| 1. |
- Cui, Weiyingqi, et al.
(författare)
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High expression of cytoplasmic FOXO3 protein associated with poor prognosis of rectal cancer patients : A study from Swedish clinical trial of preoperative radiotherapy to big database analysis
- 2023
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Ingår i: Heliyon. - : Elsevier. - 2405-8440. ; 9:5
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Accumulating evidence has implicated a pivotal role for FOXO3, FOXM1 and SIRT6 in cancer progression. The majority of researches focused on the functions of these proteins in drug resistance, but their relationships with radiotherapy (RT) response remain unclear. In this study, we examined protein expression of FOXO3, FOXM1 and SIRT6 and their clinical significance in a Swedish rectal cancer trial of preoperative RT.METHODS: Expression of FOXO3, FOXM1 and SIRT6 protein was examined by immunohistochemistry in patient samples. Genetic analysis of FOXO3, FOXM1 and SIRT6 were performed by cBioportal and MEXPRESS database. Gene-gene network analysis was conducted using GeneMANIA. Functional enrichment analysis was performed based on LinkedOmics and Metascape online software.RESULTS: FOXO3 and FOXM1were mainly expressed in the cytoplasm in both normal and tumour tissues, and SIRT6 in both the cytoplasm and nucleus in normal and tumour tissues. FOXO3 and FOXM1 expression increased from normal mucosa to primary cancer (P < 0.001), while SIRT6 expression decreased from normal mucosa to primary cancer (P < 0.001). High FOXO3 expression correlated with late TNM stage (P = 0.040), distant metastasis (P = 0.032) and independently with disease free survival (DFS) in the RT patients (HR = 7.948; P = 0.049; 95% CI = 1.002-63.032) but not in non-RT patients (P > 0.05). Genetic analysis indicated that DNA methylation status contributed to FOXO3 overexpression. Functional enrichment analysis demonstrated that FOXO3 was closely related to metabolism-related signalling pathway which in turn associated with cancer radioresistance. Moreover, there were strong gene-gene interactions between FOXO3 and metabolism-related signalling.CONCLUSIONS: Our findings suggest that FOXO3 may be a prognostic factor in rectal cancer patients with RT.
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| 2. |
- Cui, Weiyingqi
(författare)
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How tumour cells hijack apical extrusion and how they can be targeted
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Tissue development and cell behavior are influenced not only by chemical signals but also by physical ones. The responses of cells to mechanical forces can range from the immediate adjustment of cell morphology and motility to long-term genome reorganisation and cell fate changes. Mechanotransduction plays a vital role in development and tissue homeostasis, influencing cell proliferation, differentiation, and migration. Disruptions to these forces or inadequate cellular responses may result in developmental anomalies and diseases, including atherosclerosis and cancer. Cancer cells exhibit perturbed force transmission compared to normal tissue due to alterations in the force-sensing network and the downregulation of membrane molecules and cytoskeleton components. These alterations enable cancer cells to overcome mechanical constraints, proliferate, and expand spontaneously. Angiomotin-like 2 (AmotL2) has been found to play crucial roles in connecting and regulating force transmission, maintaining cell geometry, and cell polarity. The shorter isoform, p60AmotL2, has been associated with poor progression in cancer patients. This thesis builds on earlier research to gain a more thorough understanding of the functional processes and potential therapeutics related to the p60 isoform of AmotL2. We initially discovered that p60AmotL2 acts as a molecular clutch, disengaging the Ecadherin/ p100AmotL2/actin-LINC complex and thereby affecting mechanotransduction from neighbouring cells. This disrupts the structural integrity of the nucleus and increases the cells' invasive capacity. Following these findings, we investigated the potential role of p60AmotL2 in normal epithelial physiological processes. The results revealed a correlation between p60AmotL2 and cell extrusion, a key process in epithelial homeostasis. The findings indicate that p60AmotL2 expression triggers neighbouring cells to initiate live-cell apical extrusion. Since cell extrusion is a mechanism by which the epithelium removes altered cells and prevents tumour growth, these findings underscore the tumourigenic characteristics of p60AmotL2. Given the tumour-promoting properties of p60AmotL2, as demonstrated in earlier studies, our research aimed to develop a pharmacological screening technique to discover promising compounds that target cells expressing p60AmotL2. The findings revealed that BET inhibitors (BETi) are more effective on p60AmotL2-expressing cells in three-dimensional cultures. The data also suggest that p60AmotL2 may be a potential therapeutic target to prevent tumour invasion.
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| 3. |
- Liu, Na, et al.
(författare)
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Nuclear expression of lysyl oxidase enzyme is an independent prognostic factor in rectal cancer patients.
- 2017
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Ingår i: Oncotarget. - : Impact journals. - 1949-2553. ; 8:36, s. 60015-60024
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Tidskriftsartikel (refereegranskat)abstract
- Emerging evidence has implicated a pivotal role for lysyl oxidase (LOX) in cancer progression and metastasis. Whilst the majority of work has focused on the extracellular matrix cross-linking role of LOX, the exact function of intracellular LOX localisation remains unclear. In this study, we analysed the LOX expression patterns in the nuclei of rectal cancer patient samples and determined the clinical significance of this expression. Nuclear LOX expression was significantly increased in patient lymph node metastases compared to their primary tumours. High nuclear LOX expression in tumours was correlated with a high rate of distant metastasis and increased recurrence. Multivariable analysis showed that high nuclear LOX expression was also correlated with poor overall survival and disease free survival. Furthermore, we are the first to identify LOX enzyme isoforms (50 kDa and 32 kDa) within the nucleus of colon cancer cell lines by confocal microscopy and Western blot. Our results show a powerful link between nuclear LOX expression in tumours and patient survival, and offer a promising prognostic biomarker for rectal cancer patients.
