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

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, 1.43e22.97; P Z 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 G 1 /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.

A Comprehensive Analysis of Symmetric Arginine Dimethylation in Colorectal Cancer Tissues Using Immunoaffinity Enrichment and Mass Spectrometry

“…It is assumed that the increase in KSRP protein expression contributed to the increased detection of the KSRP with symmetric arginine methylation. There are also recent reports that KSRP promotes CRC tumorigenesis and survival, [ 16 ] and that KSRP down‐regulation significantly sensitizes CRC cells to 5‐fluorouracil treatment. [ 17 ] In addition, the expression of GTPase‐activating protein‐binding protein 2, thyroid hormone receptor interactor 6, and ribosomal RNA small subunit methyltransferase B proteins showing an increased fold change in SDMA‐containing peptides in CRC tissues (Table S4, Supporting Information) were also overexpressed in CRC tissues compared to paired noncancerous tissues (Figure S3, Supporting Information).…”

Role of exosomal miRNAs in brain metastasis affected by radiotherapy

“…Therefore, cellular macromolecule metabolic processes are of great significance to cancer cells. Regulatory region nucleic acid binding modulates the tumor microenvironment in colorectal cancer tumorigenesis [ 32 ]. Transcription regulator activity can regulate the proliferation or apoptosis of cancer cells by affecting cell proliferation-related genes and directly regulating the cell cycle [ 33 , 34 ].…”

Comprehensive Analysis of Prognostic Alternative Splicing Signature Reveals Recurrence Predictor for Papillary Thyroid Cancer

“…In our study, we identified five SFs related to the prognosis of PTC patients. KHSRP was reported to be oncogenic in non-small lung cancer, colorectal cancer and PTC (40)(41)(42). Overexpression of KHSRP activated IFN-aJAK-STAT1 signaling pathway and induced lung cancer cell invasion and metastasis (40).…”