Background: OCT4 and BIRC5 are preferentially expressed in human cancer cells and mediate cancer cell survival and tumor maintenance. However, the molecular mechanism that regulates OCT4 and BIRC5 expression is not well characterized. Methods: By manipulating OCT4 and BIRC5 expression in hepatocellular carcinoma (HCC) cell lines, the regulatory mechanism of OCT4 on BIRC5 and CCND1 were investigated. Results: Increasing or decreasing OCT4 expression could enhance or suppress BIRC5 expression, respectively, by regulating the activity of BIRC5 promoter. Because there is no binding site for OCT4 within BIRC5 promoter, the effect of OCT4 on BIRC5 promoter is indirect. An octamer motif for OCT4 in the CCND1 promoter has directly and partly participated in the regulation of CCND1 promoter activity, suggesting that OCT4 also could upregulated the expression of CCND1. Co-suppression of OCT4 and BIRC5 induced cancer cell apoptosis and cell cycle arrest, thereby efficiently inhibiting the proliferative activity of cancer cells and suppressing the growth of HCC xenogrfts in nude mice. Conclusion: OCT4 can upregulate BIRC5 and CCND1 expression by increasing their promoter activity. These factors collusively promotes HCC cell proliferation, and co-suppression of OCT4 and BIRC5 is potentially beneficial for HCC treatment.

Accumulating evidence has proved that autophagy serves as a tumor promoter in formed malignancies, and the autophagy-related prognostic signatures have been constructed as clinical tools to predict prognosis in many high-mortality cancers. Autophagy-related genes have participated in the development and metastasis of hepatocellular carcinoma (HCC), but the understanding of their prognostic value is limited. Thereafter, LIMMA and survival analysis were conducted in both ICGC and TCGA databases and a total of 10 hub autophagy-related genes, namely, NPC1, CDKN2A, RPTOR, SPHK1, HGS, BIRC5, SPNS1, BAK1, ATIC, and MAPK3, were collected. Then, GO, KEGG, correlation, consensus, and PCA analyses were utilized to reveal their potential targeted role in HCC treatment. Single-cell RNA-seq of cancer stem cells also indicated that there was a positive correlation between these genes and stemness. In parallel, we applied univariate, LASSO, and multivariate regression analyses to study the autophagy-related genes and finally proposed that ATIC and BIRC5 were the valuable prognostic indicators of HCC. The signature based on ATIC and BIRC5 exhibited moderate power for predicting the survival of HCC in the ICGC cohort, and its efficacy was further validated in the TCGA cohort. Taken together, we suggested that 10 aforementioned hub genes are promising therapeutic targets of HCC and the ATIC/BIRC5 prognostic signature is a practical prognostic indicator for HCC patients.

Gallbladder cancer (GBC) is a highly aggressive malignancy of the biliary tract with limited therapeutic options. Phosphoglucomutase 5 (PGM5), a key enzyme in glucose metabolism, has been implicated as a tumor suppressor in several cancers, yet its role and mechanism in GBC remain unclear. Here, we demonstrate that PGM5 is significantly downregulated in GBC tissues, and its low expression correlates with poor prognosis. Using integrated bioinformatic analysis, we found that PGM5 loss is associated with enhanced glycolysis and activation of the STAT3 signaling pathway. Functionally, PGM5 overexpression significantly inhibited GBC cell proliferation, migration, and invasion, and promoted apoptosis, whereas PGM5 knockdown exerted the opposite effects. Mechanistically, PGM5 suppressed lactate production by downregulating lactate dehydrogenase A (LDHA), leading to decreased phosphorylation of STAT3. The anti-tumor effects of PGM5 were reversed by exogenous lactate supplementation, and the glycolytic inhibitor 2-DG abrogated the oncogenic phenotypes induced by PGM5 silencing. In a mouse xenograft model, PGM5 overexpression significantly restrained tumor growth, reduced LDHA and p-STAT3 levels, and decreased intratumoral lactate content. Our findings reveal that PGM5 acts as a tumor suppressor in GBC through disruption of the lactate-STAT3 signaling axis, highlighting its potential as a therapeutic target for metabolic intervention in GBC.