转化生长因子β（TGFβ）信号在肿瘤发生和转移中发挥着关键作用。然而，人们对 TGFbeta 诱导的 lncRNA 在癌症中的生物学功能知之甚少。在这项研究中，我们发现了一种新型 TGFbeta 诱导的 lncRNA，称为 TGILR，其在癌症中的功能迄今为止仍不清楚。 TGILR 表达由经典 TGFbeta/SMAD3 信号轴直接激活，并且这种激活在癌症中高度保守。临床分析表明，TGILR过表达与淋巴结转移和不良生存显着相关，是胃癌（GC）的独立预后因素。 TGILR的缺失对体外和体内GC细胞增殖、侵袭和上皮间质转化（EMT）产生明显的抑制作用。更重要的是，我们证明GC中的TGFbeta信号传导因癌症相关成纤维细胞（CAF）浸润而过度激活。从机制上讲，CAF 分泌的 TGFbeta 水平增加会激活 TGFbeta 信号传导，导致 GC 细胞中 TGILR 过度表达。同时，TGILR过表达通过与TARBP2相互作用并降低其蛋白质稳定性来抑制miR-1306和miR-33a的microRNA生物合成，从而通过TCF4介导的EMT信号促进GC进展。总之，CAF 浸润通过激活 TGFbeta/TGILR 轴驱动 GC 转移和 EMT 信号传导。靶向阻断 CAF 衍生的 TGFbeta 应该是 GC 中一种有前景的抗癌策略。© 2024。作者。

Transforming growth factor beta (TGFβ) signaling plays a critical role in tumorigenesis and metastasis. However, little is known about the biological function of TGFbeta-induced lncRNA in cancer. In this study, we discovered a novel TGFbeta-induced lncRNA, termed TGILR, whose function in cancer remains unknown to date. TGILR expression was directly activated by the canonical TGFbeta/SMAD3 signaling axis, and this activation is highly conserved in cancer. Clinical analysis showed that TGILR overexpression showed a significant correlation with lymph node metastasis and poor survival and was an independent prognostic factor in gastric cancer (GC). Depletion of TGILR caused an obvious inhibitory effect on GC cell proliferation, invasion, and epithelial-mesenchymal transition (EMT) in vitro and in vivo. More importantly, we demonstrated that TGFbeta signaling in GC was overactivated due to cancer-associated fibroblast (CAF) infiltration. Mechanistically, increased level of CAF-secreted TGFbeta activates TGFbeta signaling, leading to TGILR overexpression in GC cells. Meanwhile, TGILR overexpression inhibited the microRNA biogenesis of miR-1306 and miR-33a by interacting with TARBP2 and reducing its protein stability, thereby promoting GC progression via TCF4-mediated EMT signaling. In conclusion, CAF infiltration drives GC metastasis and EMT signaling through activating TGFbeta/TGILR axis. Targeted blocking of CAF-derived TGFbeta should be a promising anticancer strategy in GC.© 2024. The Author(s).