Abstract
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.
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Acknowledgements
We thank Professor Simon J Harris for the English revision of the article. This study was supported by National Basic Research Program of China (2004CB518705), National High-tech R&D Program of China (2006AA02A403), National Key Technologies R&D Program of China (2006BAI02A14), Specialized Research Fund for the Doctoral Program of Higher Education of China (20060023003) and National Natural Science Foundation (30872936, 30721001).
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Du, XL., Yang, H., Liu, SG. et al. Calreticulin promotes cell motility and enhances resistance to anoikis through STAT3–CTTN–Akt pathway in esophageal squamous cell carcinoma. Oncogene 28, 3714–3722 (2009). https://doi.org/10.1038/onc.2009.237
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DOI: https://doi.org/10.1038/onc.2009.237
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