FH535, a β-catenin pathway inhibitor, represses pancreatic cancer xenograft growth and angiogenesis.
FH535, a β-catenin pathway inhibitor, represses pancreatic cancer xenograft growth and angiogenesis.
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FH535，一种 β-连环蛋白途径抑制剂，抑制胰腺癌异种移植物生长和血管生成
DOI：
10.18632/oncotarget.9975
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发表时间：
2016-07-26
期刊：
影响因子：
--
通讯作者：
Li W
中科院分区：
文献类型：
--
作者：
Liu L;Zhi Q;Shen M;Gong FR;Zhou BP;Lian L;Shen B;Chen K;Duan W;Wu MY;Tao M;Li W
WNT/β-catenin通路在胰腺癌的发生发展中起重要作用。我们评估了β-catenin通路异常激活与胰腺癌预后的相关性，以及β-catenin通路抑制剂FH 535用于胰腺癌治疗的潜力。Meta分析和免疫组化显示β-catenin通路异常激活与不良结局相关。FH 535在体内抑制胰腺癌异种移植物生长。基因本体论（GO）分析的微阵列数据表明，响应于FH 535的靶基因参与了干性维持。实时PCR和流式细胞术证实，FH 535下调了胰腺癌干细胞（CSC）标志物CD 24和CD 44，表明FH 535损害胰腺CSC的干性。β-连环蛋白染色质免疫沉淀测序数据的GO分析鉴定了血管生成相关的基因调控。免疫组化显示，较高的微血管密度与核β-catenin表达升高和不良结局相关。FH 535可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，并在体内外抑制血管生成。蛋白质和mRNA微阵列显示，FH 535下调促血管生成基因ANGPT 2、VEGFR 3、IFN-γ、PLAUR、THPO、TIMP 1和VEGF。FH 535不仅在体外抑制胰腺CSC的干性，而且通过抑制血管生成来重塑肿瘤微环境，从而阻止进一步的临床研究。
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.
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影响因子：
8
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3.7
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3.7
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