Abstract A12: Contribution of the transcription factor STAT2 in the promotion and progression of colorectal cancer

Abstract

Abstract Accumulation of genetic lesions such as loss of, or mutations in the APC, KRAS, and TP53 genes play a pivotal role in the development and progression of colorectal cancer (CRC), the third most common cancer in the United States. Yet the effects deregulated signaling pathways, caused by these canonical alterations, may have on parallel signaling networks remain less clear. Signal Transducer and Activator of Transcription-2 (STAT2) is a critical molecule in the interferon transduction pathway, best known for its role in antiviral and antitumor immunity. However, we recently discovered that the transcription factor STAT2 functions as a promoter of colorectal carcinogenesis when tested in a model of colitis-associated CRC. In our recent study, we have reproduced this finding in which deletion of Stat2 in the ApcMin/+ mouse model of sporadic CRC also decreased the incidence and number of colon adenomas. We next investigated the role of STAT2 in the progression of CRC under the setting of p53 inactivation by employing isogenic colon carcinoma cells that differed in their p53 expression (p53+/+ vs. p53-/-). Our studies show that STAT2 knockdown weakened the oncogenic effects of p53 deficiency by drastically reducing migration and invasion whereas STAT2 knockdown had no effect in tumor cells with intact p53. In vivo, STAT2 depleted/p53-/- colon carcinoma cells, when transplanted in mice, formed smaller tumors when compared to tumor cells with intact STAT2 expression. Furthermore, we demonstrate expression of STAT2 dictates the expression of E-cadherin, a key epithelial-mesenchymal transition (EMT) marker, in the absence of p53. Additionally, evaluation of human CRC tissues revealed an increased STAT2 presence in the nucleus suggesting STAT2 is transcriptionally active in cancer; and genomic data mining of human CRC databases had led us to the identification of a putative STAT2 molecular signature upregulated in human CRC tumors. In conclusion, our study provides evidence that STAT2 has oncogenic properties thus positioning STAT2 as a major contributor to the pathophysiology of CRC. Citation Format: Kevin P. Kotredes, Ana M. Gamero. Contribution of the transcription factor STAT2 in the promotion and progression of colorectal cancer. [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr A12.