ESRP1-regulated isoform switching of LRRFIP2 determines metastasis of gastric cancer.

Abstract

Although accumulating evidence indicates that alternative splicing is aberrantly altered in many cancers, the functional mechanism remains to be elucidated. Here, we show that epithelial and mesenchymal isoform switches of leucine-rich repeat Fli-I-interacting protein 2 (LRRFIP2) regulated by epithelial splicing regulatory protein 1 (ESRP1) correlate with metastatic potential of gastric cancer cells. We found that expression of the splicing variants of LRRFIP2 was closely correlated with that of ESRP1. Surprisingly, ectopic expression of the mesenchymal isoform of LRRFIP2 (variant 3) dramatically increased liver metastasis of gastric cancer cells, whereas deletion of exon 7 of LRRFIP2 by the CRISPR/Cas9 system caused an isoform switch, leading to marked suppression of liver metastasis. Mechanistically, the epithelial LRRFIP2 isoform (variant 2) inhibited the oncogenic function of coactivator-associated arginine methyltransferase 1 (CARM1) through interaction. Taken together, our data reveals a mechanism of LRRFIP2 isoform switches in gastric cancer with important implication for cancer metastasis.

• Authors: Jihee Lee, Kyoungwha Pang, Junil Kim, Eunji Hong, Jeeyun Lee, Hee Jin Cho, Jinah Park, Minjung Son, Sihyun Park, Minjung Lee, Akira Ooshima, Kyung-Soon Park, Han-Kwang Yang, Kyung-Min Yang, Seong-Jin Kim
• Journal: Nature communications (Nat Commun) Vol. 13 Issue 1 Pg. 6274 (10 28 2022) ISSN: 2041-1723 [Electronic] England
• PMID: 36307405 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Adaptor Proteins, Signal Transducing
• ESRP1 protein, human
• LRRFIP2 protein, human
• Protein Isoforms
• RNA-Binding Proteins
• Transcription Factors

Topics

• Humans
• Adaptor Proteins, Signal Transducing (genetics, metabolism)
• Alternative Splicing
• Cell Line, Tumor
• Epithelial-Mesenchymal Transition
• Liver Neoplasms (genetics)
• Protein Isoforms (genetics, metabolism)
• RNA-Binding Proteins (genetics, metabolism)
• Stomach Neoplasms (genetics)
• Transcription Factors (metabolism)
• Neoplasm Metastasis