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KH-type splicing regulatory protein controls colorectal cancer cell growth and modulates the tumor microenvironment

By Francesco Caiazza, Katarzyna Oficjalska, Miriam Tosetto, James J. Phelan, Sinéad Noonan, Petra Martin, Kate Killick, Laura Breen, Fiona O’Neill, Blathnaid Nolan, Simon Furney, Robert Power, David Fennelly, Charles S. Craik, Jacintha O’Sullivan, Kieran Sheahan, Glen A. Doherty, Elizabeth J. Ryan

Posted 08 Jun 2018
bioRxiv DOI: 10.1101/342840 (published DOI: 10.1016/j.ajpath.2019.07.004)

KH-type splicing regulatory protein (KHSRP) is a multifunctional nucleic acid binding protein implicated in key aspects of cancer cell biology: inflammation and cell-fate determination. However, the role KHSRP plays in colorectal cancer (CRC) tumorigenesis remains largely unknown. Using a combination of in silico analysis of large datasets, ex vivo analysis of protein expression in patients, and mechanistic studies using in vitro models of CRC, we investigated the oncogenic role of KHSRP. We demonstrated KHSRP expression in the epithelial and stromal compartments of both primary and metastatic tumors. Elevated expression was found in tumor versus matched normal tissue, and we validated these findings in larger independent cohorts in silico. KHSRP expression was a prognostic indicator of worse overall survival (HR=3.74, 95% CI = 1.43-22.97, p=0.0138). Mechanistic data in CRC cell line models supported a role of KHSRP in driving epithelial cell proliferation in both a primary and metastatic setting, through control of the G1/S transition. Additionally, KHSRP promoted a pro-angiogenic extracellular environment by regulating the secretion of oncogenic proteins involved in diverse cellular processes such as migration and response to cellular stress. Our study provides novel mechanistic insight into the tumor-promoting effects of KHSRP in CRC.

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