Department of Hepatobiliary and Pancreatic Gastroenterology, Jinhua People's Hospital, Jinhua 321000, Zhejiang Province, China.
Department of Gastroenterology, Jinhua People's Hospital, Jinhua 321000, Zhejiang Province, China.
Cell Signal. 2022 Jun;94:110313. doi: 10.1016/j.cellsig.2022.110313. Epub 2022 Mar 16.
Our study aimed to probe the intrinsic and concrete molecular mechanism of IGF2 mRNA-binding protein 2 (IGF2BP2) in gastric cancer (GC).
The mRNA and protein expressions were assessed using qRT-PCR and western blot, respectively. CCK-8 assay was employed to determine cell proliferation. Levels of TNFα and IL-1β were analyzed using ELISA. Furthermore, cell apoptosis was evaluated using flow cytometry analysis. Cell migration and invasion were evaluated using Transwell assay. The experiment of tumor formation in nude mice was employed to analyze the effect of IGF2BP2 in regulating GC tumor growth and lung metastasis in vivo. Finally, the binding relationship between IGF1R and IGF2BP2 was verified using RIP and RNA pull down assays.
IGF2BP2 was significantly elevated in both GC tissues and cells. Silencing of IGF2BP2 dramatically suppressed the inflammation, proliferation, migration and invasion, yet promoted cell apoptosis in vitro and in vivo. Furthermore, IGF2BP2, as a mA reader, was proved to increase the expression of IGF1R by identifying mA methylation modification sites in IGF1R mRNA, thus activating RhoA-ROCK pathway. Importantly, the anti-carcinogenic impacts of IGFBP2 silence were restrained by IGF1R overexpression, which was eliminated by the inactivation of RhoA-ROCK.
We emphasized the oncogenic role of IGF2BP2 in gastric carcinogenesis and confirmed its activation is partly due to the activation of IGF1R-RhoA-ROCK signaling pathway. Our findings identified that IGF2BP2 might be a promising prognostic biomarker and provided clinical translational potential.
本研究旨在探讨胰岛素样生长因子 2 mRNA 结合蛋白 2（IGF2BP2）在胃癌（GC）中的内在具体分子机制。
分别采用 qRT-PCR 和 Western blot 检测 mRNA 和蛋白表达。CCK-8 法检测细胞增殖。ELISA 法分析 TNFα 和 IL-1β 水平。采用流式细胞术分析细胞凋亡。Transwell 检测细胞迁移和侵袭。采用裸鼠肿瘤形成实验分析 IGF2BP2 对体内 GC 肿瘤生长和肺转移的调节作用。最后，采用 RIP 和 RNA 下拉实验验证 IGF1R 和 IGF2BP2 之间的结合关系。
IGF2BP2 在 GC 组织和细胞中均显著升高。IGF2BP2 沉默显著抑制体外和体内的炎症、增殖、迁移和侵袭，促进细胞凋亡。此外，IGF2BP2 作为 mA 阅读器，通过鉴定 IGF1R mRNA 中的 mA 甲基化修饰位点，增加 IGF1R 的表达，从而激活 RhoA-ROCK 通路。重要的是，IGF1R 过表达抑制了 IGFBP2 沉默的抗癌作用，而 RhoA-ROCK 的失活消除了这种作用。
我们强调了 IGF2BP2 在胃癌发生中的致癌作用，并证实其激活部分归因于 IGF1R-RhoA-ROCK 信号通路的激活。我们的研究结果表明，IGF2BP2 可能是一种有前途的预后生物标志物，并具有临床转化潜力。
