Pan-Cancer analysis shows that ACO2 is a potential prognostic and immunotherapeutic biomarker for multiple cancer types including hepatocellular carcinoma

Abstract

BackgroundRecent evidence increasingly suggests key roles for the tricarboxylic acid cycle and fatty acid metabolism in tumor progression and metastasis. Aconitase 2 (ACO2) is a component of the tricarboxylic acid cycle and represents a key cellular metabolic hub that promotes de novo fatty acid biosynthesis. However, there have been few reports on the role of ACO2 in tumorigenesis and cancer progression.MethodsThrough the comprehensive use of datasets from The Cancer Genome Atlas, Genotype-Tissue Expression Project, cBioPortal, Human Protein Atlas, UALCAN, Gene Expression Profiling Interactive Analysis, DNA Methylation Interactive Visualization Database, and TIMER2, we adopted bioinformatics methods to uncover the potential carcinogenic roles of ACO2, including by analysing ACO2 expression and correlations between prognosis, genetic mutations, immune cell infiltration, DNA methylation, tumor mutational burden, and microsatellite instability in different tumors. Additionally, the expression level and tumor-promoting effect of ACO2 were verified in hepatocellular carcinoma (HCC) cells. To explore the underlying mechanisms of ACO2 in human cancer, ACO2-related gene enrichment analysis and lipid metabolomics were performed using LM3 cells with or without ACO2 knockdown.ResultsThe results indicated that ACO2 was highly expressed in most cancers, showing early diagnostic value in six tumor types, and was positively or negatively associated with prognosis in different tumors. Moreover, ACO2 expression was associated with immune cell infiltration, such as CD8+ T cells and tumor-associated neutrophils, in some cancers. For most cancer types, there was a significant association between immune checkpoint-associated genes and ACO2 expression. Compared with normal hepatocytes, ACO2 was upregulated in HCC cells, which promoted their proliferation and migration. Furthermore, to explore the underlying molecular mechanism, we performed KEGG pathway enrichment analysis of ACO2-associated genes and lipidomics using LM3 cells with or without ACO2 knockdown, which screened 19 significantly altered metabolites, including 17 with reduced levels and 2 with increased levels.ConclusionThrough pan-cancer analysis, we discovered for the first time and verified that ACO2 could be a useful diagnostic biomarker for cancer detection. Additionally, ACO2 could be used as an auxiliary prognostic marker or as a marker for immunotherapy in some tumor types.

PRIM2: A Marker of MYC-driven Hyper-proliferation, Disease Progression, Tumor Aggressiveness and Poor Survival in Glioma Patients

“…Here, we identified 5 metabolic hits associated with disease onset, progression, tumor aggressiveness, and survival in glioma patients (Figure 1). As mentioned earlier, two of the metabolic hits we identified, namely ACO2 and SOAT1, have already been established as biomarkers of disease progression in gliomas through their involvement in lipid metabolism (35,36). This also aligns with previous research showing that metabolic changes, such as aberrantly regulated glucose and lipid metabolism, play a pivotal role in disease aggressiveness in gliomas (18).…”

“…In order to validate our findings at the protein level, we also checked the protein expression of these metabolic hits in the CPTAC protein abundance database; we found that protein expression of these metabolic hits aligns well with RNA expression as ACO2 is down-regulated in gliomas compared to normal tissue whereas NAGLU, NT5DC2, PRIM2 and SOAT1 are up-regulated in gliomas compared to normal tissues (Figure 1F-J). Interestingly, two of these metabolic hits have already been established as biomarker of disease progression in gliomas through their involvement in lipid metabolism (35,36), thereby validating our analysis pipeline and findings. ACO2 is a key enzyme in tricarboxylic cycle (TCA) and tightly regulates the production of mitochondrial citrate that is precursor metabolite for de novo fatty acid biosynthesis and lipogenesis.…”

“…ACO2 is a key enzyme in tricarboxylic cycle (TCA) and tightly regulates the production of mitochondrial citrate that is precursor metabolite for de novo fatty acid biosynthesis and lipogenesis. Low ACO2 expression has been established as prognostic and immunotherapeutic biomarker for multiple cancers including gliomas (35). In addition, SOAT1 is also involved in lipid metabolism as it esterifies cholesterol with fatty acids to make cholesterol esters and store fat in the form of lipid droplets.…”

Transcriptome profiling of A549 non-small cell lung cancer cells in response to Trichinella spiralis muscle larvae excretory/secretory products

“…Aconitase plays a role in regulating resistance to oxidative stress and cell death ( 31 ). ACO2 may be used as an immunotherapeutic and potential prognostic biomarker for several cancers, including hepatocellular carcinoma ( 32 ). ACO2 correlates with colorectal cancer cell survival ( 33 ).…”

Genetics of enzymatic dysfunctions in metabolic disorders and cancer

“…The knockdown of ACO2 in colorectal cancer promotes cell proliferation and colorectal cancer growth ( 235 ). However, compared with normal hepatocytes, ACO2 was overexpressed in HCC cells, promoting cell proliferation and migration by affecting molecular pathways involved in cellular energy metabolism, metabolite changes, and fatty acid metabolic pathway ( 233 ).…”