Integrative analysis of multi-omics data identified PLG as key gene related to Anoikis resistance and immune phenotypes in hepatocellular carcinoma

Abstract

Purpose The extracellular matrix (ECM) plays a pivotal role in the initiation and progression of hepatocellular carcinoma (HCC) by facilitating the proliferation of HCC cells and enabling resistance to Anoikis. ECM also provide structural support that aids in the invasion of HCC cells, thereby influencing the tumor microenvironment. Due to genetic variations and molecular heterogeneity, significant challenges exist in the treatment of HCC, particularly with immunotherapy, which frequently leads to immune tolerance and suboptimal immune responses. Therefore, there is an urgent need for a multi-omics-based classification system for HCC that clarifies the molecular mechanisms underlying the establishment of immune phenotypes and Anoikis resistance in HCC cells. In this study, we employed advanced clustering algorithms to analyze and integrate multi-omics data from HCC patients, with the objective of identifying key genes that possess prognostic potential associated with the Anoikis resistance phenotype. This methodology resulted in the development of a consensus machine learning-driven signature (CMLS), which demonstrates robust predictive capabilities by examining variations in epigenetics, transcription, and immune metabolism, as well as their effects on the core differential gene, plasminogen (PLG). Results The integrated multi-omics approach has identified PLG as a critical node within the gene regulatory network associated with Anoikis resistance and immunometabolic phenotypes. As an independent risk factor for poor prognosis in patients with HCC, PLG facilitates Anoikis resistance and enhances the migration of HCC cells. This study provides novel insights into the molecular subtypes of HCC through the application of robust clustering algorithms based on multi-omics data. The constructed CMLS serves as a valuable tool for early prognostic prediction and for screening potential drug candidates that may enhance the efficacy of immunotherapy, thereby establishing a foundation for personalized treatment strategies in HCC. Conclusions Our data underscore the pivotal role of PLG in the development of Anoikis resistance and the immunometabolic phenotype in HCC cells. Furthermore, we present compelling experimental evidence that PLG functions as a significant tumor promoter, suggesting its potential as a target for the formulation of tailored therapeutic strategies for HCC.