TIMP3 expression associates with prognosis in colorectal cancer and its novel arylsulfonamide inducer, MPT0B390, inhibits tumor growth, metastasis and angiogenesis
被引:32
作者:
Huang, Han-Li
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Taipei Med Univ, TMU Biomed Commercializat Ctr, Taipei 11031, Taiwan
Taipei Med Univ, Coll Pharm, PhD Program Biotechnol Res & Dev, Taipei 11031, TaiwanTaipei Med Univ, TMU Biomed Commercializat Ctr, Taipei 11031, Taiwan
Huang, Han-Li
[1
,2
]
Liu, Yi-Min
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Taipei Med Univ, TMU Biomed Commercializat Ctr, Taipei 11031, TaiwanTaipei Med Univ, TMU Biomed Commercializat Ctr, Taipei 11031, Taiwan
Liu, Yi-Min
[1
]
Sung, Ting-Yi
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Taipei Med Univ, Coll Pharm, PhD Program Biotechnol Res & Dev, Taipei 11031, TaiwanTaipei Med Univ, TMU Biomed Commercializat Ctr, Taipei 11031, Taiwan
Sung, Ting-Yi
[2
]
Huang, Tsui-Chin
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Taipei Med Univ, Grad Inst Canc Mol Biol & Drug Discovery, Coll Med Sci & Technol, Taipei 11031, TaiwanTaipei Med Univ, TMU Biomed Commercializat Ctr, Taipei 11031, Taiwan
Huang, Tsui-Chin
[3
]
Cheng, Ya-Wen
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Taipei Med Univ, Grad Inst Canc Mol Biol & Drug Discovery, Coll Med Sci & Technol, Taipei 11031, TaiwanTaipei Med Univ, TMU Biomed Commercializat Ctr, Taipei 11031, Taiwan
Tissue inhibitors of metalloproteinase 3 (TIMP3) are a major endogenous inhibitor of matrix metalloproteinase (MMPs) that inhibit tumor growth, invasion, metastasis and angiogenesis. In this study, we found that TIMP3 expression is associated with positive prognosis of colorectal cancer (CRC) clinicopathologically. Therefore, we developed a series of arylsulfonamide derivatives as TIMP3 inducers in order to define potential colorectal cancer therapeutic agent. Among these, MPT0B390 was selected for anti-tumor, anti-metastasis, and anti-angiogenesis property determination. Methods: The relationship between TIMP3 expression and clinical pathological features in colorectal patients and cell lines were determined by immunohistochemistry, bioinformatics analysis and western blotting. The anti-tumor function was validated by using MTT, apoptosis pathway detection and in vivo xenograft model for tumor growth inhibition determination. The anti-metastatic function was validated using a transwell migration assay, and using in vivo lung metastasis and liver metastasis models. The mechanism of MPT0B390-induced TIMP3 expression was further tested using qPCR and Chromatin IP assay. The anti-angiogenesis function was examined by using transwell migration assay, and in vivo Matrigel plug assay. Results: After screening candidate compounds, we identified MPT0B390 as an effective inducer of TIMP3. We showed that MPT0B390 induces TIMP3 expression significantly and inhibits CRC cell growth in vitro and in vivo. By inducing TIMP3 expression, MPT0B390 can also exert its anti-metastasis effect to inhibit CRC cell migration and invasion and downregulates migration markers such as uPA, uPAR, and c-Met. Subsequent Chromatin immunoprecipitation assay revealed that MPT0B390 can significantly inhibit EZH2 expression as well as its binding to TIMP3 promoter region to regulate TIMP3 induction. In addition to the anti-tumor and anti-metastasis capability, MPT0B390 can also induce TIMP3 expression in endothelial cells to inhibit tumor angiogenesis. Conclusion: These data suggest the potential therapeutic applications of the TIMP3 inducer, MPT0B390, for colorectal cancer treatment.
机构:
Toronto Ctr Phenogen, Ctr Modeling Human Dis, Toronto, ON, Canada
Hosp Sick Children, Physiol & Expt Med Res Program, Toronto, ON M5G 1X8, Canada
Univ Toronto, Fac Med, Lab Med & Pathobiol, Toronto, ON, Canada
Univ Guelph, Ontario Vet Coll, Dept Pathobiol, Guelph, ON N1G 2W1, CanadaToronto Ctr Phenogen, Ctr Modeling Human Dis, Toronto, ON, Canada
Adissu, Hibret A.
