Construction and validation of novel lactate metabolism molecular subtypes in hepatocellular carcinoma based on multi-omics analysis

Abstract

Abstract Purpose Lactate, as a metabolic byproduct, has been found to promote carcinogenesis and induce immunosuppression in certain types of cancer. The objective of this study is to investigate the role of lactate metabolism-related regulatory genes in hepatocellular carcinoma (HCC). Methods In this study, we compiled transcriptomics data, genomic structural variation data (SNV, CNV) from The Cancer Genome Atlas (TCGA), as well as our proteomics data. We constructed the lactate metabolism score (LMScore) by integrating consensus clustering, differential analysis, and principal component analysis based on TCGA transcriptome data. Subsequently, we decoded the differences in clinical outcomes, mutation landscape, biological behaviors, immune characteristics and potential therapeutic drugs between distinct subtypes. Western blot (WB) was used to evaluate the protein levels of different tissues. Results The findings demonstrated a significant negative correlation between LMScore and the progression of HCC. Patients in distinct subtypes showed significant differences at multiple omics levels, such as transcriptome profiling, mutational landscape, and protein levels. Specifically, Patients in high LMScore subtype had a better prognosis and were more likely to benefit from immune therapy and clinical first- and second-line therapy including cisplatin and lenvatinib. Moreover, Patients in the low-score subtype exhibited high levels of immune cell infiltration, upregulation of immune checkpoints, and poor response of immunotherapy, suggesting an immune-suppressive microenvironment. Drug sensitivity analysis demonstrated these patients, who were not suitable for immunotherapy, could benefit more from drugs like paclitaxel and sorafenib. In addition, we found that TTC36 is a prognostic gene that not only affects the progression of HCC but also alters lactate metabolism levels. Upregulation of TTC36 can inhibit proliferation, invasion, migration, and lactate metabolism of HCC cell. Conclusion According to the lactate metabolism regulated genes, we constructed the LMScore, which can serve as powerful tool in stratifying HCC patients and decoding HCC heterogeneity. Moreover, this model can guide the treatment of immune therapy and clinical first- and second-line drugs, offering an optimized decision-making platform for HCC patients.