Nfat Regulates A Gene Expression Program Associated With Invasiveness And Poor Prognosis In Colorectal Cancer

Colorectal cancer is the second leading cause of cancer-related death in the United States. In order to understand the regulatory mechanisms underlying poor prognosis in colorectal cancer, we analyzed fourteen human colorectal cancer microarray data sets and identified co-expressed modules using network analysis. We next filtered these modules using gene expression data from a mouse model of metastatic colon cancer, narrowing down to a candidate metastasis-related module, and identified NFAT as its potential transcriptional regulator. The NFAT family and their identified targets were found to be upregulated in human colorectal cancer patients. Analysis of NFAT family members expression in mouse and human microarray datasets, revealed NFATc1 to be differentially expressed between metastatic and non-metastatic, and between disease progression and no disease progression, respectively. We found that high NFATc1 expression correlated with significantly increased invasion (p<0.0001) and migration (p<0.005) in mouse colon cancer cells. We show that RNAi- based knockdown of NFATc1 and functional inhibition by the calcineurin inhibitor FK506 resulted in downregulation of predicted NFAT target genes from the metastatic module and decreased cancer cell invasiveness. Finally, we showed that the expression of NFAT target genes was significantly correlated with both disease-specific and disease-free survival in Stage II and III colorectal cancer patients. Our studies suggest a role for NFATs in colon cancer cell invasion and a potential application for the NFAT driven program as a biologically anchored prognostic gene expression signature. Citation Format: Manish K. Tripathi, Shinji Mima, Zhiao Shi, Naresh Prodduturi, Zhu Jing, Kristen K. Ciombor, Xi Chen, Natasha Deane, Robert D. Beauchamp, Bing Zhang. NFAT regulates a gene expression program associated with invasiveness and poor prognosis in colorectal cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B101.