FH535, a β-catenin pathway inhibitor, represses pancreatic cancer xenograft growth and angiogenesis.
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.
Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, China.
Lu
L
Liu
Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China.
Qiaoming
Q
Zhi
Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, China.
Meng
M
Shen
Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.
Fei-Ran
FR
Gong
Markey Cancer Center, University of Kentucky, Lexington, KY, USA.|Departments of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY, USA.
Binhua P
BP
Zhou
Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, China.|Department of Oncology, Suzhou Xiangcheng People's Hospital, Suzhou, China.|Department of Pathology, Suzhou Xiangcheng People's Hospital, Suzhou, China.
Lian
L
Lian
Center for Systems Biology, Soochow University, Suzhou, China.
Bairong
B
Shen
Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, China.
Kai
K
Chen
Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, China.
Weiming
W
Duan
Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, China.
Meng-Yao
MY
Wu
Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, China.|PREMED Key Laboratory for Precision Medicine, Soochow University, Suzhou, China.|Jiangsu Institute of Clinical Immunology, Suzhou, China.|Institute of Medical Biotechnology, Soochow University, Suzhou, China.
Min
M
Tao
Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, China.|Markey Cancer Center, University of Kentucky, Lexington, KY, USA.|Center for Systems Biology, Soochow University, Suzhou, China.|PREMED Key Laboratory for Precision Medicine, Soochow University, Suzhou, China.|Jiangsu Institute of Clinical Immunology, Suzhou, China.
Wei
W
Li
D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology*; D014162:Transfection; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000037:antagonists & inhibitors* / Q000378:metabolism
C575430:FH535; D013449:Sulfonamides; D051176:beta Catenin
FH535; angiogenesis; cancer stem cell; pancreatic cancer; β-catenin