FH535, a β-catenin Pathway Inhibitor, Represses Pancreatic Cancer Xenograft Growth and Angiogenesis

Authors

Lu Liu, Soochow University, China
Qiaoming Zhi, Soochow University, China
Meng Shen, Soochow University, China
Fei-Ran Gong, Soochow University, China
Binhua P. Zhou, University of KentuckyFollow
Lian Lian, Soochow University, China
Bairong Shen, Soochow University, China
Kai Chen, Soochow University, China
Weiming Duan, Soochow University, China
Meng-Yao Wu, Soochow University, China
Min Tao, Soochow University, China
Wei Li, University of Kentucky

Abstract

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.

Document Type

Article

Publication Date

6-13-2016

Notes/Citation Information

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

Licensed under a Creative Commons Attribution 3.0 License.

Digital Object Identifier (DOI)

https://doi.org/10.18632/oncotarget.9975

Funding Information

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).

Repository Citation

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; and Li, Wei, "FH535, a β-catenin Pathway Inhibitor, Represses Pancreatic Cancer Xenograft Growth and Angiogenesis" (2016). Markey Cancer Center Faculty Publications. 63.
https://uknowledge.uky.edu/markey_facpub/63