Identification of novel lactate metabolism signatures and molecular subtypes for prognosis in hepatocellular carcinoma

Abstract

Background: Evidence has shown that lactate, an immune signaling molecule, is associated with hepatocellular carcinoma (HCC) progression and immune suppression. Therefore, identifying lactate metabolism-related molecules is a promising therapeutic strategy to inhibit the development of HCC and overcome chemotherapy resistance. Long noncoding RNAs (lncRNAs) are related to tumorigenesis and metastasis. Hence, verifying the molecular subtypes of lncRNAs related to lactate metabolism will play a critical role in managing HCC. Methods: Based on HCC data in The Cancer Genome Atlas (TCGA), lactate metabolic pathway-related genes were enriched by gene collection and enrichment analysis (GSEA). Lactate metabolism-related lncRNAs (LM_lncRNAs) were identified by correlation analysis, HCC molecular subtypes were determined using nonnegative matrix factorization (NMF) clustering, and the response of the three subtypes to chemotherapeutics was further evaluated using the Genomic Tumor Sensitive Cell Line (GDSC) dataset. LM_lncRNAs were examined via Lasso-Cox regression analysis to determine prognosis for patients. A Nomagram plot was used to predict patient survival time. Results: Three molecular subtypes of HCC were identified. The survival rate of patients with C1 subtype was higher than that of those with C2 and C3. Additionally, patients with C3 subtype have higher levels of immune cell infiltration and high expression of genes related to immune checkpoints. The GDSC results indicated that patients with C3 subtypes were more sensitive to chemotherapy drugs such as sorafenib and sunitinib. The prognostic risk assessment model consisted of six risk factors (AC034229.4, AC131009.1, MYOSLID, AC008667.1, AC012073.1, AC068025.1) and two protective factors (LINC00402 and AC103858.1). Based on Kaplan-Meier analysis, low-risk HCC patients had a high survival rate, and the receiver operating characteristic curve (ROC), calibration curve, and C-index confirmed good prediction ability. Conclusion: In this study, the molecular subtyping method and prediction model of lactate metabolism-related lncRNAs (LM_lncRNAs) were constructed for the prognosis of HCC patients. This work demonstrated the potential targets of LM_lncRNAs and provided a novel perspective and therapeutic paradigm for future clinical translation.

Keywords: hepatocellular carcinoma; lactate metabolism; lncRNAs; molecular subtype; prognostic model.