| 1. |
- Kondratov, Aleksandr G, et al.
(författare)
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Alterations of the WNT7A Gene in Clear Cell Renal Cell Carcinomas
- 2012
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Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 7:10
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Tidskriftsartikel (refereegranskat)abstract
- WNT7A (wingless-type MMTV integration site family, member 7A) is a known tumor suppressor gene of non-small cell lung carcinomas (NSCLC) and is frequently inactivated due to CpG-island hypermethylation in human cancers. The members of WNT family are involved in cell signaling and play crucial roles in cancer development. In the present work hypermethylation of the WNT7A gene was detected in 66% (29/44) of analyzed clear cell renal cell carcinomas (RCCs) using methyl-specific PCR (MSP). Moreover, bisulfite sequencing confirmed intensive hypermethylation of the 5-CpG island of the WNT7A gene. Methylation analysis revealed positive correlations between tumor stage, Fuhrman nuclear grade and WNT7A hypermethylation. Additionally, restoration of WNT7A gene expression in the A498 cell line by 5-aza-2-deoxycytidine treatment confirmed a direct contribution of hypermethylation in silencing of the WNT7A gene. High frequency of loss of heterozygosity (LOH) was demonstrated on chromosome 3p25 in regions surrounding the WNT7A gene. The frequent down-regulation of WNT7A gene expression was detected in 88% (15/17) of clear cell RCCs. We have also shown that the WNT7A gene possesses tumor suppression function by colony-formation and cell proliferation assays in RCC cell lines. In summary, the WNT7A gene is inactivated by genetic/epigenetic alterations in clear cell RCC and demonstrates tumor suppressor properties.
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| 2. |
- Mushtaq, Muhammad, et al.
(författare)
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The MRPS18-2 protein levels correlate with prostate tumor progression and it induces CXCR4-dependent migration of cancer cells
- 2018
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- We have earlier found abnormal expression of the mitochondrial ribosomal protein S18-2 (MRPS18-2, S18-2) in endometrial cancer, compared to the expression in hyperplasia and in normal endometrium. Here we report that expression of S18-2 was increased with disease progression in clinical specimens of prostate cancer (PCa). The level of induction of epithelial to mesenchymal cell transition (EMT) correlated with the expression level of S18-2 in PCa cell lines. Moreover, cells acquired increased ability of migration upon S18-2 overexpression, as was evaluated in zebrafish embryo model and in trans-well assay. We found that this is due to increased CXCR4 cell surface expression. Neutralizing CXCR4 protein or abrogating S18-2 expression in cells significantly reduced their migratory ability directed toward CXCL12. The mRNA expression of TWIST2, encoding one of transcription factors that induce EMT upon CXCR4 increase, positively correlated with the S18-2 protein level. Together, these data suggest that the S18-2 protein induces EMT through the TWIST2/E-cadherin signalling and, consequently, CXCR4-mediated migration of PCa cells.
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| 3. |
- Govorov, Igor, et al.
(författare)
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STK4 protein expression pattern follows different trends in endometrioid and serous endometrial adenocarcinoma upon tumor progression
- 2022
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- In a previous study, we showed that serine/threonine-protein kinase 4 (STK4) is involved in the control on proliferation and migration of endometrial cancer (EC) cells in vitro. In the present paper, we studied STK4 expression in EC tissues from a large cohort of patients to determine whether STK4 can serve as a marker for the aggressiveness and prognosis of EC. Tissue samples from patients with EC were examined for tumor type, grade, and stage. The STK4 protein expression in EC cells was assessed by immunohistochemistry and related to clinicopathological data of patients, such as progression and patient survival rate. The STK4 mRNA levels and its relation to the survival rate were analyzed also in publicly available databases. The STK4 gene expression was low at both, the mRNA and protein levels in EC, especially in serous tumors. Comparison of STK4 expression with the patient survival rate shows that the higher expression is associated with worse prognosis in serous EC, while no such dependence was found in endometrioid EC. Hence, the determination of the SKT4 expression pattern could be used as a putative prognostic marker for serous EC.
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| 4. |
- Govorov, Igor, et al.
(författare)
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Upregulation of PKN1 as a Prognosis Biomarker for Endometrial Cancer
- 2022
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Ingår i: Cancer Control. - : Sage Publications. - 1073-2748 .- 1526-2359. ; 29
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Several markers of survival among endometrial cancer (EC) patients have been proposed, namely, the oncoprotein stathmin, RAF kinase inhibitor (RKIP), Cyclin A, GATA-binding protein 3 (GATA3), and growth and differentiation factor-15 (GDF-15). Their elevated expression correlated significantly with a high stage, serous papillary/clear cell subtypes, and aneuploidy. In a previous study, we reported the elevated expression of the serine/threonine protein kinase N1 (PKN1) in cancerous cells. In the present paper, we studied PKN1 expression in EC tissues from a large cohort of patients, to determine whether PKN1 can serve as a marker for the aggressiveness and prognosis of EC, and/or as a marker of survival among EC patients.METHODS: Tissue samples from EC patients were examined retrospectively for tumor type, tumor size, FIGO stage and grade, depth of invasion in the myometrium, and presence of lymph node metastasis. The PKN1 protein expression in EC cells was assessed by immunohistochemistry. PKN1 mRNA levels were analyzed in publicly available databases, using bioinformatic tools.RESULTS: We found that expression of PKN1 at the mRNA and proteins levels tended to increase in high-grade EC samples (P = .0001 and P = .06, respectively). In addition, patients with metastatic disease had higher PKN1 mRNA levels (P = .02). Moreover, patients with high PKN1 expression could be characterized by poorer survival.CONCLUSIONS: We have shown a trend of the higher PKN1 expression levels in EC patients with poor prognosis. Therefore, PKN1 might be considered as a candidate prognostic marker for EC.
