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 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.
Footnotes
Financial Support: This work was supported by a Newman Fellowship awarded by the UCD Foundation to FC funded by a donation from Merck Serono, from a Science Foundation Ireland Industry Fellowship (14/IFB/2715) to FC, NIH P41CA196276 to CSC and from the Irish Health Research Board (HRA _POR_2013_281) to EJR. The sponsors had no role in the study design, collection, analysis, or interpretation of data.
Disclosures: None declared.
Abbreviations: KHSRP, KH-type splicing regulatory protein; CRC, colorectal cancer; IHC, immunohistochemistry; FFPE, formalin fixed paraffin embedded; RBP, RNA-binding protein; UTR, untranslated region; ARE, AU-rich element; TCGA, The cancer genome atlas; DAMP, damage-associated molecular pattern; PAMP, pathogen-associated molecular pattern.
This version of the manuscript reflects revisions that occured during multiple peer review rounds from June 2018 to June 2019.
https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE112329