in WT1 might be associated with WT1 expression and clinical outcome in patients with ccRCC. We performed sequencing analysis on 10 exons of the WT1 gene in a total of 182 patient samples, and we identified six different SNPs in the WT1 gene. We found that at least one or two copies of the minor allele were present in 61% of ccRCC tumor samples. However, no correlation was observed between WT1 SNP genotypes and RNA expression levels. Moreover, none of the previously reported WT1 mutations were found in ccRCC. Nevertheless, we found that a favorable outcome was associated the homozygous minor allele for WT1 SNP. We then further investigated whether WT1 methylation was related to WT1 expression and its clinical significance. Methylation array and pyrosequencing analyses showed that the WT1 promoter region CpG site, cg22975913, was the most frequently hypermethylated CpG site. We found a trend that showed nearly significant correlation between WT1 mRNA levels and hypermethylation in the 5’-untranslated region. Hypermethylation in the WT1 CpG site, cg22975913, was found to be associated with patient age and a worse prognosis.One previous study reported that WT1 was overexpressed in SCCHN. That finding suggested that WT1 might play a role in oncogenesis. We found that both WT1 and p63 could promote cell proliferation. A positive correlation between WT1 and p63 expression was observed, and we identified p63 as a WT1 target gene. Furthermore, several known WT1 and p63 target genes were affected by knocking down WT1. Also, co-immunoprecipitation analyses demonstrated a protein interaction between WT1 and p53.In summary, WT1 gene expression can provide useful information for MRD detection during treatment of patients with AML. In RCC, our results suggested that the prognostic impact of WT1 SNPs was limited to the subgroup of patients that were homozygous for the minor allele, and that WT1 promoter hypermethylation could be used as a prognostic biomarker. In SCCHN, WT1 and p63 acted as oncogenes by affecting multiple genes involved in cancer cell growth.
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| 31. |
- Li, Xingru, et al.
(författare)
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Wilms' tumor gene 1 regulates p63 and promotes cell proliferation in squamous cell carcinoma of the head and neck
- 2015
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- Background: Wilms' tumor gene 1 (WT1) can act as a suppressor or activator of tumourigenesis in different types of human malignancies. The role of WT1 in squamous cell carcinoma of the head and neck (SCCHN) is not clear. Overexpression of WT1 has been reported in SCCHN, suggesting a possible oncogenic role for WT1. In the present study we aimed at investigating the function of WT1 and its previously identified protein partners p63 and p53 in the SCCHN cell line FaDu. Methods: Silencing RNA (siRNA) technology was applied to knockdown of WT1, p63 and p53 in FaDu cells. Cell proliferation was detected using MTT assay. Chromatin immunoprecipitation (ChIP)/PCR analysis was performed to confirm the effect of WT1 on the p63 promoter. Protein co-immunoprecipitation (co-IP) was used to find protein interaction between WT1 and p53/p63. Microarray analysis was used to identify changes of gene expression in response to knockdown of either WT1 or p63. WT1 RNA level was detected using real-time quantitative PCR (RT-qPCR) in patients with SCCHN. Results: We found that WT1 and p63 promoted cell proliferation, while mutant p53 (R248L) possessed the ability to suppress cell proliferation. We reported a novel positive correlation between WT1 and p63 expression. Subsequently, p63 was identified as a WT1 target gene. Furthermore, expression of 18 genes involved in cell proliferation, cell cycle regulation and DNA replication was significantly altered by downregulation of WT1 and p63 expression. Several known WT1 and p63 target genes were affected by WT1 knockdown. Protein interaction was demonstrated between WT1 and p53 but not between WT1 and p63. Additionally, high WT1 mRNA levels were detected in SCCHN patient samples. Conclusions: Our findings suggest that WT1 and p63 act as oncogenes in SCCHN, affecting multiple genes involved in cancer cell growth.
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| 32. |
- Nekulova, Marta, et al.
