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首页> 外文期刊>Oncogene >Calreticulin promotes cell motility and enhances resistance to anoikis through STAT3|[ndash]|CTTN|[ndash]|Akt pathway in esophageal squamous cell carcinoma
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Calreticulin promotes cell motility and enhances resistance to anoikis through STAT3|[ndash]|CTTN|[ndash]|Akt pathway in esophageal squamous cell carcinoma

机译：钙网蛋白通过STAT3 | nb | CTTN | nb || Akt通路促进食管鳞状细胞癌的细胞运动并增强对厌食症的抵抗力

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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.
机译：先前我们已经表明，钙网蛋白（CRT）的过表达导致食管鳞状细胞癌（ESCC）患者的预后不良。在这里，我们已经显示出CRT在肿瘤发生中的重要作用，它通过增强细胞运动性和抗神经过敏性发挥作用。 siRNA介导的CRT敲低导致细胞迁移，侵袭和对阳极的抵抗力受损。值得注意的是，CRT的下调降低了Cortactin（CTTN）的表达，以前已经报道过它是通过PI3K–Akt途径与神经过敏相关的候选致癌基因。此外，CRT下调后Akt磷酸化被取消，而CRT上调可重新激活Akt，这表明CRT通过CRT–CTTN–PI3K–Akt途径增强了细胞对阳极的抵抗力。此外，CRT–siRNA细胞中CTTN mRNA水平降低，并伴有STAT3失活。与JAK特异性抑制剂AG490孵育后，肿瘤细胞中CTTN和p-STAT3的表达均降低。染色质免疫沉淀试验表明，p-STAT3与CTTN启动子中保守的STAT3结合序列直接结合。此外，在CRT下调的ESCC细胞中CTTN的过表达恢复了其运动能力和对缺氧的抵抗力。这项研究不仅揭示了CRT在ESCC细胞的运动促进和厌食症抵抗中的作用，而且还确定了CRT是CRT–STAT3–CTTN–Akt途径中的上游调节剂。

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