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Expression and function of HOXA genes in the normal ovary and ovarian carcinoma Ota, Takayo


Homeobox genes, which code for families of transcription factors, act at the top of genetic hierarchies. HOX genes specify positional identity during development, and in adult tissues, regulate differentiation and proliferation. Most ovarian carcinomas are derived from the ovarian surface epithelium (OSE). In contrast to other carcinomas, OSE differentiates further with neoplastic progression and acquires Mtillerian duct-derived epithelial properties. I tested the hypothesis that growth and differentiation in ovarian carcinogenesis are regulated by HOX genes. I studied three genes: HOXA4, A7 and A9. HOXA7 has been reported to play a role in the differentiation of ovarian cancers, while HOXA9 is expressed in normal oviductal epithelium which resembles ovarian serous adenocarcinomas. Furthermore, microarray studies showed that HOXA4 and HOXA7, but not HOXA9, were highly expressed in ovarian carcinomas. In this study, I produced a well-characterized polyclonal anti-HOXA7 antibody and investigated its distribution in ovarian carcinomas. HOXA7 expression was not related to grade. HOXA7 was expressed mainly in the cytoplasm, however, nuclear staining correlated with prognosis, suggesting that HOXA7 in different subcellular locations has different functions. HOXA4 expression in normal OSE was not consistently related to proliferation but increased at low cell density, low [Ca ] and with EGF stimulation, and HOXA4 siRNA enhanced motility. In ovarian cancer cultures, HOXA4 siRNA enhanced motility, increased proliferation in three-dimensional cultures and reduced CA125 secretion. These results imply that HOXA4 regulates differentiation and cell-cell interrelationships, and that increased HOXA4 expression may reflect a response to maintain homeostasis during neoplastic progression. The study was expanded to investigate HOXA7 distribution in human ovarian folliculogenesis. Granulosa cells were negative in primordial, but positive in primary follicles. As they matured, HOXA7 relocated to the cytoplasm. HOXA7 expression in granulosa cells increased with proliferation, and in culture it was regulated by GDF-9. These results indicate that, in folliculogenesis, HOXA7 expression undergoes cell typeand stage-specific changes, which are regulated, in part, by GDF-9. In summary, HOX genes contribute to the development of ovarian follicles and carcinomas. Controlling HOX genes may be one of the critical methods to overcome diseases associated with ovarian folliculogenesis and carcinogenesis.

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