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

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 and Seong-Jin Kim ()
Additional contact information
Jihee Lee: GILO Institute, GILO Foundation
Kyoungwha Pang: GILO Institute, GILO Foundation
Junil Kim: Soongsil University
Eunji Hong: GILO Institute, GILO Foundation
Jeeyun Lee: Samsung Medical Center Sungkyunkwan University School of Medicine
Hee Jin Cho: Kyungpook National University
Jinah Park: GILO Institute, GILO Foundation
Minjung Son: GILO Institute, GILO Foundation
Sihyun Park: GILO Institute, GILO Foundation
Minjung Lee: Medpacto Inc.
Akira Ooshima: GILO Institute, GILO Foundation
Kyung-Soon Park: CHA University
Han-Kwang Yang: Seoul National University Hospital
Kyung-Min Yang: Medpacto Inc.
Seong-Jin Kim: GILO Institute, GILO Foundation

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-33786-9

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