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Alternative splicing variant of NRP/B promotes tumorigenesis of gastric cancer
Aram Kim 1,4,# (Research Professor), Bo Ram Mok 1,4,# (Postdoctoral Fellow), Soojung Hahn 2,3 (Research worker), Jongman Yoo2,3 (Professor), Dong Hyun Kim 4 (Professor), Tae-Aug Kim 1,4,* (Professor)
1Department of Biochemistry and 2Department of Microbiology, Institution of Basic Medical Science, School of Medicine, CHA University,
3Organoid research center, R&D Institute, Organoidsciences Ltd.,
4Department of Dermatology, Bundang CHA Medical Center, School of Medicine, CHA University
Abstract
Gastrointestinal cancer continues to be associated with a high mortality rate. Here, we report that the splice variant of NRP/B contributes to tumorigenic activity in highly malignant gastric cancer through dissociation from the tumor repressor, HDAC5. NRP/B mRNA expression is significantly higher in human gastric cancer tissues than in normal tissues. Further, high levels of both NRP/B splice variant and Lgr5, but not the full-length protein, are found in highly tumorigenic gastric tumor cells, but not in non-tumorigenic cells. The loss of NRP/B markedly inhibits cell migration and invasion, which reduces tumor formation in vivo. Importantly, the inhibition of alternative splicing increases the levels of NRP/B-1 mRNA and protein in AGS cells. The ectopic expression of full-length NRP/B exhibits tumor-suppressive activity, whereas NRP/B-2 induces the tumorigenesis of noninvasive human gastric cancer cells. The splice variant NRP/B-2 which loses the capacity to interact with tumor repressors promoted oncogenic activity, suggesting that the BTB/POZ domain in the N-terminus has a crucial role in the suppression of gastric cancer. Thus, the regulation of alternative splicing of the NRP/B gene can be a novel target for the treatment of gastrointestinal cancer.
Abstract, Accepted Manuscript(in press) [Submitted on February 23, 2022, Accepted on May 10, 2022]
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