Bile acids serve as endogenous antagonists of the Leukemia inhibitory factor (LIF) receptor in oncogenesis
Cristina Di Giorgio, Elva Morretta, Antonio Lupia, Rachele Bellini, Carmen Massa, Ginevra Urbani, Martina Bordoni, Silvia Marchianò, Ginevra Lachi, Pasquale Rapacciuolo, Claudia Finamore, Valentina Sepe, Maria Chiara Monti, Federica Moraca, Nicola Natalizi, Luigina Graziosi, Eleonora Distrutti, Michele Biagioli, Bruno Catalanotti, Annibale Donini, Angela Zampella, Stefano Fiorucci
Abstract
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.