University of Perugia, Department of Medicine and Surgery, Perugia, Italy.
University of Salerno, Department of Pharmacy, Salerno, Italy.
Biochem Pharmacol. 2024 May;223:116134. doi: 10.1016/j.bcp.2024.116134. Epub 2024 Mar 15.
The leukemia inhibitory factor (LIF) is member of interleukin (IL)-6 family of cytokines involved immune regulation, morphogenesis and oncogenesis. In cancer tissues, LIF binds a heterodimeric receptor (LIFR), formed by a LIFRβ subunit and glycoprotein(gp)130, promoting epithelial mesenchymal transition and cell growth. Bile acids are cholesterol metabolites generated at the interface of host metabolism and the intestinal microbiota. Here we demonstrated that bile acids serve as endogenous antagonist to LIFR in oncogenesis. The tissue characterization of bile acids content in non-cancer and cancer biopsy pairs from gastric adenocarcinomas (GC) demonstrated that bile acids accumulate within cancer tissues, with glyco-deoxycholic acid (GDCA) functioning as negative regulator of LIFR expression. In patient-derived organoids (hPDOs) from GC patients, GDCA reverses LIF-induced stemness and proliferation. In summary, we have identified the secondary bile acids as the first endogenous antagonist to LIFR supporting a development of bile acid-based therapies in LIF-mediated oncogenesis.
白血病抑制因子 (LIF) 是白细胞介素 (IL)-6 细胞因子家族的成员，参与免疫调节、形态发生和肿瘤发生。在癌症组织中，LIF 与由 LIFRβ 亚基和糖蛋白 (gp)130 形成的异二聚体受体 (LIFR) 结合，促进上皮间质转化和细胞生长。胆汁酸是胆固醇代谢物，在宿主代谢和肠道微生物群的界面处产生。在这里，我们证明了胆汁酸在肿瘤发生中作为 LIFR 的内源性拮抗剂。来自胃腺癌 (GC) 的非癌和癌活检对中胆汁酸含量的组织特征表明，胆汁酸在癌组织内积累，甘脱氧胆酸 (GDCA) 作为 LIFR 表达的负调节剂发挥作用。在来自 GC 患者的患者来源类器官 (hPDO) 中，GDCA 逆转了 LIF 诱导的干性和增殖。总之，我们已经确定了次级胆汁酸是 LIFR 的第一个内源性拮抗剂，支持基于胆汁酸的疗法在 LIF 介导的肿瘤发生中的发展。
