p16 Overexpression: A Potential Early Indicator of Transformation in Ovarian Carcinoma

Shigemasa, Kazushi; Hu, Changjun; West, Catherine; Clarke, John; Pharham, G.; Parmley, Tim H.; Korourian, Soheila; Baker, Vicki V.; O’Brien, Timothy J.

doi:10.1177/107155769700400209

Cited by 29 publications

(41 citation statements)

References 12 publications

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“…This is also evident from the cell cycle of SKOV3 cells; WFDC2 gene silencing arrested the cell cycle in the G0/G1 phase. Cyclin D1 belongs to the core cell cycle machinery and it is frequently overexpressed in human cancers (13,24,25). The strong positive correlation between WFDC2 and cyclin D1 expression observed in our study suggests that WFDC2 may be linked to the development and progression of ovarian cancer by regulating the cell cycle of ovarian cancer cells.…”

Section: Discussionsupporting

confidence: 56%

WAP four-disulfide core domain protein 2 mediates the proliferation of human ovarian cancer cells through the regulation of growth- and apoptosis-associated genes

Yao

Wang

et al. 2012

Oncology Reports

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Abstract. The WAP four-disulfide core domain protein 2 (WFDC2) is frequently overexpressed in epithelial ovarian cancer cells and has been proposed as a potential biomarker. The biological function of WFDC2 in tumor progression remains unclear. In this study, the stable expression of short hairpin RNA (shRNA) against WFDC2 in the human ovarian SKOV3 cell line was established. Cell proliferation in vitro was determined by MTT assay. Cell cycle and apoptosis were analyzed by FACS. The expression of genes related to cell proliferation and survival was detected by real-time RT-PCR and western blotting. In vivo tumor growth assay was performed by establishing WFDC2-knockdown xenografts in nude mice and monitoring tumor growth. The expression of WFDC2, Ki67 and activated caspase-3 was analyzed by immunohistochemistry in order to determine the role of WFDC2 in proliferation and apoptosis. Our results revealed that the silencing of WFDC2 abolished ovarian cancer cell proliferation, suppressing tumor formation and growth in ovarian cancer cells both in vitro and in vivo. The knockdown of WFDC2 induced upregulation of Fasl and the downregulation of cyclin D1 activated caspase-3 and Ki67. These results indicate that WFDC2 plays a crucial role in tumor formation and growth in ovarian cancer cells. WFDC2 may be a potential therapeutic target for epithelial ovarian cancer. IntroductionOvarian cancer is one of the most common cancers among women, and it is the leading cause of mortality among gynecological malignancies worldwide. WAP four-disulfide core domain protein 2 (WFDC2) was first identified in the epithelium of the distal epididymis and was originally predicted as a protease inhibitor involved in sperm maturation. Recent interest in WFDC2 has been generated by the consistent demonstration of its overexpression in ovarian carcinomas in comparison to normal ovarian tissue (1-3). This gene, also known as human epididymis 4 (HE4), has been consistently identified as being upregulated in ovarian carcinoma by gene expression profiling studies and has been proposed as a putative serum biomarker for malignant ovarian masses (1,4-6).The WFDC2 gene is located on human chromosome 20q12-13.1. The amplification of 20q12-13 has been demonstrated specifically in breast and ovarian carcinomas (2,7). Fourteen genes which encode proteins with a WAP-type four-disulfide core (WFDC) domain have been identified on this region. Two of these genes, SLPI and p13, encoded as antileukoproteinase 1 and elafin, which are co-expressed with WFDC2 play a role in the development or progression of various types of carcinomas (8,9). This led us to investigate whether WFDC2, a member of the WAP cluster, overexpressed in ovarian cancer, may also be involved with this disease.The most studied WAP proteins, p13 and SLPI, both identified as serine-proteinase inhibitors, are reported to be associated with aggressive, high-risk, or metastatic cancer originating from various organs (10,11). The expression of SLPI was positively correlated with the increased exp...

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Section: Discussionsupporting

confidence: 56%

WAP four-disulfide core domain protein 2 mediates the proliferation of human ovarian cancer cells through the regulation of growth- and apoptosis-associated genes

Yao

Wang

et al. 2012

Oncology Reports

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“…Dong et al showed in a much larger immunohistochemical study including 190 epithelial ovarian tumours that loss of p16 is associated with lower pathological grade, earlier clinical stage and better prognosis. Similar results were also shown by Shigemasa et al (1997) and MildeLongosch et al (1998). These findings seem to be controversial to the negative regulatory function of p16 in cell cycle control and suggest unknown inactivating mechanisms of the CDKN2A gene in OC.…”

