RBM4-SRSF3-MAP4K4 splicing cascade modulates the metastatic signature of colorectal cancer cell

Jung-Chun Lin; Yuan-Chii Lee; Tse-Hua Tan; Yu-Chih Liang; Huai-Chia Chuang; Yang C Fann; Kory R Johnson; Ying-Ju Lin

doi:10.1016/j.bbamcr.2017.11.005

RBM4-SRSF3-MAP4K4 splicing cascade modulates the metastatic signature of colorectal cancer cell

Biochim Biophys Acta Mol Cell Res. 2018 Feb;1865(2):259-272. doi: 10.1016/j.bbamcr.2017.11.005. Epub 2017 Nov 11.

Authors

Jung-Chun Lin¹, Yuan-Chii Lee², Tse-Hua Tan³, Yu-Chih Liang⁴, Huai-Chia Chuang³, Yang C Fann⁵, Kory R Johnson⁵, Ying-Ju Lin⁶

Affiliations

¹ School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; PhD program in Medicine Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan. Electronic address: lin2511@tmu.edu.tw.
² Graduate Institute of Biomedical Informatics, Taipei Medical University, Taipei, Taiwan.
³ Immunology Research Center, National Health Research Institutes, Zhunan, Taiwan.
⁴ School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; PhD program in Medicine Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
⁵ Information Technology and Bioinformatics Program, Division of Intramural Research, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
⁶ School of Chinese Medicine, China Medical University, Taichung, Taiwan.

PMID: 29138007
DOI: 10.1016/j.bbamcr.2017.11.005

Abstract

Alternative splicing (AS) of pre-messenger (m)RNA is a pivotal mechanism in expanding proteomic diversity, which determines the functions of mammalian cells. By conducting transcriptome analyses to profile splicing events in human colorectal cancer (CRC) tissues compared to adjacent normal counterparts, we noted differential splicing profiles of serine/arginine-rich splicing factor 3 (SRSF3) and mitogen-activated protein 4 kinase 4 (MAP4K4) in cancerous tissues of CRC compared to adjacent normal tissues. In addition to SRSF3-mediated autoregulation, RNA-binding motif protein 4 (RBM4) constituted another mechanism in reprogramming the splicing profile of SRSF3. Upregulated expressions of SRSF3 in CRC cells modulated utilization of MAP4K4 exon 16 in a sequence-dependent manner. Alternatively spliced MAP4K4 variants exhibited differential effects on the phosphorylation of c-Jun N-terminal protein kinase 1 (JNK1) which subsequently modulated expression profiles of E-cadherin, N-cadherin, and vimentin, all of which are involved in the migration and invasion of CRC cells. Collectively, RBM4-SRSF3-MAP4K4 constitutes a novel mechanism for manipulating the metastasis of CRC cells through the JNK1 signaling pathway.

Keywords: Alternative splicing; Colorectal cancer; MAP4K4; RBM4; SRSF3.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Colorectal Neoplasms / genetics
Colorectal Neoplasms / metabolism*
Female
Humans
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / metabolism*
MAP Kinase Signaling System*
Male
Neoplasm Metastasis
Neoplasm Proteins / genetics
Neoplasm Proteins / metabolism*
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism*
RNA Splicing*
RNA-Binding Proteins / genetics
RNA-Binding Proteins / metabolism*
Serine-Arginine Splicing Factors / genetics
Serine-Arginine Splicing Factors / metabolism*

Substances

Intracellular Signaling Peptides and Proteins
Neoplasm Proteins
RBM4 protein, human
RNA-Binding Proteins
SRSF3 protein, human
Serine-Arginine Splicing Factors
MAP4K4 protein, human
Protein Serine-Threonine Kinases