Hormonal regulation and distinct functions of semaphorin-3B and semaphorin-3F in ovarian cancer.
Semaphorins comprise a family of molecules that influence neuronal growth and guidance. Class-3 semaphorins, semaphorin-3B (SEMA3B) and semaphorin-3F (SEMA3F), illustrate their effects by forming a complex with neuropilins (NP-1 or NP-2) and plexins. We examined the status and regulation of semaphorins and their receptors in human ovarian cancer cells. A significantly reduced expression of SEMA3B (83 kDa), SEMA3F (90 kDa), and plexin-A3 was observed in ovarian cancer cell lines when compared with normal human ovarian surface epithelial cells. The expression of NP-1, NP-2, and plexin-A1 was not altered in human ovarian surface epithelial and ovarian cancer cells. The decreased expression of SEMA3B, SEMA3F, and plexin-A3 was confirmed in stage 3 ovarian tumors. The treatment of ovarian cancer cells with luteinizing hormone, follicle-stimulating hormone, and estrogen induced a significant upregulation of SEMA3B, whereas SEMA3F was upregulated only by estrogen. Cotreatment of cell lines with a hormone and its specific antagonist blocked the effect of the hormone. Ectopic expression of SEMA3B or SEMA3F reduced soft-agar colony formation, adhesion, and cell invasion of ovarian cancer cell cultures. Forced expression of SEMA3B, but not SEMA3F, inhibited viability of ovarian cancer cells. Overexpression of SEMA3B and SEMA3F reduced focal adhesion kinase phosphorylation and matrix metalloproteinase-2 and matrix metalloproteinase-9 expression in ovarian cancer cells. Forced expression of SEMA3F, but not SEMA3B in ovarian cancer cells, significantly inhibited endothelial cell tube formation. Collectively, our results suggest that the loss of SEMA3 expression could be a hallmark of cancer progression. Furthermore, gonadotropin- and/or estrogen-mediated maintenance of SEMA3 expression could control ovarian cancer angiogenesis and metastasis.
Joseph
Doina
D
Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814-4799, USA.
Ho
Shuk-Mei
SM
Syed
Viqar
V
D045744:Cell Line, Tumor; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D004967:Estrogens / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D039921:Neuropilins / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000378:metabolism*; D010053:Ovary / Q000378:metabolism; D039961:Semaphorins / Q000378:metabolism*
D004967:Estrogens; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D039921:Neuropilins; C409766:SEMA3B protein, human; C491230:SEMA3F protein, human; D039961:Semaphorins