FH535, a β-catenin pathway inhibitor, represses pancreatic cancer xenograft growth and angiogenesis

Lu Liu; Qiaoming Zhi; Meng Shen; Fei Ran Gong; Binhua P. Zhou; Lian Lian; Bairong Shen; Kai Chen; Weiming Duan; Meng Yao Wu; Min Tao; Wei Li

doi:10.18632/oncotarget.9975

FH535, a β-catenin pathway inhibitor, represses pancreatic cancer xenograft growth and angiogenesis

Lu Liu, Qiaoming Zhi, Meng Shen, Fei Ran Gong, Binhua P. Zhou, Lian Lian, Bairong Shen, Kai Chen, Weiming Duan, Meng Yao Wu, Min Tao, Wei Li

Research output: Contribution to journal › Article › peer-review

28 Scopus citations

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. Realtime 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-a, 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.

Original language	English
Pages (from-to)	47145-47162
Number of pages	18
Journal	Oncotarget
Volume	7
Issue number	30
DOIs	https://doi.org/10.18632/oncotarget.9975
State	Published - 2016

Bibliographical note

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). We thank the Novel Bioinformatics Company (Shanghai, China) for their technical support in bioinformatics analysis.

Funding

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). We thank the Novel Bioinformatics Company (Shanghai, China) for their technical support in bioinformatics analysis.

Funders	Funder number
Medical Scientific Research Project of Jiangsu Provincial Bureau of Health	Z201206
Novel Bioinformatics Company
Science and Education for Health Foundation of Suzhou for Youth	kjxw2015003, SWKQ1003, SWKQ1011
Science and Technology Foundation of Suzhou Xiangcheng	SZXC2012-70, XJ201538, XJ201451
Science and Technology Project Foundation of Suzhou	SYS201335, SYS201542, SYS201112, SYSD2012137, SYS201504
Scientific Research Project of Jiangsu Provincial Bureau of Traditional Chinese Medicine	L213236
Special Foundation of Clinical Medicine of Jiangsu Provincial Bureau of Science and Technology	BL2014039
Special Foundation of Wu Jieping Medical Foundation for Clinical Scientific Research	320.6753.1225, 320.6750.12242
National Childhood Cancer Registry – National Cancer Institute	P30CA177558
National Natural Science Foundation of China (NSFC)	81472296, 81572992, 81272542, 81101867, 81200369, 81502275
Soochow University	P112200914, P112200315
Six Talent Peaks Project in Jiangsu Province	2015-WSN-022
China International Medical Foundation	CIMF-F-H001-057

Keywords

Angiogenesis
Cancer stem cell
FH535
Pancreatic cancer
β-catenin

ASJC Scopus subject areas

Oncology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.18632/oncotarget.9975

Cite this

@article{40e071238c6947ef8ddf286fd10c13f6,

title = "FH535, a β-catenin pathway inhibitor, represses pancreatic cancer xenograft growth and angiogenesis",

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. Realtime 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-a, 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.",

keywords = "Angiogenesis, Cancer stem cell, FH535, Pancreatic cancer, β-catenin",

author = "Lu Liu and Qiaoming Zhi and Meng Shen and Gong, {Fei Ran} and Zhou, {Binhua P.} and Lian Lian and Bairong Shen and Kai Chen and Weiming Duan and Wu, {Meng Yao} and Min Tao and Wei Li",

note = "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). We thank the Novel Bioinformatics Company (Shanghai, China) for their technical support in bioinformatics analysis.",

year = "2016",

doi = "10.18632/oncotarget.9975",

language = "English",

volume = "7",

pages = "47145--47162",

number = "30",

}

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T1 - FH535, a β-catenin pathway inhibitor, represses pancreatic cancer xenograft growth and angiogenesis

AU - Liu, Lu

AU - Zhi, Qiaoming

AU - Shen, Meng

AU - Gong, Fei Ran

AU - Zhou, Binhua P.

AU - Lian, Lian

AU - Shen, Bairong

AU - Chen, Kai

AU - Duan, Weiming

AU - Wu, Meng Yao

AU - Tao, Min

AU - Li, Wei

N1 - 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). We thank the Novel Bioinformatics Company (Shanghai, China) for their technical support in bioinformatics analysis.

PY - 2016

Y1 - 2016

N2 - 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. Realtime 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-a, 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.

AB - 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. Realtime 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-a, 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.

KW - Angiogenesis

KW - Cancer stem cell

KW - FH535

KW - Pancreatic cancer

KW - β-catenin

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VL - 7

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ER -

FH535, a β-catenin pathway inhibitor, represses pancreatic cancer xenograft growth and angiogenesis

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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