Fibulin-5 (FBLN5) as a context-dependent pan-cancer regulator: integrated multi-omics analysis reveals dual roles in tumor progression and therapeutic resistance.

BACKGROUNDFibulin-5 (FBLN5) is a key member of the extracellular matrix (ECM), which plays an important role in the occurrence and development of tumors. This study aimed to determine the role of FBLN5 in the diagnosis, prognosis, and immune regulation of tumors using a pan-cancer analysis.

METHODSBy integrating and analyzing data from multiple public databases, including The Cancer Genome Atlas (TCGA), Firehose, University of California, Santa Cruz (UCSC) Xena, cBioPortal, Gene Expression Omnibus (GEO), Clinical Proteomic Tumor Analysis Consortium (CPTAC), Tumor Immune Estimation Resource 2.0 (TIMER2.0), Tumor Immune Single-cell Hub (TISCH), CellMiner, Genomics of Drug Sensitivity in Cancer (GDSC), and Cancer Therapeutics Response Portal (CTRP), we comprehensively investigated the diagnostic and prognostic potential of FBLN5 across multiple types. We further performed a gene set enrichment analysis (GSEA) to elucidate the biological functions associated with FBLN5 expression. Additionally, a survival analysis was conducted to assess its prognostic value, and genetic alteration, methylation, and pathway analyses were also performed. Finally, we examined the relationship between FBLN5 and immunity response, and identified potential drugs that may affect the efficacy of tumor treatment.

RESULTSThe analysis of TCGA data revealed that FBLN5 RNA was differentially expressed across multiple tumor types, and in 92% of tumor types, the expression level of FBLN5 protein is lower. Genetic and epigenetic alterations-including mutations, somatic copy number alterations, and DNA methylation-were associated with its dysregulated expression. FBLN5 expression was also correlated with several key clinical features. Further, functional analyses linked FBLN5 expression to various metabolism-, metastasis-, and immune-related pathways. Elevated FBLN5 expression had a controversial effect on prognosis across multiple tumors, and influenced sensitivity to numerous therapeutic agents. Additionally, FBLN5 expression showed significant correlations with immunoregulatory molecules and biomarkers indicative of lymphocyte subpopulation infiltration.

CONCLUSIONSThis study conducted a systematic analysis of FBLN5 and its regulatory network, demonstrating that FBLN5 expression is closely associated with DNA methylation and drug resistance across multiple tumor types. Further, FBLN5 was found to remodel the tumor microenvironment and cause resistance to immunotherapy.