[en] BACKGROUND: The 21-kDa Vaccinia virus VH1-related (VHR) dual-specific protein phosphatase (encoded by the DUSP3 gene) plays a critical role in cell cycle progression and is itself regulated during the cell cycle. We have previously demonstrated using RNA interference that cells lacking VHR arrest in the G1 and G2 phases of the cell cycle and show signs of beginning of cell senescence. METHODS: In this report, we evaluated successfully the expression levels of VHR protein in 62 hysterectomy or conization specimens showing the various (pre) neoplastic cervical epithelial lesions and 35 additional cases of hysterectomy performed for non-cervical pathologies, from patients under 50 years of age. We used a tissue microarray and IHC technique to evaluate the expression of the VHR phosphatase. Immunofluorescence staining under confocal microscopy, Western blotting and RT-PCR methods were used to investigate the localization and expression levels of VHR. RESULTS: We report that VHR is upregulated in (pre) neoplastic lesions (squamous intraepithelial lesions; SILs) of the uterine cervix mainly in high grade SIL (H-SIL) compared to normal exocervix. In the invasive cancer, VHR is also highly expressed with nuclear localization in the majority of cells compared to normal tissue where VHR is always in the cytoplasm. We also report that this phosphatase is highly expressed in several cervix cancer cell lines such as HeLa, SiHa, CaSki, C33 and HT3 compared to primary keratinocytes. The immunofluorescence technique under confocal microscopy shows that VHR has a cytoplasmic localization in primary keratinocytes, while it localizes in both cytoplasm and nucleus of the cancer cell lines investigated. We report that the up-regulation of this phosphatase is mainly due to its post-translational stabilization in the cancer cell lines compared to primary keratinocytes rather than increases in the transcription of DUSP3 locus. CONCLUSION: These results together suggest that VHR can be considered as a new marker for cancer progression in cervix carcinoma and potential new target for anticancer therapy.
Research center :
GIGA‐R - Giga‐Research - ULiège
Disciplines :
Oncology
Author, co-author :
Henkens, Rachel ; Université de Liège - ULiège > Département des sciences cliniques > Immunopathologie - Transplantation
Delvenne, Philippe ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Anatomie et cytologie pathologiques
Arafa, Mohammad
Moutschen, Michel ; Université de Liège - ULiège > Département des sciences cliniques > Immunopathologie - Transplantation
Zeddou, Mustapha ; Université de Liège - ULiège > Département des sciences cliniques > Hématologie
Tautz, Lutz
Boniver, Jacques ; Centre Hospitalier Universitaire de Liège - CHU > Anatomie pathologique
Mustelin, Tomas
Rahmouni, Souad ; Université de Liège - ULiège > Département des sciences cliniques > Immunopathologie - Transplantation
Language :
English
Title :
Cervix carcinoma is associated with an up-regulation and nuclear localization of the dual-specificity protein phosphatase VHR.
