Overexpression of G protein-coupled receptor GPR87 promotes pancreatic cancer aggressiveness and activates NF-κB signaling pathway.
Overexpression of G protein-coupled receptor GPR87 promotes pancreatic cancer aggressiveness and activates NF-κB signaling pathway.
复制标题
G蛋白偶联受体GPR87过度表达促进胰腺癌侵袭性并激活NF-κB信号通路
DOI：
10.1186/s12943-017-0627-6
复制
发表时间：
2017-03-14
期刊：
影响因子：
37.3
通讯作者：
Liu T
中科院分区：
文献类型：
--
作者：
Wang L;Zhou W;Zhong Y;Huo Y;Fan P;Zhan S;Xiao J;Jin X;Gou S;Yin T;Wu H;Liu T
背景胰腺癌是一种高致死性疾病，是所有主要恶性肿瘤中预后最差的。据报道，G蛋白偶联受体GPR 87在多种癌症中过表达。方法采用Western blotting和Real-time PCR方法检测GPR 87在胰腺癌细胞系、配对患者组织中的表达。采用免疫组化（IHC）方法分析96例胰腺癌组织标本，探讨GPR 87表达与胰腺癌临床病理特征的关系。使用功能测定，如锚定非依赖性生长、鸡绒毛尿囊膜（CAM）测定、transwell基质渗透测定和膜联蛋白V-FITC和PI染色以及异种移植肿瘤模型来确定GPR 87在人胰腺癌进展中的致癌作用。通过荧光素酶报告基因检测和NF-κ B信号下游基因的检测，进一步研究GPR 87对NF-κ B信号通路的影响。免疫组化分析显示GPR 87的表达与患者的临床病理特征，包括临床分期和肿瘤结节转移（TNM）分类显著相关。与GPR 87水平较低的患者相比，GPR 87表达水平较高的胰腺癌患者的总生存期较短。我们获得了有价值的见解GPR 87在胰腺癌细胞中的表达机制，证明过表达GPR 87显着增强，而沉默内源性GPR 87抑制，增殖，血管生成和增加抵抗吉西他滨诱导的胰腺癌细胞凋亡在体外和胰腺癌细胞在体内的致瘤性。最后，我们证明GPR 87通过激活NF-κB信号通路增强胰腺癌的侵袭性。结论：两者合计，这些研究结果表明，GPR 87在胰腺癌进展中起着关键的致癌作用，并突出其作为胰腺癌therapeutic.ConclusionsOur研究结果表明，GPR 87在胰腺癌进展中起着关键的致癌作用，并突出其作为胰腺癌治疗靶点的潜力。
BackgroundPancreatic cancer is a highly lethal disease and has the worst prognosis of any major malignancy. G protein-coupled receptor GPR87 is reported to be overexpressed in multiple cancers. The clinical significance and biological role of GPR87 in pancreatic cancer, however, remain to be established.MethodsGPR87 expression in pancreatic cancer cell lines, paired patient tissues were determined using western blotting and Real-time PCR. Ninety-six human pancreatic cancer tissue samples were analyzed by immunochemistry (IHC) to investigate the association between GPR87 expression and the clinicopathological characteristics of pancreatic cancer. Functional assays, such as anchorage-independent growth, chicken chorioallantoic membrane (CAM) assay, transwell matrix penetration assay, and Annexin V-FITC and PI staining and a xenograft tumor model were used to determine the oncogenic role of GPR87 in human pancreatic cancer progression. The effect of GPR87 on NF-κB signaling pathway was further investigated using the luciferase reporter assays, and by detection of the NF-κB signaling downstream genes.ResultsHerein, we reported that GPR87 was markedly overexpressed in pancreatic cancer cells and clinical tissues. Immunohistochemical analysis showed that the expression of GPR87 significantly correlated with patients’ clinicopathologic features, including clinical stage and tumor-nodule-metastasis (TNM) classification. Pancreatic cancer patients with higher levels of GPR87 expression had shorter overall survival compared to patients with lower GPR87 levels. We gained valuable insights into the mechanism of GPR87 expression in pancreatic cancer cells by demonstrating that overexpressing GPR87 significantly enhanced, whereas silencing endogenous GPR87 inhibited, the proliferation, angiogenesis and increased resistance to gemcitabine-induced apoptosis of pancreatic cancer in vitro and tumorigenicity of pancreatic cancer cells in vivo. Finally, we demonstrated that GPR87 enhanced pancreatic cancer aggressiveness by activating NF-κB signaling pathway. Conclusions: Taken together, these findings suggest that GPR87 plays a critical oncogenic role in pancreatic cancer progression and highlight its potential as a target for pancreatic cancer therapy.ConclusionsOur findings suggest that GPR87 plays a critical oncogenic role in pancreatic cancer progression and highlight its potential as a target for pancreatic cancer therapy.