Insight in the treatment for pancreatic adenocarcinoma: discovery of the semisynthetic bile alcohol steroidal agonist BAR502 as a potent leukemia inhibitory factor receptor antagonist

The leukemia inhibitory factor (LIF), is a cytokine belonging to IL-6 family, whose overexpression correlate with poor prognosis in on cancer patients. LIF signaling is mediate by its binding to the heterodimeric LIF receptor (LIFR) complex formed by the LIFR receptor and Gp13o, leading to JAK1/STAT3 activation. The JAK/STAT3 pathway is over-regulated in several type of tumors, including pancreatic ductal adenocarcinoma (PDAC). Bile acids are steroid molecules that modulates the expression/activity of membrane and nuclear receptors, including the Farnesoid-X-Receptor (FXR) and G Protein Bile Acid Activated Receptor (GPBAR)1). In this study we have investigated whether ligands to FXR and GPBAR1 modulate LIF/LIFR pathway in ductal pancreatic acinar cells (PDAC) and whether these receptors are expressed in neoplastic tissues from a cohort PDCA patients.

白血病抑制因子（leukemia inhibitory factor, LIF）是一类隶属于白细胞介素6（IL-6）家族的细胞因子，其过表达与癌症患者的不良预后密切相关。LIF信号通路通过与由LIF受体（LIFR）和Gp13o组成的异二聚体LIF受体复合物结合而介导，进而激活JAK1/STAT3通路。JAK/STAT3通路在包括胰腺导管腺癌（pancreatic ductal adenocarcinoma, PDAC）在内的多种肿瘤中存在过度调控现象。胆汁酸是一类甾体分子，可调控膜受体与核受体的表达及活性，其中包括法尼醇X受体（Farnesoid-X-Receptor, FXR）以及G蛋白偶联胆汁酸激活受体1（G Protein Bile Acid Activated Receptor, GPBAR1）。本研究旨在探究FXR与GPBAR1的配体是否可调控胰腺导管腺泡细胞中的LIF/LIFR通路，同时验证这些受体在一组PDAC患者的肿瘤组织中的表达情况。