Liu Lu, Zhi Qiaoming, Shen Meng, Gong Fei-Ran, Zhou Binhua P, Lian Lian, Shen Bairong, Chen Kai, Duan Weiming, Wu Meng-Yao, Tao Min, Li Wei
Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, China.
Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China.
Oncotarget. 2016 Jul 26;7(30):47145-47162. doi: 10.18632/oncotarget.9975.
The WNT/β-catenin pathway plays an important role in pancreatic cancer carcinogenesis. We evaluated the correlation between aberrant β-catenin pathway activation and the prognosis pancreatic cancer, and the potential of applying the β-catenin pathway inhibitor FH535 to pancreatic cancer treatment. Meta-analysis and immunohistochemistry showed that abnormal β-catenin pathway activation was associated with unfavorable outcome. FH535 repressed pancreatic cancer xenograft growth in vivo. Gene Ontology (GO) analysis of microarray data indicated that target genes responding to FH535 participated in stemness maintenance. Real-time PCR and flow cytometry confirmed that FH535 downregulated CD24 and CD44, pancreatic cancer stem cell (CSC) markers, suggesting FH535 impairs pancreatic CSC stemness. GO analysis of β-catenin chromatin immunoprecipitation sequencing data identified angiogenesis-related gene regulation. Immunohistochemistry showed that higher microvessel density correlated with elevated nuclear β-catenin expression and unfavorable outcome. FH535 repressed the secretion of the proangiogenic cytokines vascular endothelial growth factor (VEGF), interleukin (IL)-6, IL-8, and tumor necrosis factor-α, and also inhibited angiogenesis in vitro and in vivo. Protein and mRNA microarrays revealed that FH535 downregulated the proangiogenic genes ANGPT2, VEGFR3, IFN-γ, PLAUR, THPO, TIMP1, and VEGF. FH535 not only represses pancreatic CSC stemness in vitro, but also remodels the tumor microenvironment by repressing angiogenesis, warranting further clinical investigation.
WNT/β-连环蛋白信号通路在胰腺癌的发生发展中起重要作用。我们评估了β-连环蛋白信号通路异常激活与胰腺癌预后之间的相关性，以及将β-连环蛋白信号通路抑制剂FH535应用于胰腺癌治疗的潜力。荟萃分析和免疫组织化学显示，β-连环蛋白信号通路异常激活与不良预后相关。FH535在体内可抑制胰腺癌异种移植物的生长。基因本体（GO）分析微阵列数据表明，对FH535有反应的靶基因参与干性维持。实时定量PCR和流式细胞术证实，FH535下调了胰腺癌干细胞（CSC）标志物CD24和CD44，提示FH535损害胰腺CSC的干性。对β-连环蛋白染色质免疫沉淀测序数据的GO分析确定了与血管生成相关的基因调控。免疫组织化学显示，较高的微血管密度与核β-连环蛋白表达升高及不良预后相关。FH535抑制促血管生成细胞因子血管内皮生长因子（VEGF）、白细胞介素（IL）-6、IL-8和肿瘤坏死因子-α的分泌，并且在体外和体内均抑制血管生成。蛋白质和mRNA微阵列显示，FH535下调促血管生成基因ANGPT2、VEGFR3、IFN-γ、PLAUR、THPO、TIMP1和VEGF。FH535不仅在体外抑制胰腺CSC的干性，还通过抑制血管生成重塑肿瘤微环境，值得进一步进行临床研究。
