Expression of the p53 target Wig-1 is associated with HPV status and patient survival in cervical carcinoma

Li-Di Xu; Susanne Muller; Srinivasan R Thoppe; Fredrik Hellborg; Lena Kanter; Mikael Lerner; Biying Zheng; Svetlana Bajalica Lagercrantz; Dan Grandér; Keng Ling Wallin; Klas G Wiman; Catharina Larsson; Sonia Andersson

doi:10.1371/journal.pone.0111125

Expression of the p53 target Wig-1 is associated with HPV status and patient survival in cervical carcinoma

PLoS One. 2014 Nov 7;9(11):e111125. doi: 10.1371/journal.pone.0111125. eCollection 2014.

Affiliations

¹ Department of Oncology-Pathology, Cancer Center Karolinska (CCK), Karolinska University Hospital-Solna, Stockholm, Sweden.
² Department of Women's and Children's Health, Division of Obstetrics and Gynecology, Karolinska University Hospital-Solna, Stockholm, Sweden.
³ Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital-Solna, Stockholm, Sweden.

Abstract

The p53 target gene WIG-1 (ZMAT3) is located in chromosomal region 3q26, that is frequently amplified in human tumors, including cervical cancer. We have examined the status of WIG-1 and the encoded Wig-1 protein in cervical carcinoma cell lines and tumor tissue samples. Our analysis of eight cervical cancer lines (Ca Ski, ME-180, MS751, SiHa, SW756, C-4I, C-33A, and HT-3) by spectral karyotype, comparative genomic hybridization and Southern blotting revealed WIG-1 is not the primary target for chromosome 3 gains. However, WIG-1/Wig-1 were readily expressed and WIG-1 mRNA expression was higher in the two HPV-negative cervical cell lines (C33-A, HT-3) than in HPV-positive lines. We then assessed Wig-1 expression by immunohistochemistry in 38 cervical tumor samples. We found higher nuclear Wig-1 expression levels in HPV-negative compared to HPV positive cases (p = 0.002) and in adenocarcinomas as compared to squamous cell lesions (p<0.0001). Cases with moderate nuclear Wig-1 staining and positive cytoplasmic Wig-1 staining showed longer survival than patients with strong nuclear and negative cytoplasmic staining (p = 0.042). Nuclear Wig-1 expression levels were positively associated with age at diagnosis (p = 0.023) and histologic grade (p = 0.034). These results are consistent with a growth-promoting and/or anti-cell death function of nuclear Wig-1 and suggest that Wig-1 expression can serve as a prognostic marker in cervical carcinoma.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Carrier Proteins / genetics*
Carrier Proteins / metabolism
Cell Line, Tumor
Cell Nucleus / metabolism
Chromosomes, Human, Pair 3 / genetics
Female
Gene Expression Regulation, Neoplastic*
Genetic Loci / genetics
Humans
Neoplasm Grading
Neoplasm Staging
Nuclear Proteins / genetics*
Nuclear Proteins / metabolism
Papillomaviridae / physiology*
Prognosis
RNA-Binding Proteins
Survival Analysis
Tumor Suppressor Protein p53 / metabolism*
Uterine Cervical Neoplasms / diagnosis
Uterine Cervical Neoplasms / genetics*
Uterine Cervical Neoplasms / pathology
Uterine Cervical Neoplasms / virology*

Substances

Carrier Proteins
Nuclear Proteins
RNA-Binding Proteins
Tumor Suppressor Protein p53
ZMAT3 protein, human

Grants and funding

Professor Klas G. Wiman received the following funding: The Swedish Research Council (VR) - number K2013-66X-15385-09-5; The Swedish Cancer Society - number 13 0623; Radiumhemmets Forskningsfonder - number 131271; Karolinska Institutet DPA - Klas Wiman; and StratCan - Klas Wiman. Professor Sonia Andersson received the following funding: Swedish Cancer Foundation (110544, CAN 2011/471) and the Swedish Research Council (521-2008-2899). Professor Catharina Larsson received the following funding: Swedish Research Council K2014-66X-11622-19-3 and Swedish Cancer Foundation 13 0543. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.