Extracellular Matrix-Based Gene Expression Signature Defines Two Prognostic Subtypes of Hepatocellular Carcinoma With Different Immune Microenvironment Characteristics

Abstract

Background: Accumulating evidence has suggested that the extracellular matrix (ECM) plays a vital role in the development and progression of cancer, and could be recognized as a biomarker of the response to immunotherapy. However, the effect of the ECM signature in hepatocellular carcinoma (HCC) is not well understood.Methods: HCC patients derived from the TCGA-LIHC dataset were clustered according to the ECM signature. The differences in prognosis, functional enrichment, immune infiltration, and mutation characteristics between distinct molecular clusters were examined, and its predictive value on the sensitivities to chemotherapy and immunotherapy was further analyzed. Then, a prognostic model was built based on the ECM-related gene expression pattern.Results: HCC patients were assigned into two molecular subtypes. Approximately 80% of HCC patients were classified into cluster A with poor prognosis, more frequent TP53 mutation, and lower response rate to immunotherapy. In contrast, patients in cluster B had better survival outcomes and higher infiltration levels of dendritic cells, macrophages, and regulatory T cells. The prognostic risk score model based on the expression profiles of six ECM-related genes (SPP1, ADAMTS5, MMP1, BSG, LAMA2, and CDH1) demonstrated a significant association with higher histologic grade and advanced TNM stage. Moreover, the prognostic risk score showed good performance in both the training dataset and validation dataset, as well as improved prognostic capacity compared with TNM stage.Conclusions: We characterized two HCC subtypes with distinct clinical outcomes, immune infiltration, and mutation characteristics. A novel prognostic model based on the ECM signature was further developed, which may contribute to individualized prognostic prediction and aid in clinical decision-making.

PDCL3 is a prognostic biomarker associated with immune infiltration in hepatocellular carcinoma

“…Therefore, PDCL3 may serve as a relevant target in immunotherapy. Previous studies indicated that LIHC patients with high macrophage infiltration have a better prognosis [ 36 ], consistent with our findings.…”

Development and validation of an ECM-related prognostic signature to predict the immune landscape of human hepatocellular carcinoma

“…The principal cause of this difference was based on our selection of a lncRNA set that was coexpressed with ECM-related genes. Two signatures consisting of ECM-related genes have been previously reported [ 24 , 25 ]; however, these signatures were not equivalent to our lncRNA signature. Indeed, comprehensive studies were performed to evaluate the prognostic value of the models generated using these signatures, and these signatures also predicted the immune landscape as well as drug sensitivity.…”

Tumor Microenvironment Composition and Related Therapy in Hepatocellular Carcinoma

“…78 Research has identified six ECM-associated genes (namely SPP1, ADAMTS5, MMP1, BSG, LAMA2, and CDH1) that correlate with a dismal prognosis in HCC patients. 79 ECM is gradually remodeled by cancer cells in TME, which facilitates tumor development and metastasis. 80 MMPs are a class of zinc-dependent endoproteases that disrupt the ECM by destroying the structure of different proteins within it.…”