Nuclear factor of activated T-cell activity is associated with metastatic capacity in colon cancer

Manish K. Tripathi, Natasha G. Deane, Jing Zhu, Hanbing An, Shinji Mima, Xiaojing Wang, Sekhar Padmanabhan, Zhiao Shi, Naresh Prodduturi, Kristen K. Ciombor, Xi Chen, M. Kay Washington, Bing Zhang, R. Daniel Beauchamp

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Metastatic recurrence is the leading cause of cancer-related deaths in patients with colorectal carcinoma. To capture the molecular underpinnings for metastasis and tumor progression, we performed integrative network analysis on 11 independent human colorectal cancer gene expression datasets and applied expression data from an immunocompetent mouse model of metastasis as an additional filter for this biologic process. In silico analysis of one metastasis-related coexpression module predicted nuclear factor of activated T-cell (NFAT) transcription factors as potential regulators for the module. Cells selected for invasiveness and metastatic capability expressed higher levels of NFATc1 as compared with poorly metastatic and less invasive parental cells. We found that inhibition of NFATc1 in human and mouse colon cancer cells resulted in decreased invasiveness in culture and downregulation of metastasis-related network genes. Overexpression of NFATc1 significantly increased the metastatic potential of colon cancer cells, whereas inhibition of NFATc1 reduced metastasis growth in an immunocompetent mouse model. Finally, we found that an 8-gene signature comprising genes upregulated by NFATc1 significantly correlated with worse clinical outcomes in stage II and III colorectal cancer patients. Thus, NFATc1 regulates colon cancer cell behavior and its transcriptional targets constitute a novel, biologically anchored gene expression signature for the identification of colon cancers with high risk of metastatic recurrence.

Original languageEnglish (US)
Pages (from-to)6947-6957
Number of pages11
JournalCancer Research
Volume74
Issue number23
DOIs
StatePublished - Dec 1 2014

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Tripathi, M. K., Deane, N. G., Zhu, J., An, H., Mima, S., Wang, X., Padmanabhan, S., Shi, Z., Prodduturi, N., Ciombor, K. K., Chen, X., Washington, M. K., Zhang, B., & Beauchamp, R. D. (2014). Nuclear factor of activated T-cell activity is associated with metastatic capacity in colon cancer. Cancer Research, 74(23), 6947-6957. https://doi.org/10.1158/0008-5472.CAN-14-1592