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.
- 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: [email protected].
- 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.
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.