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| 5. |
- Kashuba, Elena
(författare)
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Identification of EBNA binding cellular proteins, using yeast two-hybrid system
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Epstein-Barr virus (EBV) is a common herpesvirus that establishes life-long persistence in the human host through the elaborate regulation of different latency types. Latent EBV infection of resting B cells converts them into transformed cells that can develop into tumors in immune-compromised hosts. As such, EBV infection is a unique, well-defined in vitro system for malignant transformation. The latency-associated EBV proteins are the key factors for virus-induced cell transformation. To fully understand the molecular mechanisms that lead to virusinduced transformation, the cellular targets of the transforming viral proteins have to be identified. During the work summarized in this thesis, the following EBV encoded nuclear antigen (EBNA) binding proteins were identified: epsilon-subunit of the human chaperonin TCP- 1 complex; XAP2, the minor subunit of the arylhydrocarbon receptor (AhR) complex; a novel human uridine kinase/uracil phosphoribosyltransferase (for EBNA-3); and p14ARF (for EBNA-5). Epsilon-subunit of the human chaperonin TCP-1 complex is part of a huge protein complex that helps to fold the newly synthesized polypeptides. We mapped the interacting region to the apical domain of the epsilon-subunit the most likely site for recognition of newly translated polypeptides. We concluded that nascent EBNA-3 might receive help for its folding from the TCP-1 complex. Another protein that binds to EBNA-3 is XAP-2, which also interacts with the transformation associated X-protein encoded by the hepatitis B virus. We showed that EBNA-3 induces translocation of the cytoplasmic XAP-2 to the nucleus. We also found a previously unknown EBNA-3 binding protein, which was designated F538. We have shown that the predominantly cytoplasmic F538 relocated to the nucleus in the presence of EBNA-3, where these two proteins showed high levels of co-localization. A natural splice variant with the deleted C-terminus of F538 did not translocate to the nucleus. A SWISSModel 3D structure of F538 was constructed and compared with other known proteins. This raised the possibility that F538 is a novel human uridine kinase/uracil phosphoribosyltransferase (UK/UPRT). We suggested that EBNA-3 by direct protein- protein interaction induced the nuclear accumulation of this enzyme that is most likely part of the ribonucleotide salvage pathway. Increased intra-nuclear levels of UK/UPRT might contribute to the metabolic build-up that is needed for blast transformation and rapid proliferation. We found that EBNA-5 binds to p14ARF, one of the upstream regulators of the p53 pathway. We showed that EBNA-5 prolonged the survival of the p14ARFtransfected cells. We observed the accumulation of the p14ARF in extra-nuclear inclusions where it co-localized with p53, HDM2 and Hsp70. Formation of the p14ARF inclusions induced the translocation of PML bodies and 20S proteasome subunits. Co-expression of p14ARF and EBNA-5 led to the complete relocation of EBNA-5 into the p14ARF inclusions. We suggested that EBNA-5 might play a role in regulating the degradation of p14ARF-p53-HDM2 complexes. In conclusion, using the yeast two-hybrid system we found new cellular targets for EBV-encoded transformation associated latent proteins. Some of these target molecules participate in signal transduction (Xap-2); growth associated metabolic pathways (F538); cell cycle regulation and protein degradation (p14ARF).
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| 6. |
- Ranhem, Cecilia, et al.
(författare)
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Evaluation of dyskerin expression and the Cajal body protein WRAP53 beta as potential prognostic markers for patients with primary vaginal carcinoma
- 2022
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Ingår i: Oncology Letters. - : SPANDIDOS PUBL LTD. - 1792-1074 .- 1792-1082. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Primary vaginal cancer (PVC) is a rare gynaecological malignancy, which, at present, lacks appropriate biomarkers for prognosis. The proteins dyskerin and WD repeat containing antisense to TP53 (WRAP53 beta), both of which exert their functions in the telomerase holoenzyme complex, have been shown to be upregulated in different cancer types. These proteins have also been proposed as prognostic markers in some types of cancer. The aim of the present study was to examine the expression patterns of dyskerin and WRAP53 beta in patients with PVC. Moreover, as part of a search for effective biomarkers to evaluate prognosis in PVC, the expression of these two proteins and their potential association with clinical variables and survival were also evaluated. The expression of dyskerin and WRAP53 beta was assessed in PVC tumour samples from 68 patients using immunohistochemistry. The majority of tumour samples showed low and moderate expression levels of dyskerin. Upregulation of dyskerin in tumour samples was significantly associated with a shorter survival time and a poorer cancer-specific survival rate. WRAP53 beta was also expressed in most of the cells but was not significantly associated with clinical variables or survival. This study demonstrates that upregulation of dyskerin is significantly associated with poor prognosis. Thus, dyskerin may serve as a promising prognostic marker and a potential putative therapeutic target in PVC.
