Objective

Staphylococcal nuclease domain-containing 1 (SND1) that functioned as an oncogene in a variety of tumors was upregulated in burn-injured skin tissues, and this study aims to investigate the effect of SND1 on keloid and elucidate the underlying mechanism.

Methods

Keloid fibroblasts (KFs) and normal skin fibroblasts (NFs) were isolated from the keloid tissues and adjacent normal skin tissues of keloid patients. The SND1 expression was assessed in keloid tissues and KFs with Western blot assay. Gain- and loss-of-function experiments were performed to investigate the role of SND1 in proliferation, colony formation, telomerase activity, expression of fibrogenic genes and production of pro-inflammatory factors in KFs. Chromatin immunoprecipitation (CHIP) and Dual-luciferase reporter gene assays were used to verify the interaction of Paired-box gene 5 (PAX5) on SND1 promoter. Then, a series of rescue experiments were performed to verify the effects of SND1 overexpression on PAX5 knockdown-mediated KF functions. Finally, the role of SND1 in keloid formation in vivo was validated in mice with keloid implantation.

Results

SND1 was upregulated in keloid tissues and KFs. SND1 positively regulated proliferation, colony formation, telomerase activity, production of pro-inflammatory factors and expression of fibrogenic genes. PAX5 directly bound to the SND1 promoter to transcriptionally regulate SND1 expression and positively regulated SND1-mediated KF functions via the ERK/JNK pathway. In vivo assay further demonstrated that SND1 displayed a positive effect on keloid formation.

Conclusion

SND1 transcriptionally regulated by PAX5 promotes keloid formation through activating telomerase activity via the ERK/JNK signaling pathways, which provides a promising therapeutic target for clinical treatment of burned skin keloid.

中文翻译：

---

PAX5通过SND1的转录调控激活瘢痕疙瘩成纤维细胞的端粒酶活性和增殖，从而促进烧伤皮肤瘢痕疙瘩的生长

客观的

葡萄球菌核酸酶结构域 1 (SND1) 在多种肿瘤中作为癌基因在烧伤皮肤组织中上调，本研究旨在研究 SND1 对瘢痕疙瘩的影响并阐明其潜在机制。

方法

从瘢痕疙瘩患者的瘢痕疙瘩组织和邻近的正常皮肤组织中分离出瘢痕疙瘩成纤维细胞（KFs）和正常皮肤成纤维细胞（NFs）。用蛋白质印迹法评估瘢痕疙瘩组织和 KF 中 SND1 的表达。进行了功能获得和功能丧失实验以研究 SND1 在增殖、集落形成、端粒酶活性、纤维化基因表达和促炎因子在 KF 中的产生中的作用。染色质免疫沉淀 (CHIP) 和双荧光素酶报告基因检测用于验证配对盒基因 5 (PAX5) 与 SND1 启动子的相互作用。然后，进行了一系列拯救实验以验证 SND1 过表达对 PAX5 敲低介导的 KF 功能的影响。最后，SND1 在体内瘢痕疙瘩形成中的作用在瘢痕疙瘩植入小鼠中得到验证。

结果

SND1 在瘢痕疙瘩组织和 KF 中上调。SND1 正向调节增殖、集落形成、端粒酶活性、促炎因子的产生和纤维化基因的表达。PAX5 直接与 SND1 启动子结合以转录调节 SND1 表达并通过 ERK/JNK 途径正调节 SND1 介导的 KF 功能。体内试验进一步证明 SND1 对瘢痕疙瘩形成有积极影响。

结论

PAX5转录调控的SND1通过ERK/JNK信号通路激活端粒酶活性促进瘢痕疙瘩的形成，为烧伤皮肤瘢痕疙瘩的临床治疗提供了一个有前景的治疗靶点。