3675

ITGA3

epithelial-mesenchymal transition (EMT) is a crucial event in wound healing, tissue repair, and cancer progression in adult tissues. Transforming growth factor (TGF)-beta induces EMT in mouse epithelial cells. During prolonged treatment, TGF-beta successively induces myofibroblastic differentiation with increased expression of myofibroblast marker proteins, including smooth muscle alpha actin and calponin. We recently showed that fibroblast growth factor-2 prevented myofibroblastic differentiation induced by TGF-beta, and transdifferentiated the cells to those with much more aggressive characteristics (enhanced EMT). To identify the molecular markers specifically expressed in cells undergoing enhanced EMT induced by the combination of TGF-beta and fibroblast growth factor-2, we carried out a microarray-based analysis and found that integrin alpha3 (ITGA3) and Ret were upregulated. Intriguingly, ITGA3 was also overexpressed in breast cancer cells with aggressive phenotypes and its expression was correlated with that of deltaEF-1, a key regulator of EMT. Moreover, the expression of both genes was downregulated by U0126, a MEK 1/2 inhibitor. Therefore, ITGA3 is a potential marker protein for cells undergoing enhanced EMT and for cancer cells with aggressive phenotypes, which is positively regulated by deltaEF-1 and the MEK-ERK pathway.CI - (c) 2013 Japanese cancer Association.

Human ovarian cancer is diagnosed in the late, metastatic stages but the underlying mechanisms remain poorly understood. We report a surprising functional link between CD151-alpha3beta1 integrin complexes and the malignancy of serous-type ovarian cancer. Analyses of clinical specimens indicate that CD151 expression is significantly reduced or diminished in 90% of metastatic lesions, while it remains detectable in 58% of primary tumors. These observations suggest a putative tumor-suppressing role of CD151 in ovarian cancer. Indeed, our analyses show that knocking down CD151 or alpha3 integrin enhances tumor cell proliferation, growth and ascites production in nude mice. These changes are accompanied by impaired cell-cell contacts and aberrant expression of E-cadherin, Mucin 5AC and fibronectin, largely reminiscent of an epithelial to mesenchymal transition (EMT)-like change. Importantly, Slug, a master regulator of EMT, is markedly elevated. Knocking down Slug partially restores CD151-alpha3beta1 integrin complex-dependent suppression of cell proliferation. Moreover, disruption of these adhesion protein complexes is accompanied by a concomitant activation of canonical Wnt signaling, including elevated levels of beta-catenin and Axin-2 as well as resistance to the inhibition in beta-catenin-dependent transcriptional complexes. Together, our study demonstrates that CD151-alpha3beta1 integrin complexes regulate ovarian tumor growth by repressing Slug-mediated EMT and Wnt signaling.