Integrated genetic and transcriptomic analyses suggest a miR-539-3p/SOX9-associated expression pattern in keloids
- 1Department of Dermatology, Yanbian University Hospital, Yanbian University Medical College, Yanji, China
- 2Keloid Research Center, Department of Dermatology, Yanbian University Medical College, Yanji, China
Abstract
Background: Keloids are fibroproliferative scars characterized by persistent inflammation, aberrant wound healing, and excessive extracellular matrix deposition. Although dysregulated miRNAs have been reported in keloids, their links to disease susceptibility and downstream fibrotic pathways remain incompletely defined.
Methods: We integrated miRNA-QTL-based Mendelian randomization with differential expression analysis of GSE237753 to prioritize keloid-associated miRNAs. Targets of miR-539-3p were screened using miRTarBase, miRDB, and TargetScan, followed by functional annotation and literature-guided prioritization. miR-539-3p and SOX9 expression were assessed by qRT-PCR in eight paired primary normal skin-derived and keloid-derived fibroblast samples, and SOX9 protein expression was examined by immunohistochemistry in 20 independent tissue specimens. SOX9-centered networks were constructed using STRING and GeneMANIA, followed by Gene Ontology and KEGG enrichment analyses. SOX9 mRNA and protein were also measured after miR-539-3p inhibitor treatment.
Results: Mendelian randomization identified nine miRNAs nominally associated with keloid susceptibility, but none remained significant after FDR correction. miR-539-3p showed a nominal inverse association and was the only miRNA overlapping with the differential expression results. In paired primary fibroblasts, both miR-539-3p and SOX9 expression were higher in keloid-derived cells (P = 3.69 × 10−5 and P = 1.09 × 10−5, respectively). SOX9 immunohistochemistry showed stronger staining in keloid tissue specimens (P = 5.18 × 10−5). SOX9 mRNA and protein were higher after inhibitor treatment than after negative-control treatment in three independent experiments per assay. Network analyses linked SOX9 to extracellular matrix organization, connective tissue development, Notch signaling, and TGF-β/Wnt-related remodeling.
Discussion: The genetic analysis focused on genetically predicted circulating miR-539-3p levels, whereas the expression data came from established keloid tissues and derived fibroblasts. These findings reflect different biological contexts, and their different directions are not necessarily contradictory. The increase in SOX9 after miR-539-3p inhibitor treatment warrants further investigation of its potential regulation by miR-539-3p,but does not establish direct targeting in keloid fibroblasts. The expression and network findings provide a rationale for studying whether SOX9 contributes to fibroblast activation and extracellular matrix production in keloids.
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BibTeX
@article{luo2026integrated,
title = {{Integrated genetic and transcriptomic analyses suggest a miR-539-3p/SOX9-associated expression pattern in keloids}},
author = {Zhanpeng Luo and Ling Ge and Lili Chen and Shaoyou Lin and Tianhui Wei and Bo Lu and Zhehu Jin},
journal = {Frontiers in Cell and Developmental Biology},
year = {2026},
month = oct,
doi = {10.3389/fcell.2026.1931861},
url = {https://doi.org/10.3389/fcell.2026.1931861},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Integrated genetic and transcriptomic analyses suggest a miR-539-3p/SOX9-associated expression pattern in keloids
AU - Zhanpeng Luo
AU - Ling Ge
AU - Lili Chen
AU - Shaoyou Lin
AU - Tianhui Wei
AU - Bo Lu
AU - Zhehu Jin
PY - 2026
DA - 2026/10/21
JO - Frontiers in Cell and Developmental Biology
DO - 10.3389/fcell.2026.1931861
UR - https://doi.org/10.3389/fcell.2026.1931861
AB - Background: Keloids are fibroproliferative scars characterized by persistent inflammation, aberrant wound healing, and excessive extracellular matrix deposition. Although dysregulated miRNAs have been reported in keloids, their links to disease susceptibility and downstream fibrotic pathways remain incompletely defined. Methods: We integrated miRNA-QTL-based Mendelian randomization with differential expression analysis of GSE237753 to prioritize keloid-associated miRNAs. Targets of miR-539-3p were screened using miRTarBase, miRDB, and TargetScan, followed by functional annotation and literature-guided prioritization. miR-539-3p and SOX9 expression were assessed by qRT-PCR in eight paired primary normal skin-derived and keloid-derived fibroblast samples, and SOX9 protein expression was examined by immunohistochemistry in 20 independent tissue specimens. SOX9-centered networks were constructed using STRING and GeneMANIA, followed by Gene Ontology and KEGG enrichment analyses. SOX9 mRNA and protein were also measured after miR-539-3p inhibitor treatment. Results: Mendelian randomization identified nine miRNAs nominally associated with keloid susceptibility, but none remained significant after FDR correction. miR-539-3p showed a nominal inverse association and was the only miRNA overlapping with the differential expression results. In paired primary fibroblasts, both miR-539-3p and SOX9 expression were higher in keloid-derived cells (P = 3.69 × 10−5 and P = 1.09 × 10−5, respectively). SOX9 immunohistochemistry showed stronger staining in keloid tissue specimens (P = 5.18 × 10−5). SOX9 mRNA and protein were higher after inhibitor treatment than after negative-control treatment in three independent experiments per assay. Network analyses linked SOX9 to extracellular matrix organization, connective tissue development, Notch signaling, and TGF-β/Wnt-related remodeling. Discussion: The genetic analysis focused on genetically predicted circulating miR-539-3p levels, whereas the expression data came from established keloid tissues and derived fibroblasts. These findings reflect different biological contexts, and their different directions are not necessarily contradictory. The increase in SOX9 after miR-539-3p inhibitor treatment warrants further investigation of its potential regulation by miR-539-3p,but does not establish direct targeting in keloid fibroblasts. The expression and network findings provide a rationale for studying whether SOX9 contributes to fibroblast activation and extracellular matrix production in keloids.
SN - 2296-634X
ER -