Transferrin ensures survival of ovarian carcinoma cells when apoptosis is induced by TNFα, FasL, TRAIL, or Myc

Fassl, Sandra; Leisser, Christina; Huettenbrenner, S; Maier, Susanne; Rosenberger, Georg; Strasser, Stephen; Grusch, Michael; Fuhrmann, G; Leuhuber, Katharina; Polgar, Doris; Stani, Josefine; Tichy, Brigitte; Nowotny, Christine; Krupitza, Georg

doi:10.1038/sj.onc.1207047

Cited by 37 publications

(38 citation statements)

References 57 publications

(59 reference statements)

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“…In WFDC2 knockdown cells, a series of apoptosis-related gene expression levels were altered (30,31). Fasl is an important apoptosis-related membrane protein and enhanced Fasl expression at mRNA and protein level caused by WFDC2 knockdown cells indicates that SKOV3-209 may more easily undergo apoptosis.…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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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“…on May 10, 2018. by guest www.bloodjournal.org From triggered apoptosis. 32 These data suggest a link between iron hemostasis and p21 and TRAIL.…”

Section: Discussionmentioning

confidence: 83%

Pathobiology of hemophilic synovitis I: overexpression of mdm2 oncogene

Hakobyan

Kazarian

Jabbar

et al. 2004

Blood

134

127

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“…34 Still, it is possible that the sharp accumulation of iron that occurs after menopause may be accelerated and aggravated in women carrying a single copy of the C282Y mutation, thereby increasing the chances of developing an ovarian cancer. Moreover, there is some evidence that HFE-related increased expression of TfR and consequent effect on tumor cellular homeostasis may modulate drug-induced apoptosis and ensure the survival of cancer cells, 37,38 which ultimately would affect patient outcomes.…”

Section: Discussionmentioning

confidence: 99%

Impact of hemochromatosis gene (HFE) mutations on epithelial ovarian cancer risk and prognosis

Gannon

Medelci

Page

et al. 2010

Intl Journal of Cancer

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Cancer cells require large amounts of micronutrients, particularly iron, for their rapid growth and frequent divisions. Cellular iron uptake is regulated by the transferrin receptor and the hemochromatosis protein (HFE) system. Two frequent mutations in the HFE gene, H63D and C282Y, are associated with hemochromatosis type I, an inherited iron overload disease and, possibly, with cancer. In this study, we evaluated the frequency of the H63D and C282Y mutations in a cohort of 677 consecutive cases of woman with gynecological pathologies. Cases included 80 women with tumor-free pathologies normal ovary (NOV), 124 with benign ovarian tumors (BOV), 96 with epithelial ovarian cancer (EOC) tumors of low malignant potential (LPM), 264 with invasive tumors of the ovary (TOV) and 113 with endometrial cancer. We found that the C282Y allele frequency in EOC patients was higher than that in the control NOV group (5.8% vs. 1.3%, p < 0.001) and was associated with an increased risk of ovarian cancer (OR = 4.88; 95% CI 1. 15-20.61; p = 0.018). The effect of the two HFE mutations on patient survival was also analyzed.Kaplan-Meier analyses did not find any significant association between the H63D allele and patient survival. However, EOC patients with at least one C282Y allele had a decreased overall survival compared to those with no C282Y allele (p = 0.001). These results indicate that the C282Y mutation may increase the risk of developing ovarian cancer and may be further associated with poor outcomes. Keywords CIHR Author Manuscript CIHR Author Manuscript CIHR Author ManuscriptIron is an essential trace element that can be carcinogenic through a variety of mechanisms including acting as an essential nutrient for proliferating tumor cells, 1 catalyzing the formation of mutagenic hydroxyl radicals, 2 and by suppressing the host immune response. 3,4 In the past decades, several genes were identified as being central to the maintenance of iron homeostasis. 5 One such gene is HFE, a major histocompatibility class I-like (MHC-I-like) molecule, that, when mutated, may cause hereditary hemochromatosis (HH). 6 HH is a common genetic disorder in Caucasian populations that is characterized by high levels of iron absorption from diet, which results in the presence of high circulating iron levels and iron accumulation in the body. 7 As with other MHC-I molecules, HFE needs to associate with β2-microglobulin (β2m) for its appropriate expression at the cell surface. 8 The two most common mutations in HFE are C282Y, a guanine-to-adenine transition leading to a cysteine-to-tyrosine change and H63D, a cysteine-to-guanine transition causing a histidineto-aspartic acid change. 6 HFE associates with the major protein responsible for cellular iron uptake, namely the transferrin receptor (TfR), 9 also called CD71. The association of HFE with TfR at the cell surface lowers TfR affinity for the circulating iron-transporter transferrin, thereby limiting iron uptake and thus directly implicating HFE in the modulation of cellular iron level...

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Transferrin ensures survival of ovarian carcinoma cells when apoptosis is induced by TNFα, FasL, TRAIL, or Myc

Cited by 37 publications

References 57 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

Pathobiology of hemophilic synovitis I: overexpression of mdm2 oncogene

Impact of hemochromatosis gene (HFE) mutations on epithelial ovarian cancer risk and prognosis

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