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HOXA10

Homeobox genes encode transcription factors that control cell differentiation and play essential roles in developmental patterning. Increasing evidence indicates that many homeobox genes are aberrantly expressed in cancers, and that their deregulation significantly contributes to tumor progression. The homeobox gene HOXA10 controls uterine organogenesis during embryonic development and functional endometrial differentiation in the adult. We investigated whether HOXA10 expression is deregulated in endometrial carcinomas, and how counteracting this aberrant expression modifies tumor behavior. We found that down-regulation of HOXA10 expression in endometrial carcinomas strongly correlates with increased tumor grade and is associated with methylation of the HOXA10 promoter. Enforced expression of HOXA10 in endometrial carcinoma cells inhibited invasive behavior in vitro and tumor dissemination in nude mice. The inhibitory effect of HOXA10 on invasive behavior was attributable at least in part to the ability of HOXA10 to induce expression of the epithelial cell adhesion molecule E-cadherin by down-regulating expression of Snail, a repressor of E-cadherin gene transcription. These findings reveal a novel role for HOXA10 deregulation in the progression of endometrial carcinoma by promoting epithelial-mesenchymal transition.

epithelial ovarian cancer (EOC) is the sixth most common cancer in females worldwide and, although advances have been made in the detection, diagnosis and therapies for EOC, it remains the most lethal gynecologic malignancy in advanced countries. Nevertheless, relatively little is known concerning the molecular events that lead to the development of this highly aggressive disease. Elucidating the molecular mechanism involved in this disease may prove useful to understand the pathogenesis and progression of the disease, and to identify new targets for effective therapies. In the present study, we examined the role of ARK5 in ovarian cancer and normal matched tissues using western blot analysis and migration and invasion, and woundhealing assays. The results showed that ARK5 was upregulated in ovarian cancer tissues, compared with adjacent normal tissues. Moreover, it promoted epithelialmesenchymal transition (EMT) and inhibited miR-1181 expression in ovarian cancer cells. Subsequent investigations showed that miR-1181 promoted mesenchymal-epithelial transition (MET) in ovarian cancer cells. Downstream target genes of miR-1181 were searched, and it was identified that miR-1181 degraded HOXA10 by targeting its 3' untranslated region (3'UTR) in ovarian cancer cells. The results confirmed that HOXA10 promoted EMT in ovarian cancer cells. Thus, activation of the ARK5/miR-1181/HOXA10 axis may be positively associated with EMT in ovarian cancer.