(författare)
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Delta Np63 alpha expression induces loss of cell adhesion in triple-negative breast cancer cells
- 2016
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Ingår i: BMC Cancer. - : BioMed Central. - 1471-2407. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- Background: p63, a member of the p53 protein family, plays key roles in epithelial development and carcinogenesis. In breast cancer, p63 expression has been found predominantly in basal-A (epithelial-type) triple-negative breast carcinomas (TNBC). To investigate the functional role of p63 in basal-A TNBC, we created MDA-MB-468 cell lines with inducible expression of the two major N-terminal p63 isoforms, TAp63 alpha and Delta Np63 alpha. Results: TAp63 alpha did not have significant effect on gene expression profile and cell phenotype, whilst the main effect of Delta Np63 alpha was reduction of cell adhesion. Gene expression profiling revealed genes involved in cell adhesion and migration whose expression relies on overexpression of Delta Np63 alpha. Reduced cell adhesion also led to decreased cell proliferation in vitro and in vivo. Similar data were obtained in another basal-A cell line, BT-20, but not in BT-549 basal-B (mesenchymal-like) TNBC cells. Conclusions: In basal-A TNBC cells, Delta Np63 alpha has much stronger effects on gene expression than TAp63 alpha. Although p63 is mentioned mostly in connection with breast cell differentiation and stem cell regulation, we showed that a major effect of p63 is regulation of cell adhesion, a process important in metastasis and invasion of tumour cells. That this effect is not seen in mesenchymal-type TNBC cells suggests lineage-dependent functions, mirroring the expression of Delta Np63 alpha in primary human breast cancers.
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| 33. |
- Salehi, Amir M., et al.
(författare)
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Patients with oral tongue squamous cell carcinoma and co‑existing diabetes exhibit lower recurrence rates and improved survival : implications for treatment
- 2024
-
Ingår i: Oncology Letters. - : Spandidos Publications. - 1792-1074 .- 1792-1082. ; 27:4
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Tidskriftsartikel (refereegranskat)abstract
- Locoregional recurrences and distant metastases are major problems for patients with squamous cell carcinoma of the head and neck (SCCHN). Because SCCHN is a heterogeneous group of tumours with varying characteristics, the present study concentrated on the subgroup of squamous cell carcinoma of the oral tongue (SCCOT) to investigate the use of machine learning approaches to predict the risk of recurrence from routine clinical data available at diagnosis. The approach also identified the most important parameters that identify and classify recurrence risk. A total of 66 patients with SCCOT were included. Clinical data available at diagnosis were analysed using statistical analysis and machine learning approaches. Tumour recurrence was associated with T stage (P=0.001), radiological neck metastasis (P=0.010) and diabetes (P=0.003). A machine learning model based on the random forest algorithm and with attendant explainability was used. Whilst patients with diabetes were overrepresented in the SCCOT cohort, diabetics had lower recur‑ rence rates (P=0.015 after adjusting for age and other clinical features) and an improved 2‑year survival (P=0.025) compared with non‑diabetics. Clinical, radiological and histological data available at diagnosis were used to establish a prognostic model for patients with SCCOT. Using machine learning to predict recurrence produced a classification model with 71.2% accuracy. Notably, one of the findings of the feature importance rankings of the model was that diabetics exhibited less recur‑ rence and improved survival compared with non‑diabetics, even after accounting for the independent prognostic variables of tumour size and patient age at diagnosis. These data imply that the therapeutic manipulation of glucose levels used to treatdiabetes may be useful for patients with SCCOT regardless of their diabetic status. Further studies are warranted to investigatethe impact of diabetes in other SCCHN subtypes.
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| 34. |
- Salehi, Amir M., et al.
(författare)
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Reiterative modeling of combined transcriptomic and proteomic features refines and improves the prediction of early recurrence in squamous cell carcinoma of head and neck
- 2022
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Ingår i: Computers in Biology and Medicine. - : Elsevier. - 0010-4825 .- 1879-0534. ; 149
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Tidskriftsartikel (refereegranskat)abstract
- Background: Patients with squamous cell carcinoma of the head and neck (SCCHN) have a high-risk of recurrence. We aimed to develop machine learning methods to identify transcriptomic and proteomic features that provide accurate classification models for predicting risk of early recurrence in SCCHN patients.Methods: Clinical, genomic, transcriptomic and proteomic features distinguishing recurrence risk were examined in SCCHN patients from The Cancer Genome Atlas (TCGA). Recurrence within one year after treatment was classified as high-risk and no recurrence as low-risk.Results: No significant differences in individual clinicopathological characteristics, mutation profiles or mRNA expression patterns were seen between the groups using conventional statistical analysis. Using the machine learning algorithm, extreme gradient boosting (XGBoost), ten proteins (RAD50, 4E-BP1, MYH11, MAP2K1, BECN1, NF2, RAB25, ERRFI1, KDR, SERPINE1) and five mRNAs (PLAUR, DKK1, AXIN2, ANG and VEGFA) made the greatest contribution to classification. These features were used to build improved models in XGBoost, achieving the best discrimination performance when combining transcriptomic and proteomic data, providing an accuracy of 0.939 and an Area Under the ROC Curve (AUC) of 0.951.Conclusions: This study highlights machine learning to identify transcriptomic and proteomic factors that play important roles in predicting risk of recurrence in patients with SCCHN and to develop such models by iterative cycles to enhance their accuracy, thereby aiding the introduction of personalized treatment regimens.
