Deficiency of Erbin induces resistance of cervical cancer cells to anoikis in a STAT3-dependent manner.
Deficiency of Erbin induces resistance of cervical cancer cells to anoikis in a STAT3-dependent manner.
复制标题
Erbin 的缺乏会以 STAT3 依赖性方式诱导宫颈癌细胞对失巢凋亡的抵抗。
DOI：
10.1038/oncsis.2013.18
复制
发表时间：
2013-06-17
期刊：
影响因子：
6.2
通讯作者：
Guo, N.
中科院分区：
文献类型：
--
作者：
Hu, Y.;Chen, H.;Duan, C.;Liu, D.;Qian, L.;Yang, Z.;Guo, L.;Song, L.;Yu, M.;Hu, M.;Shi, M.;Guo, N.
上皮细胞极化和整合对其功能至关重要，上皮极性和组织结构的丧失与侵袭性肿瘤的发展相关。Erbin是一种基底外侧膜相关蛋白。Erbin在建立细胞极化和调节细胞粘附中的作用已被提出。Erbin也是Ras-Raf-ERK（细胞外信号调节激酶）信号通路的负调控因子。然而，Erbin在人类癌症中的潜在功能基本上未知。在本研究中，我们第一次发现，Erbin基因的缺失使宫颈癌细胞在体外和体内都具有抗失巢凋亡的能力，并促进了人宫颈癌裸鼠移植瘤的生长和转移。我们发现Erbin基因的敲低可诱导宫颈癌细胞中信号转导和转录激活因子3（STAT 3）的磷酸化、核转位和转录活性。过表达STAT 3C或通过白细胞介素（IL）-6诱导内源性STAT 3活化明显抑制宫颈癌细胞的失巢凋亡，而有效的Janus活化激酶2（Jak 2）/STAT 3抑制剂WP 1066有效地阻断Erbin敲低对锚定非依赖性条件下细胞存活的影响，这表明Erbin的缺失以STAT 3依赖性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STAT 3活化和Erbin表达。STAT 3C的过表达也显著上调Erbin的水平，而Jak 2抑制剂AG 490不仅显著阻断STAT 3磷酸化，而且显著阻断IL-6诱导的Erbin表达。Erbin的敲低增强了IL-6对STAT 3激活和抗失巢凋亡的作用。此外，通过免疫组织化学分析Erbin的表达，我们证明Erbin的表达在宫颈癌组织中显著降低甚至消失。这些数据表明，Erbin是一种新型的STAT 3负调控因子，IL-6/STAT 3/Erbin环在宫颈癌的进展和转移中起着至关重要的作用。
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.
登录
查看更多内容
影响因子：
4.8
作者：
Dai, PG;Xiong, WC;Mei, L
通讯作者：
Mei, L
影响因子：
2.1
作者：
Izawa, I;Nishizawa, M;Inagaki, M
通讯作者：
Inagaki, M
影响因子：
4.8
作者：
Huang, YZ;Zang, MW;Mei, L
通讯作者：
Mei, L
钙网蛋白通过 STAT3-CTTN-Akt 通路促进食管鳞癌细胞运动并增强失巢抵抗力
影响因子：
8
作者：
Du, X-L;Yang, H.;Wang, M-R
通讯作者：
Wang, M-R
影响因子：
5.3
作者：
Dai, Fangyan;Chang, Chenbei;Feng, Xin-Hua
通讯作者：
Feng, Xin-Hua