title: Isorhapontigenin (ISO) Inhibits Invasive Bladder Cancer Formation In Vivo and Human Bladder Cancer Invasion In Vitro by Targeting STAT1/FOXO1 Axis.
abstract: Although our most recent studies have identified Isorhapontigenin (ISO), a novel derivative of stilbene that isolated from a Chinese herb Gnetum cleistostachyum, for its inhibition of human bladder cancer growth, nothing is known whether ISO possesses an inhibitory effect on bladder cancer invasion. Thus, we addressed this important question in current study and discovered that ISO treatment could inhibit mouse-invasive bladder cancer development following bladder carcinogen N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) exposure in vivo We also found that ISO suppressed human bladder cancer cell invasion accompanied by upregulation of the forkhead box class O 1 (FOXO1) mRNA transcription in vitro Accordingly, FOXO1 was profoundly downregulated in human bladder cancer tissues and was negatively correlated with bladder cancer invasion. Forced expression of FOXO1 specifically suppressed high-grade human bladder cancer cell invasion, whereas knockdown of FOXO1 promoted noninvasive bladder cancer cells becoming invasive bladder cancer cells. Moreover, knockout of FOXO1 significantly increased bladder cancer cell invasion and abolished the ISO inhibition of invasion in human bladder cancer cells. Further studies showed that the inhibition of Signal transducer and activator of transcription 1 (STAT1) phosphorylation at Tyr701 was crucial for ISO upregulation of FOXO1 transcription. Furthermore, this study revealed that metalloproteinase-2 (MMP-2) was a FOXO1 downstream effector, which was also supported by data obtained from mouse model of ISO inhibition BBN-induced mouse-invasive bladder cancer formation. These findings not only provide a novel insight into the understanding of mechanism of bladder cancer's propensity to invasion, but also identify a new role and mechanisms underlying the natural compound ISO that specifically suppresses such bladder cancer invasion through targeting the STAT1-FOXO1-MMP-2 axis. Cancer Prev Res; 9(7); 567-80. ©2016 AACR.
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York.
authors.forename: Guosong
authors.initials: G
authors.lastname: Jiang
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York.
authors.forename: Amy D
authors.initials: AD
authors.lastname: Wu
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York.
authors.forename: Chao
authors.initials: C
authors.lastname: Huang
authors.affiliation: Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Jiayan
authors.initials: J
authors.lastname: Gu
authors.affiliation: Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Haishan
authors.initials: H
authors.lastname: Huang
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York.
authors.forename: Xin
authors.initials: X
authors.lastname: Liao
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York.
authors.forename: Jingxia
authors.initials: J
authors.lastname: Li
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York.
authors.forename: Dongyun
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York.
authors.forename: Xingruo
authors.initials: X
authors.lastname: Zeng
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York.
authors.forename: Honglei
authors.initials: H
authors.lastname: Jin
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota.
authors.forename: Haojie
authors.initials: H
authors.lastname: Huang
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York. chuanshu@env.med.nyu.edu.
authors.forename: Chuanshu
authors.initials: C
authors.lastname: Huang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D000071161:Forkhead Box Protein O1 / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D050832:Interferon-Stimulated Gene Factor 3 / Q000187:drug effects / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009361:Neoplasm Invasiveness / Q000473:pathology*; D011897:Random Allocation; D015398:Signal Transduction / Q000187:drug effects*; D013267:Stilbenes / Q000494:pharmacology*; D001749:Urinary Bladder Neoplasms / Q000473:pathology*
chemical_list: D000970:Antineoplastic Agents; D000071161:Forkhead Box Protein O1; D050832:Interferon-Stimulated Gene Factor 3; D013267:Stilbenes; C079868:gamma interferon activation factor; C432307:isorhapontigenin; D020778:Matrix Metalloproteinase 2