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

Ji, Qing; Liu, Paul I.; Chen, Peter K.; Aoyama, Chisa

doi:10.1002/ijc.20478

Cited by 69 publications

(57 citation statements)

References 37 publications

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“…We have shown that gonadotropin-induced activation of ERK1/2 relies on both calcium-and PKCd-dependent mechanisms in two EOC cell lines representing the serous and clear cell subtypes. While other in vitro studies have shown that gonadotropins induce proliferation in normal and immortalised OSE cells, as well as in EOC cell lines (Wimalasena et al 1992, Parrott et al 2001, Syed et al 2001, Ji et al 2004, little is known about gonadotropin involvement in other aspects of ovarian tumourigenesis such as migration. We have shown that gonadotropin-induced ERK1/2 activation is required for EOC cell migration and proliferation, and that these effects are regulated by both calcium and PKCd.…”

Section: Discussionmentioning

confidence: 99%

“…Numerous studies have shown that FSH in particular has a proliferative effect on normal and malignant OSE cell growth (Wimalasena et al 1992, Parrott et al 2001, Syed et al 2001, Ji et al 2004. However, studies have shown conflicting effects of LH on the growth of benign and malignant OSE cells (Zheng et al 2000, Ivarsson et al 2001, Syed et al 2001.…”

Section: Introductionmentioning

confidence: 99%

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Gonadotropin-induced ovarian cancer cell migration and proliferation require extracellular signal-regulated kinase 1/2 activation regulated by calcium and protein kinase Cδ

Mertens‐Walker¹,

Bolitho²,

Baxter³

et al. 2010

Endocrine-Related Cancer

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The gonadotropin hypothesis proposes that elevated serum gonadotropin levels may increase the risk of epithelial ovarian cancer (EOC). We have studied the effect of treating EOC cell lines (OV207 and OVCAR-3) with FSH or LH. Both gonadotropins activated the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase 1/2 (ERK1/2) pathway and increased cell migration that was inhibited by the MAPK 1 inhibitor PD98059. Both extra-and intracellular calcium ion signalling were implicated in gonadotropin-induced ERK1/2 activation as treatment with either the calcium chelator EGTA or an inhibitor of intracellular calcium release, dantrolene, inhibited gonadotropin-induced ERK1/2 activation. Verapamil was also inhibitory, indicating that gonadotropins activate calcium influx via L-type voltage-dependent calcium channels. The cAMP/protein kinase A (PKA) pathway was not involved in the mediation of gonadotropin action in these cells as gonadotropins did not increase intracellular cAMP formation and inhibition of PKA did not affect gonadotropin-induced phosphorylation of ERK1/2. Activation of ERK1/2 was inhibited by the protein kinase C (PKC) inhibitor GF 109203X as well as by the PKCd inhibitor rottlerin, and downregulation of PKCd was inhibited by small interfering RNA (siRNA), highlighting the importance of PKCd in the gonadotropin signalling cascade. Furthermore, in addition to inhibition by PD98059, gonadotropin-induced ovarian cancer cell migration was also inhibited by verapamil, GF 109203X and rottlerin. Similarly, gonadotropin-induced proliferation was inhibited by PD98059, verapamil, GF 109203X and PKCd siRNA. Taken together, these results demonstrate that gonadotropins induce both ovarian cancer cell migration and proliferation by activation of ERK1/2 signalling in a calcium-and PKCd-dependent manner.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Gonadotropin-induced ovarian cancer cell migration and proliferation require extracellular signal-regulated kinase 1/2 activation regulated by calcium and protein kinase Cδ

Mertens‐Walker¹,

Bolitho²,

Baxter³

et al. 2010

Endocrine-Related Cancer

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“…Collectively, these studies demonstrated that FSH stimulates the growth of normal and immortalized ovarian surface epithelium (OSE) and ovarian cancer cell lines in a dose-and time-dependent manner (Feng et al 1996, Zheng et al 2000, Ji et al 2004. However, the exact role and mechanism that FSH plays in ovarian cancer development remain unclear.…”

Section: Discussionmentioning

confidence: 99%

FSH inhibits ovarian cancer cell apoptosis by up-regulating survivin and down-regulating PDCD6 and DR5

