Identification and integrative analysis of ACLY and related gene panels associated with immune microenvironment reveal prognostic significance in hepatocellular carcinoma

Abstract

Background Cumulating evidence reveals the key role of aberrant lipogenesis and immunogenomic features in hepatocellular carcinoma (HCC). However, there are still obstacles in our understanding of the complicated interaction between metabolic reprogramming and tumor immune microenvironment. Methods We compared metabolomic, transcriptomic and immunogenomic characteristics of portal vein tumor thrombosis (PVTT) and primary tumor to seek valuable markers. Human HCC samples with PVTT (n = 28) was analyzed through ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS). Transcript levels of mRNA in two cohorts from published database GEO (n = 60) and TCGA (n = 411) were downloaded to explore differentially expressed genes and functional enriched gene set. Evaluation of immune infiltration was estimated and validated from transcriptomic data in both cohorts through six immune deconvolution algorithms and in a high-resolution mode (CIBERSORTx). Survival analysis (Kaplan–Meier and multivariable Cox regression model) was performed to examine prognostic value of ACLY, related immune checkpoints and immune infiltration levels from TCGA cohort. LASSO regression was further conducted to determine a gene panel to further predict survival outcomes associated with ACLY. Results We identified a novel signature, ATP citrate lyase, through transcriptomic and metabolomic approaches. We demonstrated that the metabolism adaptations in both fatty acid and cholesterol biosynthesis triggered by ACLY oncogenic activation. We illustrated the crucial function of ACLY in lipogenesis and its potential interaction with immune microenvironment. CD276, a promising target in immune checkpoint blockade, showed correlation to ACLY and differential expression in ACLY risk classification. Combination of ACLY, CD276 and immune infiltration level and a novel ACLY-associated panel from a predictive model retrieved from published database validated the prognostic value to risk stratification in patients with HCC.ACLY blockade to counteract metabolic activation and immunosuppressive status of the tumor microenvironment highlighted attractive prospect for translational application. Conclusions We investigated ACLY and its indispensable role in metabolism, immune function and a prognostic gene panel in HCC. We anticipate that the multifaced role of ACLY may reveal the potential value for mechanistic research and combinational therapy, suggesting that the combination blockade of ACLY and immune checkpoints may work as a promising strategy.

Prognostic Biomarkers for Hepatocellular Carcinoma Based on Serine and Glycine Metabolism-related Genes

“…Currently, although many researchers have established numerous prognostic models for HCC, [29][30][31] there is no prognostic model related to SGMGs to systematically predict and evaluate the overall prognosis of HCC patients. Therefore, to reveal the potential function and unique prognostic value of SGMGs in HCC, we examined public datasets through bioinformatics analysis to provide new insights for future research.…”

ALYREF associated with immune infiltration is a prognostic biomarker in hepatocellular carcinoma

“…Xie et al [35] have stated that TNFRSF4 is strongly associated with the immune microenvironment of HCC and contributes to poor prognosis. CD276 is a potential target for HCC immunotherapy and can be utilized as a predictor of survival in HCC patients [36] , [37] , [38] . It indicated that the prognostic model we constructed provided potential therapeutic targets and prognostic assessment indicators for immunotherapy of HCC.…”

Role of ACLY in the development of gastric cancer under hyperglycemic conditions

“…Combination of ACLY inhibitor and programmed death ligand 1 antibody largely inhibits chemically induced hepatocarcinogenesis; [66] ACLY can regulate the canonical Wnt pathway by affecting the stability of β-catenin; [67] ONECUT2-FGF2-ACLY axis regulates metastasis of hepatocellular carcinoma; [65] Bioinformatics analysis shows that ACLY is significantly correlated with immune checkpoint CD276 and immune cell infiltration; [68] Downregulation of ACLY can reverse sorafenib resistance, and targeting ACLY can effectively treat drug-resistant hepatocellular carcinoma [69] Malignant tumors of the head and neck ACLY plays a key role in oral carcinogenesis; [70] ACLY affects DNA damage repair, and ACLY expression can predict the efficacy of radiotherapy for head and neck squamous cell carcinoma; [71] Long non-coding RNA TINCR can bind ACLY to protect it from ubiquitination degradation, thereby maintaining the level of acetyl-CoA, promoting the progression of nasopharyngeal carcinoma and chemotherapy resistance…”