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| 7. |
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| 8. |
- Ranhem, Cecilia, et al.
(författare)
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Evaluation of dyskerin expression and the Cajal body protein WRAP53β as potential prognostic markers for patients with primary vaginal carcinoma
- 2022
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Ingår i: Oncology Letters. - : Spandidos Publications. - 1792-1074 .- 1792-1082. ; 23:1
-
Tidskriftsartikel (refereegranskat)abstract
- Primary vaginal cancer (PVC) is a rare gynaecological malignancy, which, at present, lacks appropriate biomarkers for prognosis. The proteins dyskerin and WD repeat containing antisense to TP53 (WRAP53β), both of which exert their functions in the telomerase holoenzyme complex, have been shown to be upregulated in different cancer types. These proteins have also been proposed as prognostic markers in some types of cancer. The aim of the present study was to examine the expression patterns of dyskerin and WRAP53β in patients with PVC. Moreover, as part of a search for effective biomarkers to evaluate prognosis in PVC, the expression of these two proteins and their potential association with clinical variables and survival were also evaluated. The expression of dyskerin and WRAP53β was assessed in PVC tumour samples from 68 patients using immunohistochemistry. The majority of tumour samples showed low and moderate expression levels of dyskerin. Upregulation of dyskerin in tumour samples was significantly associated with a shorter survival time and a poorer cancer-specific survival rate. WRAP53β was also expressed in most of the cells but was not significantly associated with clinical variables or survival. This study demonstrates that upregulation of dyskerin is significantly associated with poor prognosis. Thus, dyskerin may serve as a promising prognostic marker and a potential putative therapeutic target in PVC.
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| 9. |
- Ranhem, Cecilia, et al.
(författare)
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Evaluation of dyskerin expression and the Cajal body protein WRAP53β as potential prognostic markers for patients with primary vaginal carcinoma
- 2022
-
Ingår i: Oncology Letters. - : Spandidos Publications. - 1792-1074 .- 1792-1082. ; 23:1
-
Tidskriftsartikel (refereegranskat)abstract
- Primary vaginal cancer (PVC) is a rare gynae- cological malignancy, which, at present, lacks appropriate biomarkers for prognosis. The proteins dyskerin and WD repeat containing antisense to TP53 (WRAP53β), both of which exert their functions in the telomerase holoenzyme complex, have been shown to be upregulated in different cancer types. These proteins have also been proposed as prognostic markers in some types of cancer. The aim of the present study was to examine the expression patterns of dyskerin and WRAP53β in patients with PVC. Moreover, as part of a search for effective biomarkers to evaluate prog- nosis in PVC, the expression of these two proteins and their potential association with clinical variables and survival were also evaluated. The expression of dyskerin and WRAP53β was assessed in PVC tumour samples from 68 patients using immunohistochemistry. The majority of tumour samples showed low and moderate expression levels of dyskerin. Upregulation of dyskerin in tumour samples was signifi- cantly associated with a shorter survival time and a poorer cancer-specific survival rate. WRAP53β was also expressed in most of the cells but was not significantly associated with clinical variables or survival. This study demonstrates that upregulation of dyskerin is significantly associated with poor prognosis. Thus, dyskerin may serve as a promising prognostic marker and a potential putative therapeutic target in PVC.
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| 10. |
- Yenamandra, Surya Pavan, et al.
(författare)
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Epstein-Barr virus encoded EBNA-3 binds to vitamin D receptor and blocks activation of its target genes
- 2010
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Ingår i: Cellular and Molecular Life Sciences (CMLS). - : Springer Science and Business Media LLC. - 1420-682X .- 1420-9071. ; 67:24, s. 4249-4256
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Tidskriftsartikel (refereegranskat)abstract
- Epstein-Barr virus (EBV) is a human gamma herpes virus that infects B cells and induces their transformation into immortalized lymphoblasts that can grow as cell lines (LCLs) in vitro. EBNA-3 is a member of the EBNA-3-protein family that can regulate transcription of cellular and viral genes. The identification of EBNA-3 cellular partners and a study of its influence on cellular pathways are important for understanding the transforming action of the virus. In this work, we have identified the vitamin D receptor (VDR) protein as a binding partner of EBNA-3. We found that EBNA3 blocks the activation of VDR-dependent genes and protects LCLs against vitamin-D3-induced growth arrest and/or apoptosis. The presented data shed some light on the anti-apoptotic EBV program and the role of the EBNA-3-VDR interaction in the viral strategy.
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