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Alternative microexon splicing by RBFOX2 and PTBP1 is associated with metastasis in colorectal cancer
Author(s) -
Mochizuki Yasushi,
Funayama Ryo,
Shirota Matsuyuki,
Kikukawa Yuna,
Ohira Masahiro,
Karasawa Hideaki,
Kobayashi Minoru,
Ohnuma Shinobu,
Unno Michiaki,
Nakayama Keiko
Publication year - 2021
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.33758
Subject(s) - rna splicing , alternative splicing , polypyrimidine tract binding protein , exon , biology , cancer research , gene knockdown , minigene , rna binding protein , colorectal cancer , microbiology and biotechnology , gene , cancer , genetics , messenger rna , rna
The splicing of microexons (very small exons) is frequently dysregulated in the brain of individuals with autism spectrum disorder. However, little is known of the patterns, regulatory mechanisms and roles of microexon splicing in cancer. We here examined the transcriptome‐wide profile of microexon splicing in matched colorectal cancer (CRC) and normal tissue specimens. Out of 1492 microexons comprising 3 to 15 nucleotides, 21 (1%) manifested differential splicing between CRC and normal tissue. The 21 genes harboring the differentially spliced microexons were enriched in gene ontology terms related to cell adhesion and migration. RNA interference‐mediated knockdown experiments identified two splicing factors, RBFOX2 and PTBP1, as regulators of microexon splicing in CRC cells. RBFOX2 and PTBP1 were found to directly bind to microexon‐containing pre‐mRNAs and to control their splicing in such cells. Differential microexon splicing was shown to be due, at least in part, to altered expression of RBFOX2 and PTBP1 in CRC tissue compared to matched normal tissue. Finally, we found that changes in the pattern of microexon splicing were associated with CRC metastasis. Our data thus suggest that altered expression of RBFOX2 and PTBP1 might influence CRC metastasis through the regulation of microexon splicing.