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| 35. |
- Salomao, Norman, et al.
(författare)
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Reduced murine double minute 2 and 4 protein, but not messenger RNA, expression is associated with more severe disease in myelodysplastic syndromes and acute myeloblastic leukaemia
- 2023
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Ingår i: British Journal of Haematology. - : John Wiley & Sons. - 0007-1048 .- 1365-2141. ; 201:2, s. 234-248
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Tidskriftsartikel (refereegranskat)abstract
- The human homologues of murine double minute 2 (MDM2) and 4 (MDM4) negatively regulate p53 tumour suppressor activity and are reported to be frequently overexpressed in human malignancies, prompting clinical trials with drugs that prevent interactions between MDM2/MDM4 and p53. Bone marrow samples from 111 patients with acute myeloblastic leukaemia, myelodysplastic syndrome or chronic myelomonocytic leukaemia were examined for protein (fluorescence-activated cell sorting) and messenger RNA (mRNA) expression (quantitative polymerase chain reaction) of MDM2, MDM4 and tumour protein p53 (TP53). Low protein expression of MDM2 and MDM4 was observed in immature cells from patients with excess of marrow blasts (>5%) compared with CD34+/CD45low cells from healthy donors and patients without excess of marrow blasts (<5%). The mRNA levels were indistinguishable in all samples examined regardless of disease status or blast levels. Low MDM2 and MDM4 protein expression were correlated with poor survival. These data show a poor correlation between mRNA and protein expression levels, suggesting that quantitative flow cytometry analysis of protein expression levels should be used to predict and validate the efficacy of MDM2 and MDM4 inhibitors. These findings show that advanced disease is associated with reduced MDM2 and MDM4 protein expression and indicate that the utility of MDM2 and MDM4 inhibitors may have to be reconsidered in the treatment of advanced myeloid malignancies.
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| 36. |
- Sgaramella, Nicola, et al.
(författare)
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Ethnicity based variation in expression of E-cadherin in patients with squamous cell carcinoma of the oral tongue
- 2018
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Ingår i: Oncology Letters. - : Spandidos Publications. - 1792-1074 .- 1792-1082. ; 16:5, s. 6603-6607
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Tidskriftsartikel (refereegranskat)abstract
- The oral tongue is the most common site for tumours within the oral cavity. Despite intense research, there has been no improvement in the survival rate for patients with oral tongue squamous cell carcinoma (OTSCC) during the last decades. Differences between oral cancer patients based on ethno-geographical distribution have been reported. The present study used immunohistochemistry to evaluate commonly used markers of cancer cell phenotypes, E-cadherin, -catenin and cytokeratins 5 and 19, in 120 patients with OTSCC. To evaluate the impact of ethnicity, patients from Sweden and Italy were included. A higher proportion of Swedish patients exhibited high expression of E-cadherin in their tumours (P=0.039), and high levels of E-cadherin in Swedish OTSCC patients that had succumbed to their disease were associated with poor prognosis. These data demonstrated differences in the pathological characteristics of OTSCC between two different European populations. The findings emphasise the need to take ethnicity/geographical location of patients into account when comparing results from different studies of OTSCC.
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| 37. |
- Sgaramella, Nicola, et al.
