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.
Highlights
Hepatocellular carcinoma (HCC) is the most common histological type of primary liver cancer, the third leading cause of cancer death worldwide (Sung et al, 2021)
The heat map displayed the expression of lactate metabolism-related genes (LMRGs) in HCC samples and normal samples (Figure 1A)
The primary biological processes (BP) of LMRGs were involved in mitochondrial genome maintenance, mitochondrial respiratory chain complex assembly, electron transport chain, and metabolic process
Summary
Hepatocellular carcinoma (HCC) is the most common histological type of primary liver cancer, the third leading cause of cancer death worldwide (Sung et al, 2021). As a highly malignant tumor, the 5year survival rate of HCC is less than 18% (Villanueva, 2019). Treatment options for HCC include hepatic resection, liver transplantation, image-guided ablation, transarterial therapies, chemotherapy, and molecularly targeted therapy (Llovet et al, 2021). Patients with HCC are often treated by a combination of several modalities. Even after successful tumor eradication, the recurrence rate of HCC is remarkably high. Immunotherapy has been shown to improve the clinical efficacy of advanced HCC. Unlike the mechanism of action of conventional therapy, immunotherapy is based on activating the patient’s own immune system to fight against tumors (Ringelhan et al, 2018). It is vital to identify a metabolism-related signature to assess the TME and improve the treatment efficacy of immunotherapy
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