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The expression and invasion-suppressive function of HOXB4 in epithelial ovarian cancer Zhang, Xin


HOX genes are transcription factors which act as morphological regulators during development and in adult tissues. HOX paralogs often function cooperatively or synergistically in a specific tissue both in development and carcinogenesis. We have previously shown that HOXA4 enhances cell-cell adhesion and inhibits cell migration in epithelial ovarian cancer (EOC) cells. HOXB4, a close paralog of HOXA4, is more highly expressed in EOC cells than ovarian surface epithelium (OSE), a putative source of EOC. We therefore hypothesized that HOXB4 might have functions similar or complementary to those of HOXA4 in EOC. In our present study, we found variable expression levels of HOXB4 in EOC cell lines. Treatment with a DNA hypo-methylation reagent (5-Aza-dC) significantly induced HOXB4 expression in EOC cells. Functionally, neither siRNA-mediated down-regulation nor retroviral overexpression of HOXB4 affected EOC cell proliferation, as assessed by MTT and cell counting assays. Down-regulation of endogenous HOXB4 significantly enhanced trans-well Matrigel invasion of EOC cells and immortalized fallopian tube epithelial cells (OE-E6/E7), whereas forced-expression of HOXB4 suppressed EOC cell invasiveness. Gene expression microarray analysis indicated that expression of the extracellular matrix receptor CD44 was positively regulated by HOXB4, and down-regulation of CD44 reversed the suppression of cell invasion in HOXB4 over-expressing EOC cells. Immunohistochemical analysis of HOXB4 expression was performed on two ovarian carcinoma tissue microarrays. Strong nuclear immuno-reactivity for HOXB4 was detected in the fimbrial epithelium of fallopian tube, a putative source of high-grade serous carcinoma (HGSC), whereas negative staining was observed in OSE, more iii than 85% of HGSCs and all mucinous ovarian carcinomas in both arrays. Indeed, HOXB4 staining was significantly correlated with subtype (p<0.0001) in the Cheryl Brown Ovarian Cancer Outcomes Unit array (optimal representation of subtypes). Unexpectedly, we found borderline significant associations with FIGO stage (p=0.0685) and improved disease specific survival (p=0.0906) for HGSC in the Tumor Bank array (large HGSC cohort). Taken together, our immunohistochemical and in vitro studies suggest that promoter methylation may promote the loss of HOXB4, which functions as an inhibitor of cell invasiveness partially via CD44, thereby contributing HGSC progression or metastasis.

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