Alonso A Sasin J Bottini N Friedberg I Osterman A Godzik A Hunter T Dixon J Mustelin T Protein tyrosine phosphatases in the human genome Cell 2004, 117(6):699-711. 10.1016/j.cell.2004.05.018 15186772
Ishibashi T Bottaro DP Chan A Miki T Aaronson SA Expression cloning of a human dual-specificity phosphatase Proc Natl Acad Sci USA 1992, 89(24):12170-4. 50720 1281549 10.1073/pnas.89.24.12170
Rahmouni S Cerignoli F Alonso A Tsutji T Henkens R Zhu C Louis-dit-Sully C Moutschen M Jiang W Mustelin T Loss of the VHR dual-specific phosphatase causes cell-cycle arrest and senescence Nat Cell Biol 2006, 8(5):524-31. 10.1038/ncb1398 16604064
Cerignoli F Rahmouni S Ronai Z Mustelin T Regulation of MAP kinases by the VHR dual-specific phosphatase: Implications for cell growth and differentiation Cell Cycle 2006, 5(19):2210-5. 17012840
Bosch FX Manos MM Muñoz N Sherman M Jansen AM Peto J Schiffman MH Moreno V Kurman R Shah KV Prevalence of human papillomavirus in cervical cancer: A worldwide perspective. International biological study on cervical cancer (IBSCC) Study Group J Natl Cancer Inst 1995, 87(11):796-802. 10.1093/jnci/87.11.796 7791229
Walboomers JM Jacobs MV Manos MM Bosch FX Kummer JA Shah KV Snijders PJ Peto J Meijer CJ Muñoz N Human papillomavirus is a necessary cause of invasive cervical cancer worldwide J Pathol 1992, 189(1):12-9. 10.1002/(SICI)1096-9896(199909)189:1<12::AID-PATH431>3.0.CO;2-F
Syrjanen K Long-term consequences of genital HPV infections in women Ann Med 1992, 24(4):233-5. 10.3109/07853899209149950 1327003
Delvenne P Hubert P Jacobs N Epithelial metaplasia: An inadequate environment for antitumour immunity? Trends Immunol 2004, 25(4):169-73. 10.1016/j.it.2004.02.002 15039042
McCance DJ Human papillomaviruses and cell signaling Sci STKE 2005, 288:pE29. 10.1126/stke.2882005pe29
Havard L Rahmouni S Boniver J Delvenne P High levels of p105 (NFKB1) and p100 (NFKB2) proteins in HPV16-transformed keratinocytes: Role of E6 and E7 oncoproteins Virology 2005, 331(2):357-66. 10.1016/ j.virol.2004.10.030 15629778
Andersson S Hellström AC Ren ZP Wilander E The carcinogenic role of oncogenic HPV and p53 gene mutation in cervical adenocarcinomas Med Oncol 2006, 23(1):113-9. 10.1385/MO:23:1:113 16645236
Aguilar-Lemarroy A Gariglio P Whitaker NJ Eichhorst ST zur Hausen H Krammer PH Rösl F Restoration of p53 expression sensitizes human papillomavirus type 16 immortalized human keratinocytes to CD95-mediated apoptosis Oncogene 2002, 21(2):165-75. 10.1038/sj.onc.1204979 11803460
Sano T Oyama T Kashiwabara K Fukuda D Nakajima T Oyama T Kashiwabara K Expression status of p16 protein is associated with human papillomavirus oncogenic potential in cervical and genital lesions Am J Pathol 1998, 153(6):1741-8. 1866324 9846965
Cho NH Kim YT Kim JW Correlation between G1 cyclins and HPV in the uterine cervix Int J Gynecol Pathol 1997, 16(4):339-47. 9421073
Khleif SN DeGregori J Yee CL Otterson GA Kaye FJ Nevins JR Howley PM Inhibition of cyclin D-CDK4/CDK6 activity is associated with an E2F-mediated induction of cyclin kinase inhibitor activity Proc Natl Acad Sci USA 1996, 93(9):4350-4. 39540 8633069 10.1073/pnas.93.9.4350
Milde-Langosch K Riethdorf S Kraus-Pöppinghaus A Riethdorf L Löning T Expression of cyclin-dependent kinase inhibitors p16MTS1, p21WAF1, and p27KIP1 in HPV-positive and HPV-negative cervical adenocarcinomas Virchows Arch 2001, 439(1):55-61. 10.1007/s004280100439 11499840
Poon IK Jans DA Regulation of nuclear transport: Central role in development and transformation? Traffic 2006, 6(3):173-86. 10.1111/ j.1600-0854.2005.00268.x
Engelbrecht AM Gebhardt S Louw L Ex vivo study of MAPK profiles correlated with parameters of apoptosis during cervical carcinogenesis Cancer Lett 2006, 235(1):93-9. 10.1016/j.canlet.2005.04.005 15927365