Abstract
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.
Highlights
Erbin is the founding member of the leucine-rich repeat and PDZ (PSD-95/DLG/ZO-1) domain (LAP) protein family.[1,2] The knownLAP protein family includes four mammalian proteins hScrib, Erbin, Densin-180 and Lano, one Drosophila melanogaster protein Scribble and one Caenorhabditis elegans protein LET-413.3–6 LAP proteins are generally localized at the basolateral membrane or associated with lateral junctions in polarized epithelial cells of worms, flies and humans
ISO stimulation induced a stronger activation of STAT3 in a time-dependent manner in HeLa/Erbinsh cells, compared with HeLa cells stably expressing control shRNA (HeLa/NC) cells
The data suggest that Erbin negatively regulates the STAT3 activation
Summary
LAP protein family includes four mammalian proteins hScrib, Erbin, Densin-180 and Lano, one Drosophila melanogaster protein Scribble and one Caenorhabditis elegans protein LET-413.3–6 LAP proteins are generally localized at the basolateral membrane or associated with lateral junctions in polarized epithelial cells of worms, flies and humans. The functions of LAP proteins in establishment of cell polarity and maintenance of epithelial cell integration have been discovered.[5,7,8] Mutation of LET-413 results in the absence of adherens junctions and disruption of epithelial integrity.[9] Similar characteristics are identified in Drosophila melanogaster Scribble mutant. Depletion of mammalian Scribble leads to the loss of intracellular adhesion and cell migratory directionality.[10] Erbin, a human homologue of LET-413, is localized basolaterally and proposed as a mediator of basolateral trafficking
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