FAT10 promotes hepatocellular carcinoma (HCC) carcinogenesis by mediating P53 degradation and acts as a prognostic indicator of HCC

Yue Zhang; Zhifan Zuo; Bo Liu; Pinghua Yang; Jun Wu; Lei Han; Tao Han; Tingsong Chen

doi:10.21037/jgo-21-374

FAT10 promotes hepatocellular carcinoma (HCC) carcinogenesis by mediating P53 degradation and acts as a prognostic indicator of HCC

J Gastrointest Oncol. 2021 Aug;12(4):1823-1837. doi: 10.21037/jgo-21-374.

Authors

Yue Zhang¹, Zhifan Zuo², Bo Liu³, Pinghua Yang⁴, Jun Wu², Lei Han⁵, Tao Han⁶, Tingsong Chen¹

Affiliations

¹ The Second Department of Oncology, the Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China.
² China Medical University, General Hospital of Northern Theater Command Training Base for Graduate, Shenyang, China.
³ Department of Laboratory Medicine, the First Affiliated Hospital of China Medical University, Shenyang, China.
⁴ The Fourth Department of Biliary Tract, Eastern Hepatobiliary Surgery Hospital, Shanghai, China.
⁵ Department of Hepatobiliary Surgery, General Hospital of Northern Theater Command, Shenyang, China.
⁶ Department of Oncology, the First Affiliated Hospital of China Medical University, Shenyang, China.

Abstract

Background: With the advancement of hepatocellular carcinoma (HCC) treatment technology, the treatment options for HCC patients have increased. However, due to high heterogeneity, among other reasons, the five-year survival rate of patients is still very low. Currently, gene expression prognostic models can suggest more appropriate strategies for the treatment of HCC. This study investigates the role of FAT10 in hepatocarcinogenesis and its underlying mechanism.

Methods: The expression of FAT10 was detected by immunohistochemical method using tissue arrays containing 4 specimens of patients with digestive cancer. The expression of FAT10 was determined by a tissue microarray which included 286 pairs of HCC samples and corresponding normal mucosae and was further confirmed by real-time polymerase chain reaction (PCR) and western blot. The Kaplan-Meier survival curve was used to determine the correlation of FAT10 expression with patients' recurrence and overall survival (OS) rate. In vivo, liver fibrosis, cirrhosis, and HCC models were established to assess the FAT10 expression. Moreover, FAT10 over-expressing cell lines were used to determine the molecular mechanism underlying the FAT10-induced cell proliferation and hepatocarcinogenesis by reporter gene measure, real-time PCR, and western blot. Based on TCGA database, signal pathways associated with FAT10 and HCC invasion and metastasis were analyzed by KEGG enrichment analyze.

Results: Overexpression of FAT10 in HCC was observed in this study compared with its expression in other digestive tumors. Clinicopathological analysis revealed that FAT10 expression levels were closely associated with tumor diameters and poor prognosis of HCC. This study also confirmed through in vivo experiments that the expression of FAT10 in liver fibrosis, cirrhosis, and HCC gradually increases. Further study revealed that forced FAT10 expression enhanced the growth ability of HCC cells and mediated the degradation of the critical anti-cancer protein p53, which led to carcinogenesis. Finally, 9 signal pathways related to HCC metastasis were obtained through bioinformatics analysis.

Conclusions: FAT10 may act as a proto-oncogene that facilitates HCC carcinogenesis by mediating p53 degradation, and the expression of FAT10 is negatively correlated with the prognosis of HCC patients. FAT10 is expected to become a potential combined target and prognostic warning marker for HCC treatment.

Keywords: FAT10; Hepatocellular carcinoma (HCC); P53; prognostic.