;
McKerlie, Colin
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h-index: 0
机构:
Toronto Ctr Phenogen, Ctr Modeling Human Dis, Toronto, ON, Canada
Hosp Sick Children, Physiol & Expt Med Res Program, Toronto, ON M5G 1X8, Canada
Univ Toronto, Fac Med, Lab Med & Pathobiol, Toronto, ON, CanadaToronto Ctr Phenogen, Ctr Modeling Human Dis, Toronto, ON, Canada
McKerlie, Colin
;
Di Grappa, Marco
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h-index: 0
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Princess Margaret Canc Ctr, Toronto, ON, CanadaToronto Ctr Phenogen, Ctr Modeling Human Dis, Toronto, ON, Canada
Di Grappa, Marco
;
Waterhouse, Paul
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h-index: 0
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Princess Margaret Canc Ctr, Toronto, ON, CanadaToronto Ctr Phenogen, Ctr Modeling Human Dis, Toronto, ON, Canada
Waterhouse, Paul
;
Xu, Qiang
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h-index: 0
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Toronto Ctr Phenogen, Ctr Modeling Human Dis, Toronto, ON, CanadaToronto Ctr Phenogen, Ctr Modeling Human Dis, Toronto, ON, Canada
Xu, Qiang
;
Fang, Hui
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h-index: 0
机构:
Princess Margaret Canc Ctr, Toronto, ON, CanadaToronto Ctr Phenogen, Ctr Modeling Human Dis, Toronto, ON, Canada
Fang, Hui
;
Khokha, Rama
论文数: 0引用数: 0
h-index: 0
机构:
Princess Margaret Canc Ctr, Toronto, ON, CanadaToronto Ctr Phenogen, Ctr Modeling Human Dis, Toronto, ON, Canada
Khokha, Rama
;
Wood, Geoffrey A.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Guelph, Ontario Vet Coll, Dept Pathobiol, Guelph, ON N1G 2W1, CanadaToronto Ctr Phenogen, Ctr Modeling Human Dis, Toronto, ON, Canada
机构:
IRCCS Fdn Ist Nazl Tumori, Mol Mechanisms Unit, I-20133 Milan, ItalyIRCCS Fdn Ist Nazl Tumori, Mol Mechanisms Unit, I-20133 Milan, Italy
Anania, M. C.
;
Sensi, M.
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h-index: 0
机构:
IRCCS Fdn Ist Nazl Tumori, Funct Genom Core Facil, I-20133 Milan, Italy
IRCCS Fdn Ist Nazl Tumori, Human Tumors Immunobiol Unit, I-20133 Milan, ItalyIRCCS Fdn Ist Nazl Tumori, Mol Mechanisms Unit, I-20133 Milan, Italy
Sensi, M.
;
Radaelli, E.
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h-index: 0
机构:
Univ Milan, Fac Vet Med, Dept Vet Pathol, Milan, Italy
Fdn Filarete, Mouse & Anim Pathol Lab, Milan, ItalyIRCCS Fdn Ist Nazl Tumori, Mol Mechanisms Unit, I-20133 Milan, Italy
Radaelli, E.
;
Miranda, C.
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机构:
IRCCS Fdn Ist Nazl Tumori, Mol Mechanisms Unit, I-20133 Milan, ItalyIRCCS Fdn Ist Nazl Tumori, Mol Mechanisms Unit, I-20133 Milan, Italy
Miranda, C.
;
Vizioli, M. G.
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h-index: 0
机构:
IRCCS Fdn Ist Nazl Tumori, Mol Mechanisms Unit, I-20133 Milan, ItalyIRCCS Fdn Ist Nazl Tumori, Mol Mechanisms Unit, I-20133 Milan, Italy
Vizioli, M. G.
;
Pagliardini, S.
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h-index: 0
机构:
IRCCS Fdn Ist Nazl Tumori, Mol Mechanisms Unit, I-20133 Milan, ItalyIRCCS Fdn Ist Nazl Tumori, Mol Mechanisms Unit, I-20133 Milan, Italy
Pagliardini, S.
