Integrated analysis of lactate-related genes identifies POLRMT as a novel marker promoting the proliferation, migration and energy metabolism of hepatocellular carcinoma via Wnt/β-Catenin signaling

Abstract

Hepatocellular carcinoma (HCC) is a prevalent and deadly form of cancer globally with typically unfavorable outcomes. Increasing research suggests that lactate serves as an important carbon contributor to cellular metabolism and holds a crucial part in the progression, sustenance, and treatment response of tumors. However, the contribution of lactate-related genes (LRGs) in HCC is still unclear. In this study, we analyzed TCGA datasets and screened 21 differentially expressed LRGs related to long-term survivals in HCC patients. Pan-cancer assays revealed that 21 LRGs expression exhibited a dysregulated level in man types of tumors and associated with clinical prognosis of tumor patients. The analysis of 21 LRGs successfully classified HCC samples into two molecular subtypes, and these two subtypes showed significant differences in clinical information, gene expression, and immune characteristics. Subsequently, based on the aforementioned 21 LRGs, a novel prognostic signature (DTYMK, IRAK1, POLRMT, MPV17, UQCRH, PDSS1, SLC16A3, SPP1 and LDHD) was generated by LASSO-Cox regression analysis. Survival assays demonstrated that the signature performed well in predicting the overall survival of patients with HCC. The results of Gene Set Variation Analysis indicated that the high GSVA scores were associated with poor prognosis. Moreover, we also investigated the correlation between GSVA scores and various signaling pathways in HCC. Among the nine prognostic genes, our attention focused on POLRMT which was highly expressed in HCC specimens based on TCGA datasets and several HCC cell lines. In addition, functional assays indicated that POLRMT distinctly promoted the proliferation, migration and energy metabolism of HCC cells via regulating Wnt/β-Catenin signaling. Overall, through the establishment of a novel prognostic signature, we have provided potential clinical value for assessing the prognosis of HCC patients. Furthermore, our study has identified the high expression of POLRMT in HCC and demonstrated its crucial role in HCC cell proliferation. These findings hold great importance in advancing our understanding of the pathophysiology of HCC, identifying new therapeutic targets, and improving patient survival rates.