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Gonadotropins and leptin : the role and molecular mechanism in normal and neoplastic ovarian epithelium cells Choi, Jung-Hye

Abstract

Ovarian cancer is the sixth most common cancer and the fifth leading cause of cancer-related death among women in developed countries. There is increasing evidence suggesting that the hormonal environment of the normal ovarian surface epithelium (OSE) and ovarian epithelial cancer (OEC) cells is associated with the development and progression of ovarian cancer. Exposure to excess gonadotropins and leptin, related to menopause or infertility therapy and obesity, respectively, has been implicated as a risk factor for ovarian cancer. However, the molecular mechanism underlying the response to gonadotropins is not clearly understood, and nothing is known about the role of leptin in either normal OSE or its malignant counterpart. In the present study, we hypothesized that: overexpression of the FSH receptor (FSHR) affects particular oncogenic pathways in OSE cells and treatment with FSH and/or LH alters cell proliferation and metastasis, respectively, by interacting with growth factor and/or other hormone systems, and regulating proteolysis. Whether leptin plays a proliferative role in ovarian cancer cells was also investigated. Furthermore, we examined the relevant intracellular signal transduction pathways mediating the actions of gonadotropins and leptin which may be important in the development and progression of ovarian cancer. The FSHR overexpressing-80PCF cell line showed increased levels of EGFR, HER-2/neu and c-Myc, as well as a constitutive activation of ERK1/2. The growth inhibitory effect of GnRH I/II was blocked by pretreatment with FSH or LH. Treatment of pre-neoplastic IOSE-80PC cells with gonadotropins resulted in a significant increase of EGFR mRNA and EGFR protein levels via ERK1/2 and phosphatidyi-inositol-3-kinase (PI3K) activation. Both FSH and LH induced a significant synergistic stimulation of mitogenesis in the presence of EGF. In parallel experiments on metastasis, treatment with FSH or LH significantly increased the invasion of ovarian cancer cells including BG-1, CaOV-3 and SKOV-3 cells. Treatment of SKOV-3 cells with FSH or LH enhanced net MMP/TIMP balance and proteolysis potential. With regard to leptin, treatment with leptin significantly stimulated the growth of estrogen-sensitive BG-1 cells via a ligand-independent ERα pathway. Taken together, these findings strongly support a regulatory role of gonadotropins and leptin in both normal and neoplastic OSE cells.

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