;
Favini, E.
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h-index: 0
机构:
IRCCS Fdn Ist Nazl Tumori, Mol Pharmacol Unit, I-20133 Milan, ItalyIRCCS Fdn Ist Nazl Tumori, Mol Mechanisms Unit, I-20133 Milan, Italy
Favini, E.
;
Cleris, L.
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h-index: 0
机构:
IRCCS Fdn Ist Nazl Tumori, Dept Expt Oncol & Mol Med, Chemoprevent Unit, I-20133 Milan, ItalyIRCCS Fdn Ist Nazl Tumori, Mol Mechanisms Unit, I-20133 Milan, Italy
Cleris, L.
;
Supino, R.
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机构:
IRCCS Fdn Ist Nazl Tumori, Mol Pharmacol Unit, I-20133 Milan, ItalyIRCCS Fdn Ist Nazl Tumori, Mol Mechanisms Unit, I-20133 Milan, Italy
Supino, R.
;
Formelli, F.
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机构:
IRCCS Fdn Ist Nazl Tumori, Dept Expt Oncol & Mol Med, Chemoprevent Unit, I-20133 Milan, ItalyIRCCS Fdn Ist Nazl Tumori, Mol Mechanisms Unit, I-20133 Milan, Italy
Formelli, F.
;
Borrello, M. G.
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IRCCS Fdn Ist Nazl Tumori, Mol Mechanisms Unit, I-20133 Milan, ItalyIRCCS Fdn Ist Nazl Tumori, Mol Mechanisms Unit, I-20133 Milan, Italy
Borrello, M. G.
;
Pierotti, M. A.
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机构:
IRCCS Fdn Ist Nazl Tumori, Sci Directorate, I-20133 Milan, ItalyIRCCS Fdn Ist Nazl Tumori, Mol Mechanisms Unit, I-20133 Milan, Italy
Pierotti, M. A.
;
Greco, A.
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h-index: 0
机构:
IRCCS Fdn Ist Nazl Tumori, Mol Mechanisms Unit, I-20133 Milan, ItalyIRCCS Fdn Ist Nazl Tumori, Mol Mechanisms Unit, I-20133 Milan, Italy
机构:
London Hlth Sci Ctr, Lawson Hlth Res Inst, Ctr Crit Illness Res, London, ON, Canada
Univ Western Ontario, Schulich Sch Med & Dent, Dept Physiol & Pharmacol, London, ON, CanadaLondon Hlth Sci Ctr, Lawson Hlth Res Inst, Ctr Crit Illness Res, London, ON, Canada
Arpino, Valerie
;
Brock, Michael
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h-index: 0
机构:
London Hlth Sci Ctr, Lawson Hlth Res Inst, Ctr Crit Illness Res, London, ON, Canada
Univ Western Ontario, Schulich Sch Med & Dent, Dept Physiol & Pharmacol, London, ON, CanadaLondon Hlth Sci Ctr, Lawson Hlth Res Inst, Ctr Crit Illness Res, London, ON, Canada
Brock, Michael
;
Gill, Sean E.
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h-index: 0
机构:
London Hlth Sci Ctr, Lawson Hlth Res Inst, Ctr Crit Illness Res, London, ON, Canada
Univ Western Ontario, Schulich Sch Med & Dent, Div Respirol, London, ON, Canada
Univ Western Ontario, Schulich Sch Med & Dent, Dept Med, London, ON, Canada
Univ Western Ontario, Schulich Sch Med & Dent, Dept Physiol & Pharmacol, London, ON, CanadaLondon Hlth Sci Ctr, Lawson Hlth Res Inst, Ctr Crit Illness Res, London, ON, Canada
机构:
Toronto Ctr Phenogen, Ctr Modeling Human Dis, Toronto, ON, Canada
Hosp Sick Children, Physiol & Expt Med Res Program, Toronto, ON M5G 1X8, Canada
Univ Toronto, Fac Med, Lab Med & Pathobiol, Toronto, ON, Canada
Univ Guelph, Ontario Vet Coll, Dept Pathobiol, Guelph, ON N1G 2W1, CanadaToronto Ctr Phenogen, Ctr Modeling Human Dis, Toronto, ON, Canada
Adissu, Hibret A.
