Wang Qi, Zhong Yixiu, Li Zhijia, Zhu Dingheng, Lu Hongyan, Chen Pingjiao, Li Changxing, Peng Xuebiao, Li Qian, Zeng Kang
Department of Dermatology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
Molecular Diagnosis and Treatment Center for Infectious Diseases, Dermatology Hospital, Southern Medical University, Guangzhou 510091, China.
Burns Trauma. 2022 May 9;10:tkac013. doi: 10.1093/burnst/tkac013. eCollection 2022.
A keloid is a disease of excessive fibrosis that is characterized by the aberrant proliferation of fibroblasts. However, the molecular mechanisms of fibroblasts during the development of keloids remain unclear. This study aims to identify new molecular targets that promote the proliferation and migration of keloid fibroblasts, providing new ideas for the prevention and treatment of keloids.
We utilized bioinformatics tools to analyze data from keloid fibroblasts (KFs) available in the Gene Expression Omnibus (GEO) database to identify the key genes involved in keloid development. Homeobox C6 () emerged as a hub gene in KFs from the GEO database was verified in keloid tissue samples and KFs using reverse transcription-quantitative polymerase chain reaction, western blot (WB) and immunohistochemistry. Subsequently, the effects of downregulated expression on the cellular behaviors of KFs were examined by performing Cell Counting Kit-8, flow cytometry, transwell migration and WB assays. Meanwhile, we performed transcriptome sequencing and gene set enrichment analysis (GSEA) to further explore HOXC6-related mechanisms and validated the signaling pathways by performing a series of experiments.
was the top-ranking hub gene of KFs in microarray datasets from GEO and was upregulated in keloid tissue samples and KFs. Downregulation of inhibited proliferation, migration and extracellular matrix (ECM) accumulation and promoted KF apoptosis. GSEA predicted that the hypoxia signaling pathway was associated with in KFs. Transcriptome sequencing suggested that the extracellular regulated protein kinase (ERK) pathway was one of the downstream pathways of in KFs. Our experiments confirmed that hypoxia-inducible factor-1α (HIF-1α) upregulates , contributing to KFs proliferation, migration, apoptosis inhibition and collagen accumulation through the ERK signaling pathway.
Our findings first revealed that acts as an oncogenic driver in the molecular mechanisms of fibroblasts in keloids. The HIF-1α/HOXC6/ERK axis promotes proliferation, migration and ECM production by KFs, contributing to the progression of keloids. Taken together, HOXC6 may serve as a promising novel therapeutic target and new focus for research designed to understand the pathogenesis of keloids.
瘢痕疙瘩是一种过度纤维化疾病，其特征为成纤维细胞异常增殖。然而，瘢痕疙瘩形成过程中成纤维细胞的分子机制仍不清楚。本研究旨在鉴定促进瘢痕疙瘩成纤维细胞增殖和迁移的新分子靶点，为瘢痕疙瘩的防治提供新思路。
我们利用生物信息学工具分析基因表达综合数据库（GEO）中瘢痕疙瘩成纤维细胞（KFs）的数据，以鉴定参与瘢痕疙瘩形成的关键基因。在GEO数据库中，同源盒C6（HOXC6）作为KFs中的一个枢纽基因出现，通过逆转录定量聚合酶链反应、蛋白质免疫印迹（WB）和免疫组织化学在瘢痕疙瘩组织样本和KFs中进行验证。随后，通过细胞计数试剂盒-8、流式细胞术、Transwell迁移和WB实验检测下调HOXC6表达对KFs细胞行为的影响。同时，我们进行转录组测序和基因集富集分析（GSEA）以进一步探索HOXC6相关机制，并通过一系列实验验证信号通路。
HOXC6是GEO微阵列数据集中KFs排名第一的枢纽基因，在瘢痕疙瘩组织样本和KFs中上调。下调HOXC6可抑制增殖、迁移和细胞外基质（ECM）积累，并促进KFs凋亡。GSEA预测缺氧信号通路与KFs中的HOXC6相关。转录组测序表明，细胞外调节蛋白激酶（ERK）通路是KFs中HOXC6的下游通路之一。我们的实验证实，缺氧诱导因子-1α（HIF-1α）上调HOXC6，通过ERK信号通路促进KFs增殖、迁移、抑制凋亡和胶原积累。
我们的研究结果首次揭示，HOXC6在瘢痕疙瘩成纤维细胞的分子机制中作为致癌驱动因子发挥作用。HIF-1α/HOXC6/ERK轴促进KFs增殖、迁移和ECM产生，促进瘢痕疙瘩进展。综上所述，HOXC6可能是一个有前景的新型治疗靶点，也是旨在了解瘢痕疙瘩发病机制研究的新焦点。
