U2AF2 drives malignant progression and chemo-resistance in hepatocellular carcinoma through cooperating with SRSF1 to modulate CCND1 splice-variant expression

Hepatocellular carcinoma (HCC) is a common malignancy with high risk of recurrence and metastasis. Growing evidences reveal that aberrant mRNA splicing represents a crucial molecular characteristic of Cancer, which produces numerous and complex transcript variants to drive Cancer development and progression. Here, we identified the splicing factor U2AF2 as a promising oncogenic biomarker in HCC, and subsequently explored its biological role and mechanism. Through bioinformatics analysis and clinical verification, U2AF2 was found to be significantly elevated in HCC, showing a strong correlation with the pathological grade and patient outcomes. Subsequent investigations demonstrated that U2AF2 promoted HCC growth and metastasis both in vitro and in vivo. Mechanically, U2AF2 exerted its oncogenic functions by cooperating with SRSF1 to bind to the pre-mRNA of CCND1(Cyclin D1) and facilitate the generation of CCND1b isoform. Moreover, U2AF2 could potentially be utilized for the prediction of chemo-responsiveness. Its depletion sensitized HCC cells to Doxorubicin, a first-line chemotherapy agent for advanced HCC patients. Altogether, this study deepens our understanding of U2AF2 in mRNA splicing and provides a potential therapeutic target for HCC.

CCND1; Hepatocellular carcinoma; Metastasis; Proliferation; U2AF2; mRNA splicing.