A Novel Lactate Metabolism-Related Gene Signature for Predicting Clinical Outcome and Tumor Microenvironment in Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the main subtype of primary liver cancer with high malignancy and poor prognosis. Metabolic reprogramming is a hallmark of cancer and has great importance on the tumor microenvironment (TME). As an abundant metabolite, lactate plays a crucial role in cancer progression and the immunosuppressive TME. Nonetheless, the potential roles of lactate in HCC remain unclear. In this study, we downloaded transcriptomic data of HCC patients with corresponding clinical information from the TCGA and ICGC portals. The TCGA-HCC dataset used as the training cohort, while the ICGC-LIRI-JP dataset was served as an external validation cohort. Cox regression analysis and the LASSO regression model were combined to construct the lactate metabolism-related gene signature (LMRGS). Then, we assessed the clinical significance of LMRGS in HCC. Besides, enriched molecular functions, tumor mutation burden (TMB), infiltrating immune cells, and immune checkpoint were comprehensively analyzed in different LMRGS subgroups. In total, 66 differentially expressed lactate metabolism-related genes (LMRGs) were screened. The functions of LMRGs were mainly enriched in mitochondrial activity and metabolic processes. The LMRGS comprised of six key LMRGs (FKTN, PDSS1, PET117, PUS1, RARS1, and RNASEH1) had significant clinical value for independently predicting the prognosis of HCC patients. The overall survival and median survival of patients in the LMRGS-high group were significantly shorter than in the LMRGS-low group. In addition, there were differences in TMB between the two LMRGS subgroups. The probability of genetic mutations was higher in the LMRGS-high group. Most importantly, the LMRGS reflected the TME characteristics. In the LMRGS-high group, the immune microenvironment presented a suppressed state, accompanied by more inhibitory immune cell infiltration, including follicular helper T cells and regulatory T cells. Additionally, the expression of inhibitory checkpoint molecules was much higher in the LMRGS-high group. Our study suggested that the LMRGS was a robust biomarker to predict the clinical outcomes and evaluate the TME of patients with HCC.

A Novel Risk Score Model of Lactate Metabolism for Predicting over Survival and Immune Signature in Lung Adenocarcinoma

“…They showed a low mutation rate but strong correlation with immune cells in our results, which indicated their tumorigenic roles were not as an oncogene but affected the immune microenvironment. The prognosis value of lactate was reported in hepatocellular carcinoma recently [ 26 ], while LUAD was not mentioned. In our study, multiple clustering analysis distinguished top genes into two groups according to survival.…”

Identification of m6A modification patterns and development of m6A–hypoxia prognostic signature to characterize tumor microenvironment in triple-negative breast cancer

“…Researches about PET117 indicated that it is necessary for Cox15 oligomerization and function in mitochondrial respiratory ( 51 ), which means it might related to cell energy metabolism. There was a bioinformatic analyse identified PET117 as hub gene related to TME and prognosis of hepatocellular Carcinoma ( 52 ). The TAF9(TATA-binding protein) was also identified as a prognostic gene in a DNA-repair-related gene model for esophageal cance ( 53 ), our results showed that MHPS was also associated DDR, which suggested that TAF9 might involved in tumor processes, and discovered as a potential target in TNBC.…”

Expression of lactate-related signatures correlates with immunosuppressive microenvironment and prognostic prediction in ewing sarcoma

“…NDUFB9 and NDUFB10 were associated with mitochondrial respiratory chain complex I assembly. Li et al (2021) found that deletion of NDUFB9 promoted proliferation and invasion of metastatic breast cancer cells via Akt/mTOR/p70S6K axis. Hebert-Chatelain et al (2012) revealed that activation of Src kinase could inhibit NDUFB10 phosphorylation and decrease mitochondrial respiration to increase aerobic glycolysis.…”

“…Numerous researches revealed that aberrant expression of PUS1 was closely linked to lactic acidosis and mitochondrial myopathy ( Knispel et al, 2021 ). Li et al (2021) suggested that elevated levels of PUS1 were intimately connected with poor prognosis of hepatocellular. NDUFB9 and NDUFB10 were associated with mitochondrial respiratory chain complex I assembly.…”