The progression of hepatocellular carcinoma (HCC) is coincident with aberrant splicing of numerous tumor-related genes. Identification of the tumor-specific splice variants that facilitate HCC metastasis may provide a more comprehensive insight into the mechanisms of HCC metastasis. Through RNA sequencing and bioinformatic analyses, PPM1G was identified as a biomarker associated with HCC metastasis. Our data mapped a transcriptome-wide landscape of alternative splicing events modulated by PPM1G in HCC. Notably, we characterized the exon six-skipping transcript of TBL1X as an onco-splice variant regulated by PPM1G. Experimental validation revealed the enrichment of TBL1X-S in response to PPM1G overexpression. Moreover, mRNA stability analyses revealed that PPM1G prolonged the half-life of the TBL1X-S transcript. Both PPM1G and TBL1X-S exhibited metastasis-promoting phenotypes, with PPM1G-driven metastasis in HCC being partially dependent on TBL1X-S. Mechanistically, different TBL1X splice variants showed varying affinities for ZEB1, with TBL1X-S significantly enhancing ZEB1 activation and repressing CDH1 transcription, potentially accelerating the epithelial-mesenchymal transition (EMT) process. In conclusion, our study highlights the biological role of PPM1G and TBL1X-S in tumor metastasis. The PPM1G/TBL1X-S signaling axis presents a new view for investigating liver cancer metastasis mechanisms.
Keywords: HCC; PPM1G; TBL1X; alternative splicing; metastasis.
© 2024 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.