The Role Of Gonadotropins And Cytokines In Develepment Of Ovarian Epithelial Carcinoma

Objective: To investigate the role of gonadotropins and cytokines in the develepment of epithelial ovarian carcinoma.Methods: Ten normal ovaries, thirty benign ovarian tumors, thirty-two epithelial ovarian carcinoma were examined for follicle-stimulating hormone receptor (FSHR) expression by using reverse transcription polymerase reaction (RT-PCR) and western blot .Two epithelial ovarian carcinoma cell lines (OVCAR-3,Caov-3) were culture with follicle-stimulating hormone(FSH) or luteinizing hormone (LH) or human recombinant interleukin-6 (hrIL-6). The degree of proliferation of two cell lines was determined by MTT. Expression of nuclear transcription-kB (NF-kB) mRNA and protein in all cells were determined by RT-PCR and ELISA. ELISA was used to measure the expression levels of MMP-2, MMP-9,TIMP-1 and TMMP-2 in the supernatant of ovarian carcinoma cell. MTS incorporation was employed to determine the proliferation of ovarian carcinoma cells after treatment by vehicle, rhMMP-2 or anti-MMP-2 antibody.Results: Positive FSHR mRNA expression by RT-PCR was found in 100% of normal ovaries, 97.6% (29/30) of benign ovarian tumors, 59.4 % (19/32) of epithelial ovarian carcinoma. Western blot gave similar, but somewhat less sensitive, results. A dose-response effect was seen with FSH, LH and human recombinant interleukin-6 in two epithelial ovarian carcinoma cell lines and the levels of NF-kB mRNA and protein in cytoplasm and nucleus were increasedsignificantly with FSH, LH and hrIL-6 for a period of 96 hours than the group of control. Most significantly, for all cell lines, IL-6-neutralizing antibodies partially inhibited hormones-stimulated cell proliferation but completely inhibited hrIL-6 enhanced cell proliferation. Levels of nuclear factor-kB (NF-kB) mRNAand protein increased in all cells treated with FSH, LH hrIL-6 was blocked by IL-6-neutralizing antibodies. MMP-2, MMP-9, TIMP-9 and TIMP-2 were expression in in the ovarian carcinoma cells. Different concentration of rhMMP-2 could enhance cell proliferation of the ovarian carcinoma to different degrees and anti-MMP-2 antibody could inhibit the proliferation. Conclusions: Elevated serum gonadotropin is one of factors contributing significantly to the development of epithelial ovarian carcinoma. However gonadotropins and cytokines are responsible for prognosis of the ovarian carcinoma as soon as it exists.