Development and validation of a basement membrane-associated immune prognostic model for hepatocellular carcinoma.

Abstract

Background: Hepatocellular carcinoma (HCC), one of the most common malignant tumors worldwide, has a poor prognosis primarily due to its invasive and metastatic characteristics. Cancer invasion through basement membrane (BM) is the pivotal initial step in tumor dissemination and metastasis. This study aimed to identify gene signatures associated with the BM to enhance the overall prognosis of HCC.

Methods: In this study, we performed multiple bioinformatics analyses based on the RNA sequencing (RNA-seq) data and clinical information from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. An unsupervised consistent cluster analysis was conducted on 370 HCC patients, categorizing them into two distinct groups based on the expression profiles of 222 BM-related genes. Differentially expressed genes (DEGs) between these clusters were identified, followed by functional enrichment analysis. To explore the differences between the groups, the Estimation of STromal and Immune cells in MAlignant Tumours using Expression data (ESTIMATE) and Cell type Identification By Estimating Relative Subsets Of known RNA Transcripts (CIBERSORT) algorithms were applied, along with the analysis of immune checkpoint molecules and human leukocyte antigen (HLA) expression levels. This helped in understanding the relationship between the HCC immune microenvironment and BM-related genes. A prognostic model was constructed using univariate Cox and least absolute shrinkage and selection operator (LASSO) regression analyses, with its performance subsequently estimated and validated. Additionally, hub biomarkers genes were identified using machine learning techniques, followed by an analysis of their functions and relationships with clinical characteristics. Finally, single-cell clustering analysis was employed to further investigate the expression distribution of these genes within the HCC immune microenvironment.

Results: Following consistent cluster analysis, two groups were identified: the BM high group and the BM low group. Among the 6,221 DEGs between the two groups, 5,863 were upregulated and 358 were downregulated, with enrichment functions primarily associated with extracellular matrix (ECM) organization, cell adhesion, immune response, and metabolism. The expression levels of BM-related genes were found to regulate the HCC immune microenvironment. Using univariate Cox regression analysis, 60 prognostic BM-related genes were identified, leading to the establishment of an 11-gene prognostic model named BMscore to predict the overall survival (OS) of HCC patients. The high BMscore group indicated worse prognosis, and the model's predictive performance was validated using the GEO dataset. P3H1 and ADAMTS5 were identified as hub biomarkers, playing roles in cell proliferation and ECM metabolism, with their expression distributions mapped respectively.

Conclusions: A prognostic model based on BM-related genes was successfully developed and shows promise for evaluating prognoses and offering personalized treatment recommendations.