Integrated systemic analysis of FAM72A to identify its clinical relevance, biological function, and relationship to drug sensitivity in hepatocellular carcinoma

BACKGROUND: The family with sequence similarity 72 member A (FAM72A) protein has been identified as an effector of multiple pathological processes in many cancers. The value of FAM72A in HCC remains largely unknown. METHODS: Data from TCGA-LIHC, ICGC-LIRI-JP, IMvigor210, cBioPortal, GeneMANIA, and TIMER were processed and visualized to explore the association between FAM72A and the prognosis, stemness phenotype, mutational burden, immune cell infiltration, and drug sensitivity in HCC patients. Potential pathways were also revealed. Furthermore, we experimentally verified the results in vivo and in vitro using immunohistochemistry, western blotting, and CCK-8 assays. RESULTS: First, FAM72A mRNA expression was significantly upregulated in HCC. High FAM72A expression was independently associated with a poor prognosis. Experimental validation confirmed that FAM72A was remarkably overexpressed in HCC patients and mice. Moreover, FAM72A knockdown suppressed HCC cell proliferation. In addition, the frequency of TP53 mutations was significantly higher in the high FAM72A expression group. Subsequently, the enrichment analysis revealed that FAM72A was closely related to immune processes and mTOR pathways. Silencing FAM72A increased the expression levels of mTOR in HCC cell lines. The FAM72A-mTOR pathway was strongly associated with a poor prognosis for patients with HCC. Patients with high FAM72A expression levels might be more resistant to sorafenib. Furthermore, the expression of FAM72A and mTOR was significantly associated with the abundance of some tumor-infiltrating immune cells, especially CD4(+) T cells. Finally, patients with high levels of FAM72A and mTOR were more sensitive to immunotherapy. CONCLUSIONS: FAM72A, a member of the FAM72 family, might be a prognostic and immunotherapeutic target for HCC patients.