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Nat Commun. 2019 Sep 25;10(1):4349. doi: 10.1038/s41467-019-12241-2.

c-Met activation leads to the establishment of a TGFβ-receptor regulatory network in bladder cancer progression.

Author information

1
Institute of Molecular and Cell Biology, A*STAR, Singapore, 138672, Singapore.
2
Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore.
3
Department of Cell and Chemical Biology and Oncode Institute, Leiden University Medical Center, 2333 ZC, Leiden, The Netherlands.
4
Bioinformatics Institute (A*STAR), 30 Biopolis Street, 07-01 Matrix, Singapore, 138671, Singapore.
5
Department of Physics of Complex Systems, The Weizmann Institute of Science, Rehovot, Israel.
6
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117596, Singapore.
7
Genome Institute of Singapore, A*STAR, Singapore, 138672, Singapore.
8
Department of Biological Sciences, National University of Singapore, 14 Science Drive, Singapore, 117543, Singapore.
9
School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore, 637551, Singapore.
10
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore.
11
Cancer Program, Medical Science Cluster, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
12
Curtin Medical School, Faculty of Health Sciences, Curtin University, Perth, WA, Australia.
13
Department of Urology, Hôpital Foch, Université Versailles-Saint-Quentin-en-Yvelines, Université Paris-Saclay, Suresnes, France.
14
INSERM Unit 1015, Laboratoire de Recherche Translationnelle en Immunologie (LRTI), Gustave Roussy, Université Paris-Saclay, Villejuif, France.
15
Department of Urology, Pusan National University Hospital, Pusan National University School of Medicine, Busan, 602-739, Korea.
16
Department of Pathology, Hôpital Foch, Université Versailles-Saint-Quentin-en-Yvelines, Université Paris-Saclay, Suresnes, France.
17
Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore. Pieter.Eichhorn@curtin.edu.au.
18
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore. Pieter.Eichhorn@curtin.edu.au.
19
School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin University, Bentley, 6102, Australia. Pieter.Eichhorn@curtin.edu.au.
20
Curtin Health Innovation Research Institute and Faculty of Health Sciences, Curtin University, Bentley, WA, 6102, Australia. Pieter.Eichhorn@curtin.edu.au.
21
Institute of Molecular and Cell Biology, A*STAR, Singapore, 138672, Singapore. bchtjp@nus.edu.sg.
22
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117596, Singapore. bchtjp@nus.edu.sg.
23
Guangzhou Regenerative Medicine and Health, Guangdong Laboratory, 510530, Guangzhou, China. bchtjp@nus.edu.sg.

Abstract

Treatment of muscle-invasive bladder cancer remains a major clinical challenge. Aberrant HGF/c-MET upregulation and activation is frequently observed in bladder cancer correlating with cancer progression and invasion. However, the mechanisms underlying HGF/c-MET-mediated invasion in bladder cancer remains unknown. As part of a negative feedback loop SMAD7 binds to SMURF2 targeting the TGFβ receptor for degradation. Under these conditions, SMAD7 acts as a SMURF2 agonist by disrupting the intramolecular interactions within SMURF2. We demonstrate that HGF stimulates TGFβ signalling through c-SRC-mediated phosphorylation of SMURF2 resulting in loss of SMAD7 binding and enhanced SMURF2 C2-HECT interaction, inhibiting SMURF2 and enhancing TGFβ receptor stabilisation. This upregulation of the TGFβ pathway by HGF leads to TGFβ-mediated EMT and invasion. In vivo we show that TGFβ receptor inhibition prevents bladder cancer invasion. Furthermore, we make a rationale for the use of combinatorial TGFβ and MEK inhibitors for treatment of high-grade non-muscle-invasive bladder cancers.

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