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| 4. |
- Liu, Na, et al.
(författare)
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The Critical Role of Dysregulated RhoB Signaling Pathway in Radioresistance of Colorectal Cancer
- 2019
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Ingår i: International Journal of Radiation Oncology, Biology, Physics. - : Elsevier. - 0360-3016 .- 1879-355X. ; 104:5, s. 1153-1164
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Tidskriftsartikel (refereegranskat)abstract
- PurposeTo explore whether the Rho protein is involved in the radioresistance of colorectal cancer and investigate the underlying mechanisms.Methods and MaterialsRho GTPase expression was measured after radiation treatment in colon cancer cells. RhoB knockout cell lines were established using the CRISPR/Cas9 system. In vitro assays and zebrafish embryos were used for analyzing radiosensitivity and invasive ability. Mass cytometry was used to detect RhoB downstream signaling factors. RhoB and Forkhead box M1 (FOXM1) expression were detected by immunohistochemistry in rectal cancer patients who participated in a radiation therapy trial.ResultsRhoB expression was related to radiation resistance. Complete depletion of the RhoB protein increased radiosensitivity and impaired radiation-enhanced metastatic potential in vitro and in zebrafish models. Probing signaling using mass cytometry–based single-cell analysis showed that the Akt phosphorylation level was inhibited by RhoB depletion after radiation. FOXM1 was downregulated in RhoB knockout cells, and the inhibition of FOXM1 led to lower survival rates and attenuated migration and invasion abilities of the cells after radiation. In the patients who underwent radiation therapy, RhoB overexpression was related to high FOXM1, late Tumor, Node, Metastasis stage, high distant recurrence, and poor survival independent of other clinical factors.ConclusionsRhoB plays a critical role in radioresistance of colorectal cancer through Akt and FOXM1 pathways.
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| 5. |
- Mi, Yushuai, et al.
(författare)
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miR-181a-5p promotes the progression of gastric cancer via RASSF6-mediated MAPK signalling activation
- 2017
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Ingår i: Cancer Letters. - : ELSEVIER IRELAND LTD. - 0304-3835 .- 1872-7980. ; 389, s. 11-22
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Tidskriftsartikel (refereegranskat)abstract
- We previously discovered that Ras association domain family member 6 (RASSF6) was downregulated and predicted poor prognosis in GC patients. However, the mechanisms of the down regulation of RASSF6 in GC remained unclear. Increasing evidence indicates that dysregulation of microRNAs promotes the progression of cancer through the repression of tumour suppressors. Here, we identified miR-181a-5p as a novel regulator of RASSF6 in GC. Functionally, ectopic expression or silencing of miR-181a-5p, respectively, promoted or inhibited GC cell proliferation, colony formation and cell cycle transition, as well as enhanced or prevented the invasion, metastasis of GC cells and epithelial to mesenchymal transition of GC cells in vitro and in vivo. Molecularly, miR-181a-5p functioned as an onco-miRNA by activating the RASSF6-regulated MAKP pathway. Overexpression or silencing of RASSF6 could partially reverse the effects of the overexpression or repression of miR-181a-5p on GC progress caused by activation of the MAKP pathway in vitro and in vivo. Clinically, high miR-181a-5p expression predicted poor survival in GC patients, especially combined with low RASSF6 expression. Collectively, we identified miR-181a-5p as an onco-miRNA, which acts by directly repressing RASSF6 in GC. (C) 2017 The Authors. Published by Elsevier Ireland Ltd.
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| 6. |
- Zhao, Senlin, et al.
(författare)
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miR-4775 promotes colorectal cancer invasion and metastasis via the Smad7/TGF beta-mediated epithelial to mesenchymal transition
- 2017
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Ingår i: Molecular Cancer. - : BIOMED CENTRAL LTD. - 1476-4598. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- Background: Despite advancements in the diagnosis and treatment of colorectal cancer (CRC), many patients die because of tumor metastasis or recurrence. Therefore, identifying new prognostic markers and elucidating the mechanisms of CRC metastasis and recurrence will help to improve the prognosis of the disease. As dysregulation of microRNAs is strongly related to cancer progression, the aim of this study was to identify the role of miR-4775 in the prognosis of CRC patients and the underling mechanisms involved in CRC progression. Methods: qPCR and in situ hybridization were used to evaluate the expression of miR-4775 in 544 pairs of paraffin-embedded normal and CRC tissues. Kaplan-Meier analysis with the log-rank test was used for survival analyses. Immunohistochemical staining was applied to investigate the expression of miR-4775-regulated Smad7/TGF beta pathway-associated markers. In vitro and in vivo invasion and metastasis assays were used to explore the function of miR-4775 in the progression of CRC. Results: miR-4775 was identified as a high-risk factor for CRC metastasis and recurrence, with high levels predicting poor survival among the 544 studied CRC patients. Furthermore, high miR-4775 expression promoted the invasion of CRC cells as well as metastasis and the epithelial to mesenchymal transition (EMT) via Smad7-mediated activation of TGF beta signaling both in vitro and in vivo. Downregulating miR-4775 or overexpressing Smad7 reversed the tumor-promoting roles of miR-4775/ Smad7/TGF beta in vitro and in vivo. Conclusion: miR-4775 promotes CRC metastasis and recurrence in a Smad7/TGF beta signaling-dependent manner, providing a new therapeutic target for inhibiting the metastasis or recurrence of the disease.
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