Section: Expression Of Cdkn2a Gene At Mrna and Protein Levelsupporting

confidence: 80%

CDKN2A gene inactivation in epithelial sporadic ovarian cancer

Niederacher

et al. 1999

Br J Cancer

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SummaryThe tumour suppressor gene CDKN2A, located on chromosome 9p21, encodes the cell cycle regulatory protein p16. Inactivation of the CDKN2A gene could lead to uncontrolled cell growth. In order to determine the role of CDKN2A in the development of sporadic ovarian cancer, loss of heterozygosity at 9p21-22, homozygous deletion, mutation and methylation status of the CDKN2A gene as well as CDKN2A expression were examined in a panel of serous papillary ovarian cancer. The frequency of loss of heterozygosity (LOH) for one or more informative markers at 9p21-22 was 65% (15/23). The most common deleted region was located between interferon (IFN)-α and D9S171. Homozygous deletions and mutations of the CDKN2A gene were not found. There was no evidence of methylation in exon 1, but methylation in exon 2 of CDKN2A gene was found in 26% (6/23). Absence of CDKN2A gene expression was shown in 27% (6/22) at mRNA level and 21% (4/19) at protein level. These data suggest that the CDKN2A gene is involved in the tumorigenesis of ovarian cancer, but the mechanisms of CDKN2A gene inactivation in serous papillary ovarian cancer remains unclear.

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“…Extraction of mRNA from ovarian tissue specimens and cDNA synthesis were carried out according to methods described previously (25)(26)(27)(28). mRNA was isolated using a RiboSep mRNA isolation kit (Becton Dickinson Labware, Bedford, MA) and the amount of mRNA recovered measured using a UV spectrophotometer.…”

Section: Tissue Samples and Clinical And Pathological Datamentioning

confidence: 99%

“…KLK11 mRNA expression levels were determined by semiquantitative PCR, which was performed according to a method described previously with some modifications (25)(26)(27)(28). The oligonucleotide primer sequences used for PCR were KLK11 sense primer, 5Ј-CCG CTA CAT AGT TCA CCT GG-3Ј; and KLK11 antisense primer, 5Ј-AGG TGT GAG GCA GGC GTA ACT-3Ј.…”

Section: Tissue Samples and Clinical And Pathological Datamentioning

confidence: 99%

Human Kallikrein Gene 11 ( KLK11 ) mRNA Overexpression Is Associated with Poor Prognosis in Patients with Epithelial Ovarian Cancer

Shigemasa

Tanimoto³

et al. 2004

Clinical Cancer Research

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Purpose: The purpose of this study was to examine expression levels of the human tissue kallikrein 11 gene (KLK11) in epithelial ovarian tumors and to identify the relationship between KLK11 expression and patient survival.Experimental Design: KLK11 mRNA expression was examined by semiquantitative PCR in 64 epithelial ovarian tumors (7 adenomas, 6 low malignant potential tumors, and 51 adenocarcinomas) and in 10 normal ovaries. Semiquantitative PCR results were correlated with clinicopathologic variables and overall survival. cDNA from human normal tissues and tumor tissues was also analyzed.Results: KLK11 mRNA expression was detected in various human cancer tissues including breast, lung, colon, prostate, pancreas, and ovarian carcinoma. The mean value of relative KLK11 expression ratio was significantly higher in ovarian tumor samples than in normal ovary samples (compared with normal samples: adenoma, P ‫؍‬ 0.0006; low malignant potential tumor, P ‫؍‬ 0.0049; and carcinoma, P < 0.0001). No statistically significant associations between KLK11 mRNA expression level and clinical stage, histological type, or histological grade were observed. The log-rank test showed that high KLK11 mRNA expression and advanced clinical stage significantly correlated with poor patient survival (P ‫؍‬ 0.0185 and P ‫؍‬ 0.0043, respectively). High KLK11 mRNA expression and clinical stage remained significantly associated with overall survival (P ‫؍‬ 0.0225 and P ‫؍‬ 0.0202, respectively) after multivariate analysis.Conclusions: KLK11 expression may play an important role in ovarian cancer development and act as an independent prognostic marker in ovarian cancer patients.

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p16 Overexpression: A Potential Early Indicator of Transformation in Ovarian Carcinoma

Cited by 29 publications

References 12 publications

WAP four-disulfide core domain protein 2 mediates the proliferation of human ovarian cancer cells through the regulation of growth- and apoptosis-associated genes

WAP four-disulfide core domain protein 2 mediates the proliferation of human ovarian cancer cells through the regulation of growth- and apoptosis-associated genes

CDKN2A gene inactivation in epithelial sporadic ovarian cancer

Human Kallikrein Gene 11 ( KLK11 ) mRNA Overexpression Is Associated with Poor Prognosis in Patients with Epithelial Ovarian Cancer

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