(författare)
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Searching for new targets and treatments in the battle against squamous cell carcinoma of the head and neck, with specific focus on tumours of the tongue
- 2018
-
Ingår i: Current Topics in Medicinal Chemistry. - : Bentham Science Publishers. - 1568-0266 .- 1873-4294. ; 18:3, s. 214-218
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Forskningsöversikt (refereegranskat)abstract
- Squamous cell carcinoma of the head and neck, SCCHN, is a heterogeneous group of tumours not only concerning the site of origin but also regarding aetiology. The 5-year survival for the whole group of SCCHN tumours has not significantly improved over the last 20-25 years. Apart from tumour spread to lymph nodes, N status, gains and losses of specific chromosomes are the only factors shown to be independent prognostic markers for these tumours. Worldwide, an increasing number of people ≤ 40 years are seen being affected by tongue SCC, the most common tumour within the SCCHN group. Even without any clinical signs of metastasis, up to 30% of all tongue SCC have histologically detectable spread to lymph nodes. In this mini review, field cancerization, tumour microenvironment, the so called EMT (epithelial mesenchymal transition) process and the role of viruses in development of SCCHN are discussed as well as potential new therapeutic targets. For the group of tongue SCC, with the increasing incidence seen in young patients and particularly women, new data with impact on prognosis and treatment are urgently needed. But as long as data from the analyses of several sub sites are presented as valid for the whole group of tumours, this vital point is missed.
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| 38. |
- Strindlund, Klas, et al.
(författare)
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Patients with high c-MYC-expressing squamous cell carcinomas of the tongue show better survival than those with low- and medium-expressing tumours
- 2017
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Ingår i: Journal of Oral Pathology & Medicine. - : John Wiley & Sons. - 0904-2512 .- 1600-0714. ; 46:10, s. 967-971
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Tidskriftsartikel (refereegranskat)abstract
- Backgroundc-MYC is a potent oncoprotein with roles in a wide range of cellular processes such as differentiation, apoptosis and growth control. Deregulation of the MYC gene is commonly seen in human tumours resulting in overexpression of the protein. Here we studied expression of c-MYC in correlation to clinical outcome in patients with primary squamous cell carcinoma of the mobile tongue. MethodsImmunohistochemistry was used to identify c-MYC in a group of 104 tongue squamous cell carcinomas with an antibody directed against the N-terminal part of the protein. Staining was evaluated by multiplying the percentage of c-MYC-expressing cells with staining intensity, giving a quick score for each tumour. ResultsAll 104 tumours expressed c-MYC at varying levels. Quantitation according to per cent of positive cells and staining intensity revealed that most (15/21; 71%) high-expressing tumours were seen in males. Within the group of high c-MYC-expressing tumours, the majority were alive 2 and 5 years after treatment. ConclusionsThe present findings show that expression of c-MYC has prognostic value in squamous cell carcinoma of the tongue, and could be useful in choice of therapy.
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| 39. |
- Troiano, Giuseppe, et al.
(författare)
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Expression of the long non-coding RNA HOTAIR as a prognostic factor in squamous cell carcinoma of the head and neck : a systematic review and meta-analysis
- 2017
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Ingår i: Oncotarget. - : Impact Journals LLC. - 1949-2553. ; 8:42, s. 73029-73036
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Forskningsöversikt (refereegranskat)abstract
- Introduction: Long noncoding RNAs (lncRNAs) are often dysregulated in cancer tissue and seem to play an important role in neoplastic processes. Recent studies have shown that the HOX transcript antisense intergenic RNA (HOTAIR) may play a role as a marker of prognosis in squamous cell carcinoma of the head and neck (SCCHN). The aim of this study was to perform a meta-analysis of studies focused on the prognostic role of HOTAIR in SCCHN.Results: At the end of the selection process, four studies were considered eligible for inclusion in the meta-analysis, comprising a total of 271 patients. Meta-analysis revealed that high expression of HOTAIR was associated with poor overall survival (HR, 1.90; 95% CI: [1.42, 2.53]; p < 0,0001), advanced tumor stage (OR, 3.44; 95% CI: [1.84, 6.43]; p < 0,001) and lymph-node metastasis (OR, 3.31; 95% CI: [1.24, 8.79]; p = 0,02).Materials and Methods: The literature search was performed in the following databases: PUBMED, SCOPUS, EMBASE and Web of Science, in order to find studies that met the inclusion criteria.Conclusions: Findings from this systematic review and meta-analysis revealed that HOTAIR represents a potential biomarker of prognosis in patients with squamous cell carcinoma of the head and neck.
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| 40. |
- Wang, Bo, et al.
