Calreticulin promotes cell motility and enhances resistance to anoikis through STAT3-CTTN-Akt pathway in esophageal squamous cell carcinoma
Calreticulin promotes cell motility and enhances resistance to anoikis through STAT3-CTTN-Akt pathway in esophageal squamous cell carcinoma
复制标题
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
DOI：
10.1038/onc.2009.237
复制
发表时间：
2009-10-22
期刊：
影响因子：
8
通讯作者：
Wang, M-R
中科院分区：
文献类型：
--
作者：
Du, X-L;Yang, H.;Wang, M-R
我们早先已经发现钙网蛋白（CRT）的过度表达导致食管鳞状细胞癌（ESCC）患者预后不良。在这里，我们已经显示了CRT在肿瘤发生中的重要作用，通过增强细胞运动性和抗失巢凋亡。siRNA介导的CRT敲低导致细胞迁移、侵袭和抗失巢凋亡受损。值得注意的是，CRT下调降低了Corpus n（CTTN）的表达，CTTN先前已被报道为通过PI 3 K-Akt途径与失巢凋亡相关的候选癌基因。此外，CRT下调后Akt磷酸化被消除，CRT上调可恢复其激活，表明CRT通过CRT-CTTN-PI 3 K-Akt途径增强细胞对失巢凋亡的抵抗。此外，CTTN mRNA水平在CRT-siRNA细胞中降低，与STAT 3的失活偶联。在与JAK特异性抑制剂AG 490孵育后，肿瘤细胞中CTTN和p-STAT 3的表达均降低。染色质免疫沉淀实验显示p-STAT 3与CTTN启动子中保守的STAT 3结合序列直接结合。此外，CTTN在CRT下调的ESCC细胞中的过表达恢复了其运动性和抗失巢凋亡。本研究不仅揭示了CRT在ESCC细胞运动促进和抗失巢凋亡中的作用，而且确定CRT是CRT-STAT 3-CTTN Akt通路的上游调节剂。Oncogene（2009）28，3714-3722; doi：10.1038/onc.2009.237; 2009年8月17日在线发表
We have shown earlier that overexpression of Calreticulin (CRT) contributed to a poor prognosis for patients with esophageal squamous cell carcinoma (ESCC). Here, we have shown an important role of CRT in tumorigenesis through enhancing cell motility and anoikis resistance. SiRNA-mediated knockdown of CRT caused impaired cell migration, invasion and resistance to anoikis. Notably, CRT downregulation decreased the expression of Cortactin (CTTN), which has been previously reported as a candidate oncogene associated with anoikis through the PI3K-Akt pathway. In addition, Akt phosphorylation was abolished after CRT downregulation and its activation can be refreshed by CRT upregulation, suggesting that CRT-enhanced cell resistance to anoikis through the CRT-CTTN-PI3K-Akt pathway. Moreover, the CTTN mRNA level was decreased in CRT-siRNA cells, coupled with the inactivation of STAT3. Expression of both CTTN and p-STAT3 was reduced in tumor cells following incubation with the JAK-specific inhibitor, AG490. Chromatin immunoprecipitation assay showed direct binding of p-STAT3 to the conservative STAT3-binding sequences in CTTN promoter. Furthermore, overexpression of CTTN in CRT-downregulated ESCC cells restored its motility and resistance to anoikis. This study not only reveals a role of CRT in motility promotion and anoikis resistance in ESCC cells, but also identifies CRT as an upstream regulator in the CRT-STAT3-CTTN Akt pathway. Oncogene (2009) 28, 3714-3722; doi: 10.1038/onc.2009.237; published online 17 August 2009