PDF(Pubmed)
Abstract：
UNASSIGNED: The leukemia inhibitory factor (LIF), is a cytokine belonging to IL-6 family, whose overexpression correlate with poor prognosis in cancer patients, including pancreatic ductal adenocarcinoma (PDAC). LIF signaling is mediate by its binding to the heterodimeric LIF receptor (LIFR) complex formed by the LIFR receptor and Gp130, leading to JAK1/STAT3 activation. Bile acids are steroid that modulates the expression/activity of membrane and nuclear receptors, including the Farnesoid-X-Receptor (FXR) and G Protein Bile Acid Activated Receptor (GPBAR1).
UNASSIGNED: Herein we have investigated whether ligands to FXR and GPBAR1 modulate LIF/LIFR pathway in PDAC cells and whether these receptors are expressed in human neoplastic tissues.
UNASSIGNED: The transcriptome analysis of a cohort of PDCA patients revealed that expression of LIF and LIFR is increased in the neoplastic tissue in comparison to paired non-neoplastic tissues. By in vitro assay we found that both primary and secondary bile acids exert a weak antagonistic effect on LIF/LIFR signaling. In contrast, BAR502 a non-bile acid steroidal dual FXR and GPBAR1 ligand, potently inhibits binding of LIF to LIFR with an IC50 of 3.8 µM.
UNASSIGNED: BAR502 reverses the pattern LIF-induced in a FXR and GPBAR1 independent manner, suggesting a potential role for BAR502 in the treatment of LIFR overexpressing-PDAC.
UNASSIGNED: Herein we have investigated whether ligands to FXR and GPBAR1 modulate LIF/LIFR pathway in PDAC cells and whether these receptors are expressed in human neoplastic tissues.
UNASSIGNED: The transcriptome analysis of a cohort of PDCA patients revealed that expression of LIF and LIFR is increased in the neoplastic tissue in comparison to paired non-neoplastic tissues. By in vitro assay we found that both primary and secondary bile acids exert a weak antagonistic effect on LIF/LIFR signaling. In contrast, BAR502 a non-bile acid steroidal dual FXR and GPBAR1 ligand, potently inhibits binding of LIF to LIFR with an IC50 of 3.8 µM.
UNASSIGNED: BAR502 reverses the pattern LIF-induced in a FXR and GPBAR1 independent manner, suggesting a potential role for BAR502 in the treatment of LIFR overexpressing-PDAC.
摘要：
■白血病抑制因子（LIF），是属于IL-6家族的细胞因子，其过度表达与癌症患者的不良预后相关，包括胰腺导管腺癌（PDAC）。LIF信号传导通过其与由LIFR受体和Gp130形成的异二聚体LIF受体(LIFR)复合物的结合来介导,导致JAK1/STAT3激活。胆汁酸是类固醇，调节膜和核受体的表达/活性，包括法尼醇-X-受体(FXR)和G蛋白胆汁酸激活受体(GPBAR1)。
本文中,我们研究了FXR和GPBAR1的配体是否调节PDAC细胞中的LIF/LIFR途径以及这些受体是否在人肿瘤组织中表达。
■一组PDCA患者的转录组分析显示，与配对的非肿瘤组织相比，肿瘤组织中LIF和LIFR的表达增加。通过体外测定，我们发现初级和次级胆汁酸对LIF/LIFR信号传导都具有弱的拮抗作用。相比之下,BAR502一种非胆汁酸甾体双FXR和GPBAR1配体，有效抑制LIF与LIFR的结合，IC50为3.8µM。
■BAR502以FXR和GPBAR1独立的方式反转LIF诱导的模式，提示BAR502在LIFR过表达PDAC治疗中的潜在作用。
本文中,我们研究了FXR和GPBAR1的配体是否调节PDAC细胞中的LIF/LIFR途径以及这些受体是否在人肿瘤组织中表达。
■一组PDCA患者的转录组分析显示，与配对的非肿瘤组织相比，肿瘤组织中LIF和LIFR的表达增加。通过体外测定，我们发现初级和次级胆汁酸对LIF/LIFR信号传导都具有弱的拮抗作用。相比之下,BAR502一种非胆汁酸甾体双FXR和GPBAR1配体，有效抑制LIF与LIFR的结合，IC50为3.8µM。
■BAR502以FXR和GPBAR1独立的方式反转LIF诱导的模式，提示BAR502在LIFR过表达PDAC治疗中的潜在作用。
