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 (
extracellular signal-regulated kinase) signaling pathway. However, the potential functions of Erbin in human
cancer are basically unknown. 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 signal transducer and activator of
transcription factor 3 (STAT3) in
cervical cancer cells. Overexpression of STAT3C or induction of endogenous STAT3 activation by
interleukin (IL)-6 evidently inhibited anoikis of
cervical cancer cells, whereas
WP1066, a potent inhibitor of Janus-activated
kinase 2 (Jak2)/STAT3, effectively 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-6 induced STAT3 activation and Erbin expression simultaneously. Overexpression of STAT3C also significantly upregulated the level of Erbin, whereas the Jak2 inhibitor
AG490 remarkably blocked not only STAT3 phosphorylation but also IL-6-induced Erbin expression. Knockdown of Erbin augmented the effects of
IL-6 on STAT3 activation 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. These data reveal that Erbin is a novel negative regulator of STAT3, and the IL-6/STAT3/Erbin loop has a crucial role in
cervical cancer progression and
metastasis.