(författare)
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An organoid library of salivary gland tumors reveals subtype-specific characteristics and biomarkers
- 2022
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Ingår i: Journal of Experimental & Clinical Cancer Research. - : BioMed Central (BMC). - 1756-9966. ; 41:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Salivary gland tumors (SGTs) include a large group of rare neoplasms in the head and neck region, and the heterogeneous and overlapping features among the subtypes frequently make diagnostic difficulties. There is an urgent need to understand the cellular mechanisms underlying the heterogeneity and overlap among the subtypes, and explore the subtype-specific diagnostic biomarkers.Methods: The tumor tissue and the adjacent normal tissue from the 6 most common types of SGTs were processed for organoid culture which only maintained tumor epithelial cells. Organoids were histologically evaluated based on phenotype markers, followed by transcriptional profiling using RNA-sequencing. The transcriptomic similarities and differences among the subtypes were analyzed by subtype consensus clustering and hierarchical clustering. Furthermore, by comparative transcriptional analysis for these 6 types of SGTs and the matched organoids, the potential diagnostic biomarkers from tumor epithelium were identified, in which two selected biomarkers were evaluated by qPCR and confirmed by immunohistochemistry staining using a tissue microarray.Results: We generated a biobank of patient-derived organoids (PDOs) with 6 subtypes of SGTs, including 21 benign and 24 malignant SGTs. The PDOs recapitulated the morphological and transcriptional characteristics of the parental tumors. The overlap in the cell types and the heterogenous growth patterns were observed in the different subtypes of organoids. Comparing the bulk tissues, the cluster analysis of the PDOs remarkably revealed the epithelial characteristics, and visualized the intrinsic relationship among these subtypes. Finally, the exclusive biomarkers for the 6 most common types of SGTs were uncovered by comparative analysis, and PTP4A1 was demonstrated as a useful diagnostic biomarker for mucoepidermoid carcinoma.Conclusions: We established the first organoid biobank with multiple subtypes of SGTs. PDOs of SGTs recapitulate the morphological and transcriptional characteristics of the original tumors, which uncovers subtype-specific biomarkers and reveals the molecular distance among the subtype of SGTs.
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| 41. |
- Wilms, Torben, et al.
(författare)
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High Levels of Low-Density Lipoproteins Correlate with Improved Survival in Patients with Squamous Cell Carcinoma of the Head and Neck
- 2021
-
Ingår i: Biomedicines. - : MDPI. - 2227-9059. ; 9:5
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Tidskriftsartikel (refereegranskat)abstract
- Circulating lipoproteins as risk factors or prognostic indicators for various cancers have been investigated previously; however, no clear consensus has been reached. In this study, we aimed at evaluating the impact of serum lipoproteins on the prognosis of patients with squamous cell carcinoma of the head and neck (SCCHN). Levels of total cholesterol, low-density lipoproteins (LDL), high-density lipoproteins (HDL), triglycerides and lipoprotein(a) were measured in serum samples from 106 patients and 28 healthy controls. We found that HDL was the only lipoprotein exhibiting a significant difference in concentration between healthy controls and patients (p = 0.012). Kaplan–Meier survival curves indicated that patients with high levels of total cholesterol or LDL had better overall survival than patients with normal levels (p = 0.028 and p = 0.007, respectively). Looking at patients without lipid medication (n = 89) and adjusting for the effects of TNM stage and weight change, multivariate Cox regression models indicated that LDL was an independent prognostic factor for both overall (p = 0.005) and disease-free survival (p = 0.013). In summary, our study revealed that high LDL level is beneficial for survival outcome in patients with SCCHN. Use of cholesterol-lowering medicines for prevention or management of SCCHN needs to be evaluated carefully.
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| 42. |
- Wilms, Torben, et al.
(författare)
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PD-L1 in squamous cell carcinoma of the oral tongue shows gender-specific association with prognosis
- 2020
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Ingår i: Oral Diseases. - : John Wiley & Sons. - 1354-523X .- 1601-0825. ; 26:7, s. 1414-1423
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To use alternative quantitation approaches to clarify the clinical implication of programmed cell death ligand 1 (PD‐L1) in squamous cell carcinoma of the oral tongue (SCCOT).Materials and Methods: Ventana SP263 immunohistochemistry assay and a multiplicative QuickScore method were applied to quantify PD‐L1 in tumor and surrounding immune cells from 101 patients with SCCOT. Tumor‐infiltrating immune cells were estimated from bulk tissue transcriptional profiles of 25 patients. Circulating PD‐L1 levels were measured in serum from 30 patients using an electrochemiluminescence assay platform.Results: We found higher tumor cell PD‐L1 levels in females than males (p = .019). For patients with low PD‐L1 in tumor cells, better survival was seen in males than females (overall survival p = .021, disease‐free survival p = .020). Tumor‐infiltrating natural killer T cells, immature dendritic cells, and M1 macrophages were positively associated with tumor cell PD‐L1 (p < .05).Conclusions: Our data confirmed the significance of gender on tumor cell PD‐L1 expression and demonstrated combined effects of gender and PD‐L1 levels on clinical outcome in patients with SCCOT. The data also indicated the involvement of specific immune cell types in PD‐L1‐regulated immune evasion.
