Liu Yining, Zhang Wei, Lin Nan, Yang Zelei, Liu Yanxin, Chen Huaxia
Department of Burn and Plastic Surgery, the Affiliated Hospital of Qingdao University, Qingdao, 266100, Shandong, People's Republic of China.
Department of Burn and Plastic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324 JingWu Road, Jinan, 250021, Shandong, People's Republic of China.
Inflamm Regen. 2024 Oct 31;44(1):44. doi: 10.1186/s41232-024-00357-y.
Keloids are currently challenging to treat because they recur after resection which may affect patients' quality of life. At present, no universal consensus on treatment regimen has been established. Thus, finding new molecular mechanisms underlying keloid formation is imminent. This study aimed to explore the function of secreted protein acidic and cysteine rich (SPARC) on keloids and its behind exact mechanisms.
The expression of SPARC, p38γ, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), α-SMA, and Ki67 in patients with keloid and bleomycin (BLM)-induced fibrosis mice was assessed utilizing western blot, qRT-PCR, and immunohistochemical staining. After transfected with pcDNA-SPARC, si-SPARC-1#, si-SPARC-2#, and si-p38γ, and treated with glycolytic inhibitor (2-DG) or p38 inhibitor (SB203580), CCK-8, EdU, transwell, and western blot were utilized for assessing the proliferation, migration, and collagen production of keloid fibroblasts (KFs).
SPARC, p38γ, and PFKFB3 were highly expressed in patients with keloid and BLM-induced fibrosis mice. SPARC promoted the proliferation, migration, and collagen production of KFs via inducing glycolysis. Moreover, SPARC could activate p38γ signaling to stabilize PFKFB3 protein expression in KFs. Next, we demonstrated that SPARC promoted the proliferation, migration, collagen production, and glycolysis of KFs via regulating p38γ signaling. In addition, in BLM-induced fibrosis mice, inhibition of p38γ and PFKFB3 relieved skin fibrosis.
Our findings indicated that SPARC could activate p38γ pathway to stabilize the expression of PFKFB3, and thus promote the glycolysis of KFs and the progression of keloid.
瘢痕疙瘩目前治疗具有挑战性，因为切除后会复发，这可能会影响患者的生活质量。目前，对于治疗方案尚未达成普遍共识。因此，迫切需要找到瘢痕疙瘩形成背后的新分子机制。本研究旨在探讨富含酸性和半胱氨酸的分泌蛋白（SPARC）在瘢痕疙瘩中的作用及其确切机制。
利用蛋白质免疫印迹法、qRT-PCR和免疫组织化学染色评估瘢痕疙瘩患者及博来霉素（BLM）诱导的纤维化小鼠中SPARC、p38γ、6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶3（PFKFB3）、α-平滑肌肌动蛋白（α-SMA）和Ki67的表达。用pcDNA-SPARC、si-SPARC-1#、si-SPARC-2#和si-p38γ转染后，并用糖酵解抑制剂（2-DG）或p38抑制剂（SB203580）处理，采用CCK-8、EdU、Transwell和蛋白质免疫印迹法评估瘢痕疙瘩成纤维细胞（KFs）的增殖、迁移和胶原产生。
SPARC、p38γ和PFKFB3在瘢痕疙瘩患者及BLM诱导的纤维化小鼠中高表达。SPARC通过诱导糖酵解促进KFs的增殖、迁移和胶原产生。此外，SPARC可激活p38γ信号通路以稳定KFs中PFKFB3蛋白的表达。接下来，我们证明SPARC通过调节p38γ信号通路促进KFs的增殖、迁移、胶原产生和糖酵解。此外，在BLM诱导的纤维化小鼠中，抑制p38γ和PFKFB3可减轻皮肤纤维化。
我们的研究结果表明，SPARC可激活p38γ通路以稳定PFKFB3的表达，从而促进KFs的糖酵解和瘢痕疙瘩的进展。
