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

Oncogene. 2009 Oct 22;28(42):3714-22. doi: 10.1038/onc.2009.237. Epub 2009 Aug 17.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Agar
  • Animals
  • Anoikis*
  • Calreticulin / deficiency
  • Calreticulin / genetics
  • Calreticulin / metabolism*
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / pathology*
  • Cell Line, Tumor
  • Cell Movement*
  • Cortactin / genetics
  • Cortactin / metabolism*
  • Down-Regulation
  • Esophageal Neoplasms / genetics
  • Esophageal Neoplasms / pathology*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Mice
  • Mice, Nude
  • Promoter Regions, Genetic / genetics
  • Proto-Oncogene Proteins c-akt / metabolism*
  • RNA Interference
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction
  • Transcription, Genetic


  • CTTN protein, human
  • Calreticulin
  • Cortactin
  • STAT3 Transcription Factor
  • Agar
  • Proto-Oncogene Proteins c-akt