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Integrative Transcriptomic, Proteomic and Functional Analysis Reveals ATP1B3 as a Diagnostic and Potential Therapeutic Target in Hepatocellular Carcinoma.

ABSTRACT: The Na+/K+-ATPase (NKA), has been proposed as a signal transducer involving various pathobiological processes, including tumorigenesis. However, the clinical relevance of NKA in hepatocellular carcinoma (HCC) has not been well studied. This study revealed the upregulation of mRNA of ATP1A1, ATP1B1, and ATP1B3 in HCC using TCGA, ICGC, and GEO database. Subsequently, ATP1B3 was demonstrated as an independent prognostic factor of overall survival (OS) of HCC. To investigate the potential mechanisms of ATP1B3 in HCC, we analyzed the co-expression network using LinkedOmics and found that ATP1B3 co-expressed genes were associated with immune-related biological processes. Furthermore, we found that ATP1B3 was correlated immune cell infiltration and immune-related cytokines expression in HCC. The protein level of ATP1B3 was also validated as a prognostic significance and was correlated with immune infiltration in HCC using two proteomics datasets. Finally, functional analysis revealed that ATP1B3 was increased in HCC cells and tissues, silenced ATP1B3 repressed HCC cell proliferation, migration, and promoted HCC cell apoptosis and epithelial to mesenchymal transition (EMT). In conclusion, these findings proved that ATP1B3 could be an oncogene and it was demonstrated as an independent prognostic factor and correlated with immune infiltration in HCC, revealing new insights into the prognostic role and potential immune regulation of ATP1B3 in HCC progression and provide a novel possible therapeutic strategy for HCC.

SUBMITTER: Lu S

PROVIDER: S-EPMC8050352 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:There is an urgent need to develop more effective therapies for hepatocellular carcinoma (HCC) because of its aggressiveness. Guadecitabine (SGI-110) is a second-generation DNA methyltransferase inhibitor (DNMTi), which is currently in clinical trials for HCC and shows greater stability and performance over first-generation DNMTis. In order to identify potential therapeutic targets of SGI-110 for clinical trials, HCC cell lines (SNU398, HepG2, and SNU475) were used to evaluate the effects of transient SGI-110 treatment by an integrative analysis of DNA methylation, nucleosome accessibility, gene expression profiles, and its clinical relevance by comparison to The Cancer Genome Atlas (TCGA) HCC clinical data. Each HCC cell line represents a different DNA methylation subtype of primary HCC tumors based on TCGA data. After SGI-110 treatment, all cell lines were sensitive to SGI-110 with prolonged antiproliferation effects. Expression of up-regulated genes, including tumor suppressors, was positively correlated with nucleosome accessibility and negatively correlated with gene promoter DNA methylation. Alternatively, expression of down-regulated genes, such as oncogenes, was negatively correlated with nucleosome accessibility and positively correlated with gene body DNA methylation. SGI-110 can also act as a dual inhibitor to down-regulate polycomb repressive complex 2 (PRC2) genes by demethylating their gene bodies, resulting in reactivation of PRC2 repressed genes without involvement of DNA methylation. Furthermore, it can up-regulate endogenous retroviruses to reactivate immune pathways. Finally, about 48% of frequently altered genes in primary HCC tumors can be reversed by SGI-110 treatment. CONCLUSION:Our integrative analysis has successfully linked the antitumor effects of SGI-110 to detailed epigenetic alterations in HCC cells, identified potential therapeutic targets, and provided a rationale for combination treatments of SGI-110 with immune checkpoint therapies.

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Integrative Transcriptomic, Proteomic and Functional Analysis Reveals ATP1B3 as a Diagnostic and Potential Therapeutic Target in Hepatocellular Carcinoma.

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