Research Center of Basic Medicine, Jinan Central Hospital, Shandong University, Jinan, China.
Research Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, China.
Cancer Sci. 2024 Jul;115(7):2301-2317. doi: 10.1111/cas.16193. Epub 2024 Apr 27.
GLI1, a key transcription factor of the Hedgehog (Hh) signaling pathway, plays an important role in the development of cancer. However, the function and mechanisms by which GLI1 regulates gene transcription are not fully understood in gastric cancer (GC). Here, we found that GLI1 induced the proliferation and metastasis of GC cells, accompanied by transcriptional upregulation of INHBA. This increased INHBA expression exerted a promoting activity on Smads signaling and then transcriptionally activated GLI1 expression. Notably, our results demonstrate that disrupting the interaction between GLI1 and INHBA could inhibit GC tumorigenesis in vivo. More intriguingly, we confirmed the N6-methyladenosine (m6A) activation mechanism of the Helicobacter pylori/FTO/YTHDF2/GLI1 pathway in GC cells. In conclusion, our study confirmed that the GLI1/INHBA positive feedback loop influences GC progression and revealed the mechanism by which H. pylori upregulates GLI1 expression through m6A modification. This positive GLI1/INHBA feedback loop suggests a novel noncanonical mechanism of GLI1 activity in GC and provides potential therapeutic targets for GC treatment.
GLI1 是 Hedgehog（Hh）信号通路的关键转录因子，在癌症的发展中起着重要作用。然而，GLI1 如何调节基因转录的功能和机制在胃癌（GC）中尚未完全阐明。在这里，我们发现 GLI1 诱导 GC 细胞的增殖和转移，同时 INHBA 的转录上调。这种增加的 INHBA 表达对 Smads 信号具有促进活性，然后转录激活 GLI1 的表达。值得注意的是，我们的结果表明，破坏 GLI1 和 INHBA 之间的相互作用可以抑制体内 GC 肿瘤发生。更有趣的是，我们证实了幽门螺杆菌/FTO/YTHDF2/GLI1 通路在 GC 细胞中 N6-甲基腺苷（m6A）的激活机制。总之，我们的研究证实了 GLI1/INHBA 正反馈回路影响 GC 的进展，并揭示了幽门螺杆菌通过 m6A 修饰上调 GLI1 表达的机制。这种积极的 GLI1/INHBA 正反馈回路提示了 GC 中 GLI1 活性的一种新的非典型机制，并为 GC 的治疗提供了潜在的治疗靶点。