;
McKerlie, Colin
论文数: 0引用数: 0
h-index: 0
机构:
Toronto Ctr Phenogen, Ctr Modeling Human Dis, Toronto, ON, Canada
Hosp Sick Children, Physiol & Expt Med Res Program, Toronto, ON M5G 1X8, Canada
Univ Toronto, Fac Med, Lab Med & Pathobiol, Toronto, ON, CanadaToronto Ctr Phenogen, Ctr Modeling Human Dis, Toronto, ON, Canada
McKerlie, Colin
;
Di Grappa, Marco
论文数: 0引用数: 0
h-index: 0
机构:
Princess Margaret Canc Ctr, Toronto, ON, CanadaToronto Ctr Phenogen, Ctr Modeling Human Dis, Toronto, ON, Canada
Di Grappa, Marco
;
Waterhouse, Paul
论文数: 0引用数: 0
h-index: 0
机构:
Princess Margaret Canc Ctr, Toronto, ON, CanadaToronto Ctr Phenogen, Ctr Modeling Human Dis, Toronto, ON, Canada
Waterhouse, Paul
;
Xu, Qiang
论文数: 0引用数: 0
h-index: 0
机构:
Toronto Ctr Phenogen, Ctr Modeling Human Dis, Toronto, ON, CanadaToronto Ctr Phenogen, Ctr Modeling Human Dis, Toronto, ON, Canada
Xu, Qiang
;
Fang, Hui
论文数: 0引用数: 0
h-index: 0
机构:
Princess Margaret Canc Ctr, Toronto, ON, CanadaToronto Ctr Phenogen, Ctr Modeling Human Dis, Toronto, ON, Canada
Fang, Hui
;
Khokha, Rama
论文数: 0引用数: 0
h-index: 0
机构:
Princess Margaret Canc Ctr, Toronto, ON, CanadaToronto Ctr Phenogen, Ctr Modeling Human Dis, Toronto, ON, Canada
Khokha, Rama
;
Wood, Geoffrey A.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Guelph, Ontario Vet Coll, Dept Pathobiol, Guelph, ON N1G 2W1, CanadaToronto Ctr Phenogen, Ctr Modeling Human Dis, Toronto, ON, Canada
机构:
IRCCS Fdn Ist Nazl Tumori, Mol Mechanisms Unit, I-20133 Milan, ItalyIRCCS Fdn Ist Nazl Tumori, Mol Mechanisms Unit, I-20133 Milan, Italy
Anania, M. C.
;
Sensi, M.
论文数: 0引用数: 0
h-index: 0
机构:
IRCCS Fdn Ist Nazl Tumori, Funct Genom Core Facil, I-20133 Milan, Italy
IRCCS Fdn Ist Nazl Tumori, Human Tumors Immunobiol Unit, I-20133 Milan, ItalyIRCCS Fdn Ist Nazl Tumori, Mol Mechanisms Unit, I-20133 Milan, Italy
Sensi, M.
;
Radaelli, E.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Milan, Fac Vet Med, Dept Vet Pathol, Milan, Italy
Fdn Filarete, Mouse & Anim Pathol Lab, Milan, ItalyIRCCS Fdn Ist Nazl Tumori, Mol Mechanisms Unit, I-20133 Milan, Italy
Radaelli, E.
;
Miranda, C.
论文数: 0引用数: 0
h-index: 0
机构:
IRCCS Fdn Ist Nazl Tumori, Mol Mechanisms Unit, I-20133 Milan, ItalyIRCCS Fdn Ist Nazl Tumori, Mol Mechanisms Unit, I-20133 Milan, Italy
Miranda, C.
;
Vizioli, M. G.
论文数: 0引用数: 0
h-index: 0
机构:
IRCCS Fdn Ist Nazl Tumori, Mol Mechanisms Unit, I-20133 Milan, ItalyIRCCS Fdn Ist Nazl Tumori, Mol Mechanisms Unit, I-20133 Milan, Italy
Vizioli, M. G.
;
Pagliardini, S.
