FH535, a β-catenin pathway inhibitor, represses pancreatic cancer xenograft growth and angiogenesis
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Lu Liu1,*, Qiaoming Zhi2,*, Meng Shen1,*, Fei-Ran Gong3, Binhua P. Zhou4,5, Lian Lian1,6,7, Bairong Shen8, Kai Chen1, Weiming Duan1, Meng-Yao Wu1, Min Tao1,9,10,11, Wei Li1,4,8,9,10
1Department of Oncology, the First Affiliated Hospital of Soochow University, Suzhou, China
2Department of General Surgery, the First Affiliated Hospital of Soochow University, Suzhou, China
3Department of Hematology, the First Affiliated Hospital of Soochow University, Suzhou, China
4Markey Cancer Center, University of Kentucky, Lexington, KY, USA
5Departments of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY, USA
6Department of Oncology, Suzhou Xiangcheng People’s Hospital, Suzhou, China
7Department of Pathology, Suzhou Xiangcheng People’s Hospital, Suzhou, China
8Center for Systems Biology, Soochow University, Suzhou, China
9PREMED Key Laboratory for Precision Medicine, Soochow University, Suzhou, China
10Jiangsu Institute of Clinical Immunology, Suzhou, China
11Institute of Medical Biotechnology, Soochow University, Suzhou, China
*These authors contributed equally to this work
Meng-Yao Wu, email: [email protected]
Keywords: pancreatic cancer, FH535, β-catenin, cancer stem cell, angiogenesis
Received: February 25, 2016 Accepted: May 17, 2016 Published: June 13, 2016
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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