Exploration of signature-related FAM genes and correlation between FAM50A expression and the pathogenesis and prognosis of hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) ranks among the deadliest malignancies worldwide, with limited therapeutic options and poor prognosis for advanced-stage patients. The family with sequence similarity (FAM) genes are expected to be potential regulators in tumorigenesis, but their roles in HCC remain poorly understood. This study aimed to systematically investigate the expression profiles and functional roles of FAM genes in HCC.

Methods: We leveraged multiple databases, including The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), International Cancer Genome Consortium (ICGC), Gene Expression Omnibus (GEO), Human Protein Atlas (HPA), and Clinical Proteomic Tumor Analysis Consortium (CPTAC), to assess the expression patterns, prognostic implications, DNA methylation, genomic alterations, and associated tumor immune microenvironments of FAM genes. Differentially expressed genes were pinpointed using the DESeq2 package. Least absolute shrinkage and selection operator (LASSO) Cox regression and a nomogram model were employed to identify prognostic FAM genes and estimate the survival outcomes for HCC patients. We performed tissue microarrays and immunohistochemistry on samples from 48 HCC patients to evaluate FAM50A expression. FAM50A was also knocked down in HCC cell lines to investigate its biological functions.

Results: Five overexpressed and signature-related FAM genes (FAM50A, FAM83D, FAM104B, FAM220A, and FAM222B) were identified and validated at both mRNA and protein levels. Elevated FAM50A expression was linked to advanced tumor stage, higher grade, and unfavorable prognosis. The constructed prognostic nomogram accurately predicted 1- and 3-year survival outcomes based on tumor stage, status, and FAM50A expression levels. Pathways enriched in FAM50A co-expressed genes included RNA processing, oxidative phosphorylation, and cell cycle regulation. Additionally, FAM50A expression was associated with immune cell infiltration and immune checkpoint activity. Knockdown of FAM50A led to the suppression of HCC cell proliferation, migration, and invasion.

Conclusions: This study identifies five FAM genes with prognostic relevance in HCC, among which FAM50A emerges as a potential independent prognostic biomarker and therapeutic target.