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| 43. |
- Wilms, Torben, 1973-
(författare)
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Squamous cell carcinoma of the head and neck, focusing on Epstein-Barr-virus, programmed cell death ligand 1 and serum lipoproteins
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Squamous cell carcinoma of the head and neck (SCCHN)comprises a large group of tumours including the oral cavity and nasopharyngealarea, and typically affects older males in association with alcohol/tobacco usage.Within the oral cavity, the mobile tongue is the most common site for tumourdevelopment. The incidence of squamous cell carcinoma of the oral tongue(SCCOT) is increasing in younger people, which has been suggested to associatewith other than the traditional risk factors for this disease. Two common humanoncogenic viruses, human papillomavirus (HPV) and Epstein-Barr virus (EBV)are connected to certain types of SCCHN, in oropharynx and nasopharynxrespectively. The receptor programmed cell death 1 (PD)-1 and its ligandprogrammed cell death ligand 1 (PD-L1) are particularly relevant in immunecheckpoint control, and elevated levels have been seen in various cancer types. Alink between hyperlipidemia and cancer risk has previously been suggested. Theaim of this thesis was to investigate risk factors and prognostic features forSCCHN, by focusing on EBV, PD-L1 and serum lipoproteins.Materials and methods: Ninety-eight cases of SCCOT and 15 cases of tonsillarsquamous cell carcinoma were examined for the presence of EBV-encodedribonucleic acids (EBERs), EBV deoxyribonucleic acid (DNA) and the proteinEBV-encoded nuclear antigen-1 (EBNA-1), using in situ hybridisation,polymerase chain reaction (PCR) and immunohistochemistry respectively. Onehundred and one cases of SCCOT were examined for expression of PD-L1 intumour and surrounding immune cells using Ventana SP263immunohistochemistry assay and a QuickScore (QS) method. An estimation oftumour-infiltrating immune cells was also performed in 25 of the patients.Circulating levels of PD-L1 were measured using an electrochemiluminescenceassay platform in serum from 30 patients. Finally, serum samples from 106patients and 28 healthy controls were investigated for levels of total cholesterol,low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides andlipoprotein(a).Results: In the first study, using an in situ hybridisation kit no EBER transcriptswere detected. No EBV DNA was identified with PCR analysis, andimmunohistochemistry for EBNA-1 was also negative. In the second study, highertumour cell PD-L1 levels were found in females than males (p = 0.019). Forpatients with low PD-L1 in tumour cells, better survival was shown in males thanfemales (overall survival p = 0.021, disease-free survival p = 0.020). Tumourinfiltrating natural killer (NK) T cells, immature dendritic cells (DCs) and M1macrophages correlated positively with tumour cell PD-L1 (p < 0.05). In the laststudy, the only lipoprotein showing significant difference in concentration iiibetween healthy controls and patients was HDL (p = 0.012). Kaplan-Meiersurvival curves showed that patients with high levels of total cholesterol or LDLhad better survival than patients with normal levels (p = 0.028 and p = 0.007respectively). Adjusting for the effects of age at diagnosis, TNM stage and weightchange, multivariate Cox regression models showed LDL to be an independentprognostic factor for both overall (p = 0.010) and disease-free survival (p =0.018).Conclusion: We excluded EBV as a potential player in SCCOT in both old andyoung patients and highlight the importance of appropriate controls for EBVencoded RNA in-situ hybridization (EBER-ISH) when investigating EBV inhuman diseases. Regarding PD-L1, our data supported the significance of genderon tumour cell PD-L1 expression and demonstrated combined effects of genderand PD-L1 levels on clinical outcome in patients with SCCOT. Data also indicatedthe involvement of specific immune cell types in PD-L1-regulated immuneevasion. Looking at serum lipoproteins, we found high LDL levels to be beneficialfor survival outcome in patients with SCCHN. Furthermore, the use of cholesterollowering medicine for prevention or management of SCCHN needs to be carefullyevaluated.
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