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| Objectives: Human epididymis protein 4 (HE4) is a promising novel biomarker for the detection of epithelial ovarian cancer (EOC). The role of HE4 in EOC tumorigenesis is unclear. This study investigated the cellular and molecular mechanisms of HE4 in ovarian cancer cell proliferation.
Methods: We generated HE4-overexpressing SKOV3 cells and silenced HE4 gene expression in SKOV3.ip1 cells. We used the Cell Counting Kit-8 assay to evaluate cell proliferation and western blotting to analyze the expression of proliferation- and apoptosis-associated proteins such as Bax, Bcl-2, and caspase 3.
Results: Overexpression of HE4 in SKOV3, an ovarian carcinoma cell line, inhibited cell proliferation. In contrast, HE4 silencing in SKOV3.ip1 cells promoted cell proliferation; however, conditioned medium containing HE4 and human recombinant HE4 protein (hrHE4) had no effect on proliferation in SKOV3 or SKOV3.ip1 cells. HE4 inhibited MEK, ERK1/2, and AKT phosphorylation, but promoted JNK1/2/3 and c-JUN phosphorylation; however, p38 phosphorylation was impaired in HE4-overexpressing and silenced cells. HE4 had no effect on EGFR phosphorylation or on the apoptosis-associated proteins Bax, Bcl-2, and caspase 3.
Conclusions: HE4 might play a protective role in the progression of EOC by inhibiting cell proliferation. Antiproliferative activity was mediated by intracellular HE4, and not the secreted protein. HE4 might inhibit cell proliferation by regulating MAPK and PI3K/AKT signal transduction in vitro.?? |
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| Keywords:epithelial ovarian cancer; human epididymis protein 4; proliferation; apoptosis |
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