Enhanced glycolysis is associated with aggressive tumor phenotype and worse outcomes in hepatocellular carcinoma patients

Masanori Oshi^1*Colin Rog²Li Yan²Itaru Endo¹Kazuaki Takabe²

• ¹Yokohama City University Hospital, Yokohama, Japan
• ²Roswell Park Comprehensive Cancer Center, University at Buffalo, Buffalo, New York, United States

In non-malignant cells, ATP is mainly generated by oxidative phosphorylation in nonmalignant cells, whereas malignant cells rely predominantly on increased glycolysis for energy production, known as the "Warburg effect," for energy production. This study used the gene set variation analysis (GSVA) algorithm to evaluate glycolysis signaling in hepatocellular carcinoma (HCC), finding it linked to and investigated its relationship with tumor aggressiveness and patient prognosis tumor phenotype and poor prognosis, highlighting glycolysis markers as potential prognostic indicators. Methods: Enhanced level of glycolysis signaling was measured using the "Hallmark-GLYCOLYSIS" gene set in the MSigDB, applied via by gene set variation analysisGSVA in across multiple independent HCC cohorts. Results: There was no significant difference in glycolysis signaling scores between HCC and other liver disease statusess in two cohorts. However, Enhanced enhanced glycolysis signaling linked to gene sets associated with cell proliferation-and cancer-promotingother precancerous-related pathways, such as unfolded protein response, epithelial mesenchymal transition, and apoptosis, consistently in both cohorts. HCC with high glycolysis signaling score showed increased homologous recombination defects deficiency (p= 0.004), intratumor heterogeneity (p = 0.005), and higher mutation rates burden (p= 0.022). Except for Th1 cells, nNo significant consistent associations with glycolysis were observed with various immune cells infiltration nor in tumor microenvironment and cytolytic activity, except for Th1 cells. of HCC were found consistently across both cohorts. Finally Clinically, high glycolysis signaling scores correlated were associated with advanced tumor stage and significantly aggressive clinicopathological features and worse patient survival outcomes, serving as an independent, poor 2 of 15 prognostic factorsbiomarker for HCC patients (hazard ratio (HR)=6.78 and p< 0.001 in OS, HR= 6.56 and p=0.027 in DSS). Conclusions: High Elevated glycolysis signaling scores were is linked to correlated with enhanced malignant pathways, genomic instability, and ment of several hallmark cancer-related signaling pathways, advanced worse clinical outcomes in HCCdisease stage, and comparatively worse survival outcomes, indicating its potential as a they are an independent prognostic biomarkerfactor for HCC.