Ovarian Epithelial Tumor Growth Promotion by Follicle-Stimulating Hormone and Inhibition of the Effect by Luteinizing Hormone

Zheng, Wenxin; Lu, Jean; Luo, Feng; Zheng, Yu; Feng, Yongzeng; Felix, Janine F.; Lauchlan, Stuart C.; Pike, Malcolm C.

doi:10.1006/gyno.1999.5628

Cited by 131 publications

(113 citation statements)

References 28 publications

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“…Similar to the previous reports, 3,7,14,15 we showed a significant increase in cell proliferation by FSH treatment on human OSE cell lines, all proven to express FSHR, in dose-and time-dependent manner. Several mechanisms were discussed by other investigators for the FSH stimulated cell proliferation, such as mitogen-activated protein kinase (MAPK) cascade 15 and extracellular-regulated kinase (ERK1 and ERK2) cascade.…”

Section: Discussionsupporting

confidence: 91%

“…[2][3][4][5][6] It has been reported that FSH treatment stimulates cell proliferation on normal human OSE cells, immortalized OSE cells and OC cell lines. 7,8 However, little has been known on the effects of FSH in the process of tumorigenesis and growth stimulation on human OSE at molecular levels.In this study, we first determined FSHR expression levels quantitatively in human ovarian normal and neoplastic tissues. Then the effects of FSH treatment on cell proliferation were examined using human OSE cell lines as well as Chinese hamster ovary (CHO) cell lines permanently transfected with human FSHR.…”

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confidence: 99%

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confidence: 99%

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Follicle stimulating hormone‐induced growth promotion and gene expression profiles on ovarian surface epithelial cells

Liu

Chen

et al. 2004

Intl Journal of Cancer

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Ovarian cancer (OC) is one of the leading causes of death in patients with gynecologic malignancies. The vast majority of ovarian cancers have a cell origin of ovarian surface epithelium (OSE), which is derived from Mullerian epithelium covering embryonic gonads. Since the incidence of OC sharply increases after menopause, critical roles of gonadotropins and their receptors in ovarian carcinogenesis are speculated by investigators. 1 Follicle stimulating hormone (FSH), through interaction with its specific receptor, FSHR, plays an essential role in mammalian reproduction and ovarian folliculogenesis. 2 Binding of FSH to FSHR results in adenylyl cyclase activation leading to cAMP synthesis, associated with intracellular rise of Ca 2ϩ , activation of protein kinase A (PKA) and other downstream signal transduction pathways. [2][3][4][5][6] It has been reported that FSH treatment stimulates cell proliferation on normal human OSE cells, immortalized OSE cells and OC cell lines. 7,8 However, little has been known on the effects of FSH in the process of tumorigenesis and growth stimulation on human OSE at molecular levels.In this study, we first determined FSHR expression levels quantitatively in human ovarian normal and neoplastic tissues. Then the effects of FSH treatment on cell proliferation were examined using human OSE cell lines as well as Chinese hamster ovary (CHO) cell lines permanently transfected with human FSHR. Finally, gene expression profiles for FSH treatment were analyzed by cDNA MicroArray using a selected human OSE cell line that has best growth response to FSH treatment from cell proliferation assays. MATERIAL AND METHODS

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Section: Discussionsupporting

confidence: 91%

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confidence: 99%

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Follicle stimulating hormone‐induced growth promotion and gene expression profiles on ovarian surface epithelial cells

Liu

Chen

et al. 2004

Intl Journal of Cancer

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“…The effects of LH or the LHR receptor agonist CG on ovarian cancer cell proliferation are controversial and have been reported to be stimulatory (12,31) as well as suppressive (11,32). We obtained 7-day growth curves for SLHR1 and SMOCK2 cells in the presence or absence of 16.7 nmol/L LH ( Fig.…”

Section: Lhr Associated With Reduced Invasion Migration and Prolifementioning

confidence: 99%

Luteinizing Hormone–Induced Up-Regulation of ErbB-2 Is Insufficient Stimulant of Growth and Invasion in Ovarian Cancer Cells

