Department of Pathophysiology, Institute of Basic Medical Sciences, Beijing, People's Republic of China.
Oncogenesis. 2013 Jun 17;2(6):e52. doi: 10.1038/oncsis.2013.18.
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.
上皮细胞极化和整合对于其功能至关重要，而上皮极性的丧失和组织架构的破坏与侵袭性肿瘤的发生发展相关。Erbin 是一种基底外侧膜相关蛋白。已经提出 Erbin 在建立细胞极化和调节细胞黏附方面的作用。Erbin 也是 Ras-Raf-ERK（细胞外信号调节激酶）信号通路的负调节剂。然而，Erbin 在人类癌症中的潜在功能基本上是未知的。在本研究中，我们首次表明，Erbin 的缺失使宫颈癌细胞在体外和体内均对失巢凋亡产生抗性，并促进裸鼠体内人宫颈癌异种移植物的生长和转移。我们发现，Erbin 的敲低诱导宫颈癌细胞中信号转导和转录激活因子 3（STAT3）的磷酸化、核转位和转录活性。STAT3C 的过表达或白细胞介素（IL）-6 诱导内源性 STAT3 的激活明显抑制了宫颈癌细胞的失巢凋亡，而 Janus 激活激酶 2（Jak2）/STAT3 的有效抑制剂 WP1066 有效地阻断了 Erbin 敲低在无锚定条件下对细胞存活的影响，表明 Erbin 的缺失以 STAT3 依赖的方式赋予宫颈癌细胞对失巢凋亡的抗性。有趣的是，IL-6 同时诱导 STAT3 的激活和 Erbin 的表达。STAT3C 的过表达也显著上调 Erbin 的水平，而 Jak2 抑制剂 AG490 不仅显著阻断 STAT3 的磷酸化，而且阻断 IL-6 诱导的 Erbin 表达。Erbin 的敲低增强了 IL-6 对 STAT3 激活和失巢凋亡抗性的影响。此外，通过对 Erbin 表达的免疫组织化学分析，我们证明 Erbin 在宫颈癌组织中的表达显著降低甚至缺失。这些数据表明 Erbin 是 STAT3 的一种新型负调节剂，IL-6/STAT3/Erbin 环路在宫颈癌的进展和转移中具有关键作用。