Huang

Jin

Liu

et al. 2010

Endocrine Related Cancer

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Ovarian epithelial cancer is the leading cause of death among gynecological malignancies. FSH may increase the risk of ovarian malignancy and play an important role in ovarian carcinogenesis. Our previous studies showed that FSH increases the expression of VEGF through survivin. In this study, the function and mechanism of FSH in ovarian cancer were further explored. We found that FSH promoted proliferation and prevented apoptosis of ovarian cancer cells by activating survivin through the SAPK/JNK and PI3K/AKT pathways. FSH also down-regulated the expression of programmed cell death gene 6 (PDCD6) and death receptor 5 (DR5), two molecules required for induction of apoptosis. RNA interference was applied to knock down survivin and PDCD6 expression, and we found that the blockage of survivin reversed the effects of FSH on apoptosis and proliferation, whereas knock down of PDCD6 enhanced these effects. The expression of DR5, cyclin D1, and cyclin E correlated with survivin expression, but PDCD6 did not. Using immunohistochemical staining, we further showed that ovarian serous cystadenocarcinoma samples had higher expression of survivin than did benign ovarian cystadenoma and borderline cystadenoma samples (P!0.01). Furthermore, survivin expression in the ovarian serous cystadenocarcinoma specimens was correlated with disease stage (P!0.05). Our results suggest that FSH promotes ovarian cancer development by regulating the expression of survivin, PDCD6, and DR5. Greater understanding of the molecular mechanisms of FSH in ovarian epithelial carcinogenesis and development will ultimately help in the development of a novel targeted therapy for ovarian cancer.

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“…3). Besides the observed effect on normal ovaries, FSH treatment is also reported to activate epithelial cell proliferation and oncogenesis in several human OSE immortalized normal, neoplastic (IOSE-29, IOSE-29E, and HOSE), and ovarian cancer cell lines (OVCAR-3 and OVCA) (Schiffenbauer et al 1997, Zheng et al 2000, Syed et al 2001, Choi et al 2004, Ji et al 2004, Abd-Elaziz et al 2005. Interestingly, this effect of FSH is associated with activation of MAPK/ERK rather than via the cAMP pathway (Choi et al 2002(Choi et al , 2005.…”

Section: R39mentioning

confidence: 96%

“…Several groups have reported FSHR in normal OSE (Table 2) as well as in cancerous tissues. Ji et al (2004) reported that FSHR mRNA was expressed in higher Table 2). The canonical FSHR1 comprises ten exons with the tenth exon being the largest.…”

Section: Ose Stem Cells and Fshmentioning

confidence: 98%

FSH–FSHR3–stem cells in ovary surface epithelium: basis for adult ovarian biology, failure, aging, and cancer

Bhartiya

Singh

2015

Reproduction

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Despite extensive research, genetic basis of premature ovarian failure (POF) and ovarian cancer still remains elusive. It is indeed paradoxical that scientists searched for mutations in FSH receptor (FSHR) expressed on granulosa cells, whereas more than 90% of cancers arise in ovary surface epithelium (OSE). Two distinct populations of stem cells including very small embryonic-like stem cells (VSELs) and ovarian stem cells (OSCs) exist in OSE, are responsible for neo-oogenesis and primordial follicle assembly in adult life, and are modulated by FSH via its alternatively spliced receptor variant FSHR3 (growth factor type 1 receptor acting via calcium signaling and the ERK/MAPK pathway). Any defect in FSH-FSHR3-stem cell interaction in OSE may affect folliculogenesis and thus result in POF. Ovarian aging is associated with a compromised microenvironment that does not support stem cell differentiation into oocytes and further folliculogenesis. FSH exerts a mitogenic effect on OSE and elevated FSH levels associated with advanced age may provide a continuous trigger for stem cells to proliferate resulting in cancer, thus supporting gonadotropin theory for ovarian cancer. Present review is an attempt to put adult ovarian biology, POF, aging, and cancer in the perspective of FSH-FSHR3-stem cell network that functions in OSE. This hypothesis is further supported by the recent understanding that: i) cancer is a stem cell disease and OSE is the niche for ovarian cancer stem cells; ii) ovarian OCT4-positive stem cells are regulated by FSH; and iii) OCT4 along with LIN28 and BMP4 are highly expressed in ovarian cancers.Reproduction (2015) 149 R35-R48

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

Cited by 69 publications

References 37 publications

Gonadotropin-induced ovarian cancer cell migration and proliferation require extracellular signal-regulated kinase 1/2 activation regulated by calcium and protein kinase Cδ

Gonadotropin-induced ovarian cancer cell migration and proliferation require extracellular signal-regulated kinase 1/2 activation regulated by calcium and protein kinase Cδ

FSH inhibits ovarian cancer cell apoptosis by up-regulating survivin and down-regulating PDCD6 and DR5

FSH–FSHR3–stem cells in ovary surface epithelium: basis for adult ovarian biology, failure, aging, and cancer

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