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.
Highlights
Cervical cancer ranks the third among the most common cancers in women worldwide and is the most common type of cancer in Eastern Africa, South-Central Asia and Melanesia [1]
We first assessed structural and numerical alterations of the WIG-1 locus in cervical carcinoma cell lines by spectral karyotyping (SKY) and comparative genomic hybridization (CGH) analyses, which showed that WIG-1 is not a primary target for chromosome 3 alterations in these cells (Figure 1 A, Table 1)
We investigated whether the expression levels of Wig-1 differed between human papillomavirus (HPV)-positive and HPV-negative adenocarcinomas (ADCA) and found a statistically significant difference in nuclear Wig-1 staining intensity between HPV-positive and HPV-negative ADCA samples (p = 0.049, univariate analysis)
Summary
Cervical cancer ranks the third among the most common cancers in women worldwide and is the most common type of cancer in Eastern Africa, South-Central Asia and Melanesia [1]. Persistent infection with high risk (HR) human papillomavirus (HPV) is a major risk factor for the development of cervical cancer and the two predominant types are HPV18 and HPV16, followed by HPV45, 31, 33, 58, 52, 35, 59, 56, 6, 51, 68, 39, 82, 73, 66 and 70 in order of prevalence [5]. HR-HPV encodes two early proteins, E6 and E7, that target two major cellular tumor suppressor pathways. E6 targets the p53 tumor suppressor for degradation, resulting in loss of p53dependent apoptosis and/or senescence [6,7]. E7 binds to the pRb tumor suppressor, thereby disrupting G1/S transition control [8]. HR-HPV infection may lead to malignant transformation and tumor development
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