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

Li Zhang; Kun Jiao; Yun Liu; Guiqin Xu; Zhaojuan Yang; Lvzhu Xiang; Zehong Chen; Chen Xu; You Zuo; Zhibai Wu; Ningqian Zheng; Xiaoren Zhang; Qiang Xia; Yongzhong Liu

doi:10.1097/HEP.0000000000000711

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

Hepatology. 2023 Dec 5. doi: 10.1097/HEP.0000000000000711. Online ahead of print.

Authors

Li Zhang¹, Kun Jiao^{1

2}, Yun Liu¹, Guiqin Xu¹, Zhaojuan Yang¹, Lvzhu Xiang¹, Zehong Chen¹, Chen Xu¹, You Zuo¹, Zhibai Wu¹, Ningqian Zheng¹, Xiaoren Zhang³, Qiang Xia⁴, Yongzhong Liu^{1

2}

Affiliations

¹ State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiaotong University Shanghai, China.
² State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.
³ Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China.
⁴ Department of Liver Surgery, Renji Hospital,School of Medicine, Shanghai Jiaotong University Shanghai, China.

PMID: 38051955
DOI: 10.1097/HEP.0000000000000711

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 (Alveolar Soft Part Sarcoma Chromosomal Region Candidate Gene 1 Protein/Alveolar Soft Part Sarcoma Locus) expression was decreased in autochthonous oncogene-induced mouse liver tumors and ~47.7% of human HCCs, and associated with poor prognosis in patients with HCC. 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-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 retinoic acid-inducible gene-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 retinoic acid-inducible gene-I-interferon 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.