Loss Of Erbin Induces Resistance Of Cervical Cancer Cells To Anoikis

Objective:Epithelial cell polarization and integration are essential to their function and loss of epithelial polarity and tissue architecture correlates with the development of aggressive tumors. Erbin is a basolateral membrane-associated protein. The roles of Erbin in establishing cell polarization and regulating cell adhesion have been suggested. Erbin is also a negative regulator in Ras-Raf-ERK signaling pathway. However, the potential functions of Erbin in human cancer are basically unknown.Methods:When HeLa cells transfected with Erbin siRNA or control siRNA were cultured in the plates coated with PolyHEMA, they grew predominantly as a single-cell suspension and underwent anoikis. After incubation for different time periods, the cells were harvested and cell apoptosis was measured by flow cytometry. The effect of Erbin deletion on the expression of different signaling pathways and phosphorylation was analyzed by Western blot. The STAT3promoter activity was examined by luciferase assays. Using Immunohist-ochemical staining, Erbin expression was observed in human cervical cancer tissues.Results:In the present study, we show for the first time that loss of Erbin endows cervical cancer cells with resistance to anoikis both in vitro and in vivo and promotes the growth and metastasis of human cervical cancer xenografts in nude mice. We found that knockdown of Erbin induced the phosphorylation, nuclear translocation and transcriptional activities of STAT3in cervical cancer cells. Overexpression of STAT3C or induction of endogenous STAT3activation by IL-6evidently inhibited anoikis of cervical cancer cells, whereas WP1066, a potent inhibitor of Jak2/STAT3effectively blocked the effect of Erbin knockdown on cell survival under anchorage-independent conditions, indicating that loss of Erbin confers resistance of cervical cancer cells to anoikis in a STAT3-dependent manner. Interestingly, IL-6induced STAT3activation and Erbin expression simultaneously. Overexpression of STAT3C also significantly upregulated the level of Erbin, whereas the Jak2inhibitor AG490remarkably blocked not only STAT3phosphorylation but also IL-6-induced Erbin expression. Knockdown of Erbin augmented the effects of IL-6on STAT3activation and anoikis resistance. In addition, by immunohistochemical analysis of Erbin expression, we demonstrate that the expression of Erbin is significantly decreased or even lost in cervical cancer tissues.Conclusions:These data reveals that Erbin is a novel negative regulator of STAT3and the IL-6/STAT3/Erbin loop plays a crucial role in cervical cancer progression and metastasis. Picture51,References46.