The multifaceted roles of COL4A4 in lung adenocarcinoma: An integrated bioinformatics and experimental study

• Published in: Computers in biology and medicine 2024-03, Vol.170, p.107896, Article 107896
• Main Authors: Zheng, Tiaozhan, Zheng, Zhiwen, Zhou, Hanxi, Guo, Yiqing, Li, Shikang
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Adenocarcinoma of Lung - genetics; Bioinformatics; Cancer; Cell growth; Cloning; COL4A4; Collagen; Collagen (type IV); Collagen IV; Collagen Type IV - genetics; Computational Biology; Databases, Factual; Disease; Drug resistance; Experimental methods; Gene expression; Genes; Genotype & phenotype; Humans; Immune checkpoint; Immunoregulation; Immunotherapy; Lung adenocarcinoma; Lung cancer; Lung Neoplasms - genetics; Lungs; Medical prognosis; Parameters; Pathogenesis; Prognosis; RNA-protein interactions; Senescence; Software packages; Stat3 protein; Therapeutic targets; Thoracic surgery; Tumor microenvironment; Tumor Microenvironment - genetics; Tumors
• ISSN: 0010-4825; 1879-0534; 1879-0534
• DOI: 10.1016/j.compbiomed.2023.107896

Abnormal expression of collagen IV subunits has been reported in cancers, but the significance is not clear. No study has reported the significance of COL4A4 in lung adenocarcinoma (LUAD). COL4A4 expression data, single-cell sequencing data and clinical data were downloaded from public databases. A range of bioinformatics and experimental methods were adopted to analyze the association of COL4A4 expression with clinical parameters, tumor microenvironment (TME), drug resistance and immunotherapy response, and to investigate the roles and underlying mechanism of COL4A4 in LUAD. COL4A4 is differentially expressed in most of cancers analyzed, being associated with prognosis, tumor stemness, immune checkpoint gene expression and TME parameters. In LUAD, COL4A4 expression is down-regulated and associated with various TME parameters, response to immunotherapy and drug resistance. LUAD patients with lower COL4A4 have worse prognosis. Knockdown of COL4A4 significantly inhibited the expression of cell-cycle associated genes, and the expression and activation of signaling pathways including JAK/STAT3, p38, and ERK pathways, and induced quiescence in LUAD cells. Besides, it significantly induced the expression of a range of bioactive molecule genes that have been shown to have critical roles in TME remodeling and immune regulation. COL4A4 is implicated in the pathogenesis of cancers including LUAD. Its function may be multifaceted. It can modulate the activity of LUAD cells, TME remodeling and tumor stemness, thus affecting the pathological process of LUAD. COL4A4 may be a prognostic molecular marker and a potential therapeutic target. •Multifaceted roles of COL4A4 in lung adenocarcinoma.•Correlation of COL4A4 with the prognosis of lung adenocarcinoma.•COL4A4 regulates lung adenocarcinoma cells' activity.•COL4A4 regulates tumor microenvironment in lung adenocarcinoma.•COL4A4 regulates IL-6, AREG, EREG, VEGFC, LIF, IL-1α, CCL20 and CCL5 expression.