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Up-regulation of an epithelial miRNA is associated with immune evasion in progressive bronchial premalignant lesions [PCGA_miRNA_BX]

ABSTRACT: Bronchial premalignant lesions (PMLs), precursors of lung squamous cell carcinoma, have distinct molecular subtypes. The proliferative subtype, enriched with bronchial dysplasia, had decreased expression of an antigen processing/presentation gene co-expression module in progressive/persistent versus regressive PMLs, suggesting a functional impact of these genes on immune evasion. Here, we performed miRNA sequencing, miRNA in situ hybridization (ISH), and spatial proteomics of bronchial biopsies from patients at high risk for lung cancer. A miRNA-gene network analysis identified hsa-miR-149-5p as a potential regulator of the antigen presentation gene module. Staining on adjacent biopsy tissue showed that hsa-miR-149-5p was predominantly expressed in the epithelium and up-regulated in progressive/persistent proliferative lesions. Targets of this miRNA, the transcriptional coactivator of MHC-I gene expression, NLRC5, and the genes it regulates were down-regulated in these lesions. Decreased NLRC5 expression reduced both IFN-gamma induced MHC-I surface expression and CD8 T cell cytotoxicity in lung squamous cancer cells. In PMLs, basal cells with high levels of NLRC5 were in close spatial proximity to CD8 T cells, suggesting that these cells exhibit increased functional MHC-I gene expression in vivo. These findings indicate a functional role for hsa-miR-149-5p in PML progression/persistence and suggest this axis as a potential therapeutic target for PML immunomodulation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE313145 | GEO | 2025/12/10

REPOSITORIES: GEO

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Project description:Invasive lobular carcinoma (ILC) of the breast accounts for 5-15% of breast cancers and is characterized by loss of E-cadherin and believed to arise via a linear histological progression. Genomic studies have identified a clonal relationship between ILC and concurrent lobular carcinoma in situ (LCIS) lesions, suggesting that LCIS may be a precursor lesion. It has been shown that an LCIS diagnosis confers a 15-20% risk of progression to ILC, over a lifetime. Currently no molecular test or markers can identify LCIS lesions likely to progress to ILC. Since microRNA (miRNA) expression changes have been detected in a number of other cancer types, we explored whether their dysregulation might be detected during progression from LCIS to ILC. Using the Illumina miRNA profiling platform, designed for simultaneous analysis of 470 mature miRNAs, we analyzed the profiles of archived normal breast epithelium, LCIS lesions found alone, LCIS lesions concurrent with ILC, and the concurrent ILCs, as a model of linear histological progression toward ILC. We identified two sets of differentially expressed miRNAs, the first set highly expressed in normal epithelium, including hsa-miR-224, -139, -10b, -450, 140 and -365 and the second set upregulated during lobular neoplasia, including hsa-miR-375, -203, -425-5p, -183, -565 and -182. Using quantitative RT-PCR, we validated a trend of increased expression for hsa-mir-375, hsa-mir-182, and hsa-mir-183 correlating with ILC progression. As we detected increased expression of hsa-miR-375 in LCIS lesions synchronous with ILC, we sought to determine whether hsa-mir-375 might induce phenotypes reminiscent of lobular neoplasia by expressing it in the MCF10A 3D culture model of mammary acinar morphogenesis. Increased expression of hsa-miR-375 resulted in loss of cellular organization and acquisition of a hyperplastic phenotype. These data suggest that dysregulated miRNA expression contributes to lobular neoplastic progression.

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Up-regulation of an epithelial miRNA is associated with immune evasion in progressive bronchial premalignant lesions [PCGA_miRNA_BX]

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