A novel TGFbeta/TGILR axis mediates crosstalk between cancer-associated fibroblasts and tumor cells to drive gastric cancer progression

Abstract 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 TG Fbeta- i nduced l nc R NA, 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.