Ca2+/nuclear factor of activated T cells signaling is enriched in early-onset rectal tumors devoid of canonical Wnt activation

Kumar, Raju and Raman, Ratheesh (2018) Ca2+/nuclear factor of activated T cells signaling is enriched in early-onset rectal tumors devoid of canonical Wnt activation. Journal of Molecular Medicine, 96. pp. 135-146. ISSN 0946-2716

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Our previous extensive analysis revealed a significant proportion of early-onset colorectal tumors from India to be localized to the rectum in younger individuals and devoid of deregulated Wnt/β-catenin signaling. In the current study, we performed a comprehensive genome-wide analysis of clinically well-annotated microsatellite stable early-onset sporadic rectal cancer (EOSRC) samples. Results revealed extensive DNA copy number alterations in rectal tumors in the absence of deregulated Wnt/β-catenin signaling. More importantly, transcriptome profiling revealed a (non-Wnt/β-catenin, non- MSI) genetic signature that could efficiently and specifically identify Wnt− rectal cancer. The genetic signature included a significant representation of genes belonging to Ca2+/NFAT signaling pathways that were validated in additional samples. The validated NFAT target genes exhibited significantly higher expression levels than canonical Wnt/β-catenin targets in Wnt− samples, an observation confirmed in other CRC expression data sets as well.We confirmed the validated genes to be transcriptionally regulated by NFATc1 by (a) evaluating their respective transcript levels and (b) performing promoterluciferase and chromatin immunoprecipitation assays following ectopic expression as well as knockdown of NFATc1 in CRC cells. NFATc1 and its targets RUNX2 and GSN could drive increased migration in CRC cells. Finally, the validated genes were associated with poor survival in the cancer genome atlas CRC expression data set. This study is the first comprehensive molecular characterization of EOSRC that appears to be driven by noncanonical tumorigenesis pathways.

Item Type: Article
Uncontrolled Keywords: Rectal cancer ;Wnt ;DNA copy number alterations ; Calciumsignaling ; NFAT.
Subjects: Research > Research Center - Health Sciences
Depositing User: KMC Library
Date Deposited: 17 Apr 2019 10:35
Last Modified: 17 Apr 2019 10:35

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