DIS3L2 Promotes Progression of Hepatocellular Carcinoma via hnRNP U-Mediated Alternative Splicing

Area of Science:

• Molecular Biology
• Cancer Research
• RNA Biology

Background:

• DIS3-like 3'-5' exoribonuclease 2 (DIS3L2) is known to degrade aberrant RNAs.
• Its specific role in tumorigenesis, particularly in hepatocellular carcinoma (HCC), is not well understood.

Purpose of the Study:

• To investigate the function of DIS3L2 in hepatocellular carcinoma (HCC) progression.
• To elucidate the molecular mechanism by which DIS3L2 influences liver cancer development.

Main Methods:

• Investigated DIS3L2 expression in HCC tissues.
• Utilized co-immunoprecipitation to study DIS3L2 and hnRNP U interaction.
• Analyzed alternative splicing of pre-Rac1 using molecular biology techniques.
• Assessed the impact of DIS3L2 and Rac1b on HCC development in vitro and in vivo models.

Main Results:

• Aberrant DIS3L2 expression was found to promote HCC progression.
• DIS3L2 directly interacted with heterogeneous nuclear ribonucleoprotein U (hnRNP U) via its cold-shock domains.
• DIS3L2 induced the inclusion of exon 3b in pre-Rac1, generating the oncogenic Rac1b splicing variant, independent of its exonuclease activity.
• Rac1b was essential for DIS3L2-mediated liver cancer development.
• High DIS3L2 and Rac1b expression levels correlated significantly with advanced HCC and poorer patient survival.

Conclusions:

• DIS3L2 plays a significant oncogenic role in hepatocellular carcinoma.
• DIS3L2 promotes liver cancer by regulating hnRNP U-mediated alternative splicing of Rac1, leading to the formation of the oncogenic Rac1b variant.
• This study uncovers a novel mechanism of HCC carcinogenesis involving DIS3L2 and Rac1b.