Deficiency of Erbin induces resistance of cervical cancer cells to anoikis in a STAT3-dependent manner

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.

Erbin loss promotes cancer cell proliferation through feedback activation of Akt-Skp2-p27 signaling

“…Erbin dysregulation has previously been reported in cervical tumors, colon carcinomas and breast carcinomas [12,13,20]. Here, we provide evidence to support the mechanistic connection between Erbin loss and aberrant Skp2-p27 axis, which coordinately drives cancer cells to uncontrolledly proliferate through cell cycle regulation.…”

“…As our previous study shows that Erbin is significantly downregulated in cervical cancer tissues [12], we sought to determine whether Erbin, like another LAP family member scribble, is involved in signal transduction to negatively regulate cell proliferation. We first used two independent siRNAs to silence the expression of Erbin in human cervical carcinoma cell line HeLa and then examined the effect of Erbin deficiency on cell proliferation by monitoring ATP levels using the ATPLite assay.…”

“…Accordingly, Erbin is clearly implicated in regulating many aspects of biological behaviors of cancer cells such as cellular proliferation, apoptosis and inflammatory response. A recent study form our group demonstrated that Erbin is significantly decreased or lost in cervical cancer tissues and loss of Erbin endows cervical cancer with resistance to anoikis by inhibiting STAT3 signaling [12]. Of note is that other group recently found that Erbin plays a positive role in ErbB2-dependent breast tumor growth [13].…”

Acquisition of resistance to trastuzumab in gastric cancer cells is associated with activation of IL-6/STAT3/Jagged-1/Notch positive feedback loop

“…NCI-N87 and NCI-N87-R cells were cultured in the plates coated with PolyHEMA (Sigma) to avoid the adhesion of cells as described previously [56]. After incubation for 72 h, the cells were harvested and cell apoptosis was measured using Annexin V-fluorescein isothiocyanate (FITC) detection kit (Calbiochem).…”

Involvement of MicroRNA-296 in the Inhibitory Effect of Epigallocatechin Gallate against the Migratory Properties of Anoikis-Resistant Nasopharyngeal Carcinoma Cells

“…The detrimental effect of EGCG on the phosphorylation of STAT3 has been described in hepatocellular carcinoma cell lines and colorectal carcinoma [44,45]. Furthermore, an increasing number of studies suggest that STAT3 plays a crucial role in the regulation of anoikis resistance and invasion of cancer cells [46][47][48]. Based on our previous findings, we investigated whether the NPC AR cells were more invasive than parental cells and whether the NPC AR cells exhibited significantly higher expression of STAT3 with enhanced downstream gene expression than the parental cells [18].…”