Department of General Surgery, First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
Hongqiao International Institute of Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, No. 1111, XianXia Road, Shanghai, 200336, China.
Adv Sci (Weinh). 2022 Sep;9(27):e2200546. doi: 10.1002/advs.202200546. Epub 2022 Jul 28.
Extracellular matrix (ECM) remodeling is crucial in the regulation of gastric cancer (GC) progression. This work aims to reveal novel posttranslational modifications and their relevant mechanisms in GC. In 3D matrix culture and animal models, it is found that fibrillin 1 (FBN1) expression is increased in advanced GC and has succinylation modification. The succinylation modification of FBN1 blocks its degradation by matrix metalloproteinases (MMPs). The long-term accumulation and deposition of FBN1 enhance tumor progression by activating TGF-β1 and intracellular PI3K/Akt pathway. The FBN1 succinylation site monoclonal antibody can effectively intervene the effect of succinylation modification and inhibit GC progression. FBN1 is specifically upregulated in the progression of GC compared with other tumors. In conclusion, FBN1 is widely present in the form of K672-succinylated modifications in GC. Besides, the succinyl group of FBN1 blocks its binding to MMP2, inhibits its degradation by MMP2, and leads to the accumulation of FBN1, which poses a long-term risk to the poor prognosis of GC.
细胞外基质（ECM）重塑在调控胃癌（GC）进展中至关重要。本研究旨在揭示 GC 中新颖的翻译后修饰及其相关机制。在 3D 基质培养和动物模型中，发现纤连蛋白 1（FBN1）在晚期 GC 中表达增加，并发生琥珀酰化修饰。FBN1 的琥珀酰化修饰阻止了基质金属蛋白酶（MMPs）对其的降解。FBN1 的长期积累和沉积通过激活 TGF-β1 和细胞内 PI3K/Akt 通路促进肿瘤进展。FBN1 琥珀酰化位点单克隆抗体可有效干预琥珀酰化修饰的作用并抑制 GC 进展。与其他肿瘤相比，FBN1 在 GC 的进展中特异性地上调。总之，GC 中广泛存在 FBN1 的 K672-琥珀酰化修饰形式。此外，FBN1 的琥珀酰基阻止其与 MMP2 结合，抑制 MMP2 对其的降解，导致 FBN1 积累，从而对 GC 的不良预后构成长期风险。