论文数: 0引用数: 0
h-index: 0
机构:
IRCCS Fdn Ist Nazl Tumori, Mol Mechanisms Unit, I-20133 Milan, ItalyIRCCS Fdn Ist Nazl Tumori, Mol Mechanisms Unit, I-20133 Milan, Italy
Pagliardini, S.
;
Favini, E.
论文数: 0引用数: 0
h-index: 0
机构:
IRCCS Fdn Ist Nazl Tumori, Mol Pharmacol Unit, I-20133 Milan, ItalyIRCCS Fdn Ist Nazl Tumori, Mol Mechanisms Unit, I-20133 Milan, Italy
Favini, E.
;
Cleris, L.
论文数: 0引用数: 0
h-index: 0
机构:
IRCCS Fdn Ist Nazl Tumori, Dept Expt Oncol & Mol Med, Chemoprevent Unit, I-20133 Milan, ItalyIRCCS Fdn Ist Nazl Tumori, Mol Mechanisms Unit, I-20133 Milan, Italy
Cleris, L.
;
Supino, R.
论文数: 0引用数: 0
h-index: 0
机构:
IRCCS Fdn Ist Nazl Tumori, Mol Pharmacol Unit, I-20133 Milan, ItalyIRCCS Fdn Ist Nazl Tumori, Mol Mechanisms Unit, I-20133 Milan, Italy
Supino, R.
;
Formelli, F.
论文数: 0引用数: 0
h-index: 0
机构:
IRCCS Fdn Ist Nazl Tumori, Dept Expt Oncol & Mol Med, Chemoprevent Unit, I-20133 Milan, ItalyIRCCS Fdn Ist Nazl Tumori, Mol Mechanisms Unit, I-20133 Milan, Italy
Formelli, F.
;
Borrello, M. G.
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h-index: 0
机构:
IRCCS Fdn Ist Nazl Tumori, Mol Mechanisms Unit, I-20133 Milan, ItalyIRCCS Fdn Ist Nazl Tumori, Mol Mechanisms Unit, I-20133 Milan, Italy
Borrello, M. G.
;
Pierotti, M. A.
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h-index: 0
机构:
IRCCS Fdn Ist Nazl Tumori, Sci Directorate, I-20133 Milan, ItalyIRCCS Fdn Ist Nazl Tumori, Mol Mechanisms Unit, I-20133 Milan, Italy
Pierotti, M. A.
;
Greco, A.
论文数: 0引用数: 0
h-index: 0
机构:
IRCCS Fdn Ist Nazl Tumori, Mol Mechanisms Unit, I-20133 Milan, ItalyIRCCS Fdn Ist Nazl Tumori, Mol Mechanisms Unit, I-20133 Milan, Italy
机构:
London Hlth Sci Ctr, Lawson Hlth Res Inst, Ctr Crit Illness Res, London, ON, Canada
Univ Western Ontario, Schulich Sch Med & Dent, Dept Physiol & Pharmacol, London, ON, CanadaLondon Hlth Sci Ctr, Lawson Hlth Res Inst, Ctr Crit Illness Res, London, ON, Canada
Arpino, Valerie
;
Brock, Michael
论文数: 0引用数: 0
h-index: 0
机构:
London Hlth Sci Ctr, Lawson Hlth Res Inst, Ctr Crit Illness Res, London, ON, Canada
Univ Western Ontario, Schulich Sch Med & Dent, Dept Physiol & Pharmacol, London, ON, CanadaLondon Hlth Sci Ctr, Lawson Hlth Res Inst, Ctr Crit Illness Res, London, ON, Canada
Brock, Michael
;
Gill, Sean E.
论文数: 0引用数: 0
h-index: 0
机构:
London Hlth Sci Ctr, Lawson Hlth Res Inst, Ctr Crit Illness Res, London, ON, Canada
Univ Western Ontario, Schulich Sch Med & Dent, Div Respirol, London, ON, Canada
Univ Western Ontario, Schulich Sch Med & Dent, Dept Med, London, ON, Canada
Univ Western Ontario, Schulich Sch Med & Dent, Dept Physiol & Pharmacol, London, ON, CanadaLondon Hlth Sci Ctr, Lawson Hlth Res Inst, Ctr Crit Illness Res, London, ON, Canada