title: Decreasing CNPY2 Expression Diminishes Colorectal Tumor Growth and Development through Activation of p53 Pathway.
abstract: Neovascularization drives tumor development, and angiogenic factors are important neovascularization initiators. We recently identified the secreted angiogenic factor CNPY2, but its involvement in cancer has not been explored. Herein, we investigate CNPY2's role in human colorectal cancer (CRC) development. Tumor samples were obtained from CRC patients undergoing surgery. Canopy 2 (CNPY2) expression was analyzed in tumor and adjacent normal tissue. Stable lines of human HCT116 cells expressing CNPY2 shRNA or control shRNA were established. To determine CNPY2's effects on tumor xenografts in vivo, human CNPY2 shRNA HCT116 cells and controls were injected into nude mice, separately. Cellular apoptosis, growth, and angiogenesis in the xenografts were evaluated. CNPY2 expression was significantly higher in CRC tissues. CNPY2 knockdown in HCT116 cells inhibited growth and migration and promoted apoptosis. In xenografts, CNPY2 knockdown prevented tumor growth and angiogenesis and promoted apoptosis. Knockdown of CNPY2 in the HCT116 CRC cell line reversibly increased p53 activity. The p53 activation increased cyclin-dependent kinase inhibitor p21 and decreased cyclin-dependent kinase 2, thereby inhibiting tumor cell growth, inducing cell apoptosis, and reducing angiogenesis both in vitro and in vivo. CNPY2 may play a critical role in CRC development by enhancing cell proliferation, migration, and angiogenesis and by inhibiting apoptosis through negative regulation of the p53 pathway. Therefore, CNPY2 may represent a novel CRC therapeutic target and prognostic indicator.
authors.affiliation: Department of Biochemistry and Molecular Biology, Ministry of Education Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Yan
authors.affiliation: Department of Biochemistry and Molecular Biology, Ministry of Education Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Gong
authors.affiliation: Department of Biochemistry and Molecular Biology, Ministry of Education Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zhai
authors.affiliation: Department of Biochemistry and Molecular Biology, Ministry of Education Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, China; Department of Colorectal Surgery, Shanxi Cancer Hospital, Taiyuan, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Division of Cardiovascular Surgery, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Biochemistry and Molecular Biology, Ministry of Education Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: He
authors.affiliation: Division of Cardiovascular Surgery, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Jian
authors.initials: J
authors.lastname: Guo
authors.affiliation: Department of Biochemistry and Molecular Biology, Ministry of Education Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, China.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, Ministry of Education Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Guo
authors.affiliation: Department of Biochemistry and Molecular Biology, Ministry of Education Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, China. Electronic address: xiejun1968@126.com.
authors.forename: Jun
authors.initials: J
authors.lastname: Xie
authors.affiliation: Division of Cardiovascular Surgery, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada. Electronic address: renkeli@uhnres.utoronto.ca.
authors.forename: Ren-Ke
authors.initials: RK
authors.lastname: Li
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D045325:HCT116 Cells / Q000166:cytology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008819:Mice, Nude; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000235:genetics; D011379:Prognosis; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C502333:CNPY2 protein, human; C000603106:Canopy 2 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D016159:Tumor Suppressor Protein p53