UBXN9 inhibits the RNA exosome function to promote T cell control of liver tumorigenesis

Abstract

Background and Aims: Liver tumorigenesis encompasses oncogenic activation and self-adaptation of various biological processes in premalignant hepatocytes to circumvent the pressure of cellular stress and host immune control. Ubiquitin regulatory X domain-containing proteins (UBXNs) participate in the regulation of certain signaling pathways. However, whether UBXN proteins function in the development of liver cancer remains unclear. Approach and Results: Here, we demonstrated that UBXN9 (ASPSCR1/ASPL) expression was decreased in autochthonous oncogene-induced mouse liver tumors and approximately 47.7% of human hepatocellular carcinomas (HCCs), and associated with poor prognosis in HCC patients. UBXN9 attenuated liver tumorigenesis induced by different oncogenic factors and tumor growth of transplanted liver tumor cells in immuno-competent mice. Mechanistically, UBXN9 significantly inhibited the function of the RNA exosome, resulting in increased expression of RLR-stimulatory RNAs and activation of the retinoic acid-inducible gene-I (RIG-I)-IFN-Ι signaling in tumor cells, and hence potentiated T cell recruitment and immune control of tumor growth. Abrogation of the CD8+ T cell response or inhibition of tumor cell RIG-I signaling efficiently counteracted the UBXN9-mediated suppression of liver tumor growth. Conclusions: Our results reveal a modality in which UBXN9 promotes the stimulatory RNA-induced RIG-I-IFN signaling that induces anti-tumor T cell response in liver tumorigenesis. Targeted manipulation of the UBXN9-RNA exosome circuit may have the potential to reinstate the immune control of liver tumor growth.