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Calreticulin promotes cell motility and enhances resistance to anoikis through STAT3–CTTN–Akt pathway in esophageal squamous cell carcinoma

Oncogene volume 28, pages 3714–3722 (2009)Cite this article

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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Authors and Affiliations

  1. State Key Laboratory of Molecular Oncology, Cancer Institute (Hospital), Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China

    X-L Du, H Yang, S-G Liu, M-L Luo, J-J Hao, Y Zhang, D-C Lin, X Xu, Y Cai, Q-M Zhan & M-R Wang

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  1. X-L Du
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Correspondence to M-R Wang.

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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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