Warrenfeltz

Lott

Palmer

et al. 2008

Molecular Cancer Research

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The effects of luteinizing hormone (LH), a gonadotropic hormone implicated in the development of ovarian cancer, are mediated by specific binding to its G protein -coupled receptor, the LH receptor (LHR). Activated LHR initiates second messenger responses, including cyclic AMP (cAMP) and inositol phosphate. Because cAMP increases expression of ErbB-2, a receptor tyrosine kinase whose overexpression in cancers correlates with poor survival, we hypothesized that LH may regulate ErbB-2 expression. Cell surface LHR expression in stable transformants of the ErbB-2 -overexpressing ovarian cancer cell line SKOV3 was confirmed by PCR and whole-cell ligand binding studies. Second messenger accumulation in the LHR-expressing cells confirmed signaling through Gs and Gq. Western blots of total protein revealed that LHR introduction up-regulated ErbB-2 protein expression 2-fold and this was further up-regulated in a time-and dose-dependent manner in response to LH. Forskolin and 8Br-cAMP also up-regulated ErbB-2 in both LHR-expressing and mock-transfected cells, indicating that regulation of ErbB-2 is a cAMP-mediated event. Kinase inhibitor studies indicated the involvement of protein kinase A -mediated, protein kinase C -mediated, epidermal growth factor receptor -mediated, and ErbB-2 -mediated mechanisms. The LH-induced up-regulation of ErbB-2 was insufficient to overcome the negative effects of LH on proliferation, invasion, and migration. A molecular signature for this nonaggressive phenotype was determined by Taqman array to include increased and decreased expression of genes encoding adhesion proteins and metalloproteinases, respectively. These data establish a role for LH and LHR in the regulation of ErbB-2 expression and suggest that, in some systems, ErbB-2 up-regulation alone is insufficient in producing a more aggressive phenotype.

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“…Additionally, reduced risk for ovarian cancer is associated with multiple pregnancies, breast-feeding, oral contraceptives, and estrogen replacement therapy, which are related to lower levels of and reduced exposure to FSH and LH [19,20]. The FSH receptor (FSHR) and LH receptor (LHR) have been shown in normal and neoplastic ovarian surface epithelium (OSE) cells [21,22]. Moreover, levels of ovarian and peritoneal FSH and LH seem to be elevated in ovarian cancer patients [23,24].…”

Section: Introductionmentioning

confidence: 99%

Activation of the PI3K/AKT pathway mediates FSH-stimulated VEGF expression in ovarian serous cystadenocarcinoma

et al. 2008

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There is evidence to suggest that follicle-stimulating hormone (FSH) can facilitate the neovascularization of ovarian cancers by increasing vascular endothelial growth factor (VEGF) expression in cancer cells, although the underlying molecular mechanism of this process is not well known. Therefore, we investigated the effect of FSH on VEGF expression in the ovarian cancer cell lines SKOV-3 and ES-2. Treatment with FSH significantly increased VEGF expression in a dose-and time-dependent manner. In addition, FSH treatment enhanced the expression of survivin and hypoxiainducible factor-1 (HIF-1α). Knockdown of survivin or HIF-1α suppressed VEGF expression, but only knockdown of survivin inhibited FSH-stimulated VEGF expression. Pretreatment with LY294002, a phosphoinositide 3-kinase (PI3K)/AKT inhibitor, neutralized the enhanced expression of survivin induced by FSH, but treatment with U0126, a mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor, had no such effect. We further showed that ovarian serous cystadenocarcinoma samples had much higher incidence of positive AKT and phosphorylated AKT (pAKT) protein staining than did benign ovarian cystadenoma samples (p < 0.01). The 5-year survival rate was only about 15% in patients with ovarian serous cystadenocarcinoma who had AKT and pAKT expression, whereas it was about 80% in those who did not have AKT or pAKT expression. Taken together, these results indicate that FSH increases the expression of VEGF by upregulating the expression of survivin, which is activated by the PI3K/AKT signaling pathway. Understanding the role of the PI3K/AKT pathway in FSH-stimulated expression of survivin and VEGF will be beneficial for evaluating the prognosis for patients with ovarian serous cystadenocarcinoma and for pursuing effective treatment against this disease.

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Ovarian Epithelial Tumor Growth Promotion by Follicle-Stimulating Hormone and Inhibition of the Effect by Luteinizing Hormone

Cited by 131 publications

References 28 publications

Follicle stimulating hormone‐induced growth promotion and gene expression profiles on ovarian surface epithelial cells

Follicle stimulating hormone‐induced growth promotion and gene expression profiles on ovarian surface epithelial cells

Luteinizing Hormone–Induced Up-Regulation of ErbB-2 Is Insufficient Stimulant of Growth and Invasion in Ovarian Cancer Cells

Activation of the PI3K/AKT pathway mediates FSH-stimulated VEGF expression in ovarian serous cystadenocarcinoma

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