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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Published in Oncotarget, v. 7, no. 30, p. 47145-47162.

Licensed under a Creative Commons Attribution 3.0 License.

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This work was supported by the National Natural Science Foundation of China (grant numbers 81472296, 81101867, 81272542, 81200369, 81502275, 81572992), the China International Medical Foundation (grant number CIMF-F-H001-057), the Six Major Talent Peak Project of Jiangsu Province (grant number 2015-WSN-022), the Special Foundation of Clinical Medicine of Jiangsu Provincial Bureau of Science and Technology (grant number BL2014039), the Scientific Research Project of Jiangsu Provincial Bureau of Traditional Chinese Medicine (grant number L213236), the Medical Scientific Research Project of Jiangsu Provincial Bureau of Health (grant number Z201206), the Special Foundation of Wu Jieping Medical Foundation for Clinical Scientific Research (grant numbers 320.6753.1225, 320.6750.12242), the Science and Education for Health Foundation of Suzhou for Youth (grant numbers SWKQ1003, SWKQ1011, kjxw2015003), the Science and Technology Project Foundation of Suzhou (grant numbers SYS201112, SYSD2012137, SYS201335, SYS201542, SYS201504), the Science and Technology Foundation of Suzhou Xiangcheng (grant numbers SZXC2012-70, XJ201451, XJ201538) and Transverse Project of Soochow University (grant numbers P112200315, P112200914).

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Supplementary Information

Oncotarget_7_47145-47162_suppl1.xls (1979 kB)
Supplementary Table S1

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Oncotarget_7_47145-47162_suppl4.xls (91 kB)
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Oncotarget_7_47145-47162_suppl5.xls (2023 kB)
Supplementary Table S5

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