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Am J Pathol. 2019 Oct;189(10):1916-1932. doi: 10.1016/j.ajpath.2019.07.004. Epub 2019 Aug 9.

KH-Type Splicing Regulatory Protein Controls Colorectal Cancer Cell Growth and Modulates the Tumor Microenvironment.

Author information

1
Centre for Colorectal Disease, St. Vincent's University Hospital, Dublin, Ireland; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California. Electronic address: francesco.caiazza@ucsf.edu.
2
Centre for Colorectal Disease, St. Vincent's University Hospital, Dublin, Ireland; School of Medicine, University College Dublin, Dublin, Ireland.
3
Centre for Colorectal Disease, St. Vincent's University Hospital, Dublin, Ireland.
4
Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland.
5
Systems Biology Ireland, University College Dublin, Dublin, Ireland.
6
National Institute for Cellular Biotechnology, Dublin City University, Dublin, Ireland.
7
Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
8
School of Medicine, University College Dublin, Dublin, Ireland.
9
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California.

Abstract

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 data sets, 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 these findings were validated in larger independent cohorts in silico. KHSRP expression was a prognostic indicator of worse overall survival (hazard ratio, 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. In addition, KHSRP promoted a proangiogenic 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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