Two Secreted Proteoglycans, Activators of Urothelial Cell–Cell Adhesion, Negatively Contribute to Bladder Cancer Initiation and Progression
Osteomodulin (OMD) and proline/arginine-rich end leucine repeat protein (PRELP) are secreted extracellular matrix proteins belonging to the small leucine-rich proteoglycans family. We found that OMD and PRELP were specifically expressed in umbrella cells in bladder epithelia, and their expression le...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-11-01
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| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/12/11/3362 |
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doaj-06031738d23742d7b87b785ae7131c70 |
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| record_format |
Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Vasiliki Papadaki Ken Asada Julie K. Watson Toshiya Tamura Alex Leung Jack Hopkins Margaret Dellett Noriaki Sasai Hongorzul Davaapil Serena Nik-Zainal Rebecca Longbottom Makoto Nakakido Ryo Torii Abhi Veerakumarasivam Syuzo Kaneko Mandeep S. Sagoo Gillian Murphy Akihisa Mitani Kohei Tsumoto John D. Kelly Ryuji Hamamoto Shin-ichi Ohnuma |
| spellingShingle |
Vasiliki Papadaki Ken Asada Julie K. Watson Toshiya Tamura Alex Leung Jack Hopkins Margaret Dellett Noriaki Sasai Hongorzul Davaapil Serena Nik-Zainal Rebecca Longbottom Makoto Nakakido Ryo Torii Abhi Veerakumarasivam Syuzo Kaneko Mandeep S. Sagoo Gillian Murphy Akihisa Mitani Kohei Tsumoto John D. Kelly Ryuji Hamamoto Shin-ichi Ohnuma Two Secreted Proteoglycans, Activators of Urothelial Cell–Cell Adhesion, Negatively Contribute to Bladder Cancer Initiation and Progression Cancers OMD PRELP tumor suppression gene bladder cancer initiation tight junction partial EMT |
| author_facet |
Vasiliki Papadaki Ken Asada Julie K. Watson Toshiya Tamura Alex Leung Jack Hopkins Margaret Dellett Noriaki Sasai Hongorzul Davaapil Serena Nik-Zainal Rebecca Longbottom Makoto Nakakido Ryo Torii Abhi Veerakumarasivam Syuzo Kaneko Mandeep S. Sagoo Gillian Murphy Akihisa Mitani Kohei Tsumoto John D. Kelly Ryuji Hamamoto Shin-ichi Ohnuma |
| author_sort |
Vasiliki Papadaki |
| title |
Two Secreted Proteoglycans, Activators of Urothelial Cell–Cell Adhesion, Negatively Contribute to Bladder Cancer Initiation and Progression |
| title_short |
Two Secreted Proteoglycans, Activators of Urothelial Cell–Cell Adhesion, Negatively Contribute to Bladder Cancer Initiation and Progression |
| title_full |
Two Secreted Proteoglycans, Activators of Urothelial Cell–Cell Adhesion, Negatively Contribute to Bladder Cancer Initiation and Progression |
| title_fullStr |
Two Secreted Proteoglycans, Activators of Urothelial Cell–Cell Adhesion, Negatively Contribute to Bladder Cancer Initiation and Progression |
| title_full_unstemmed |
Two Secreted Proteoglycans, Activators of Urothelial Cell–Cell Adhesion, Negatively Contribute to Bladder Cancer Initiation and Progression |
| title_sort |
two secreted proteoglycans, activators of urothelial cell–cell adhesion, negatively contribute to bladder cancer initiation and progression |
| publisher |
MDPI AG |
| series |
Cancers |
| issn |
2072-6694 |
| publishDate |
2020-11-01 |
| description |
Osteomodulin (OMD) and proline/arginine-rich end leucine repeat protein (PRELP) are secreted extracellular matrix proteins belonging to the small leucine-rich proteoglycans family. We found that OMD and PRELP were specifically expressed in umbrella cells in bladder epithelia, and their expression levels were dramatically downregulated in all bladder cancers from very early stages and various epithelial cancers. Our in vitro studies including gene expression profiling using bladder cancer cell lines revealed that OMD or PRELP application suppressed the cancer progression by inhibiting TGF-β and EGF pathways, which reversed epithelial–mesenchymal transition (EMT), activated cell–cell adhesion, and inhibited various oncogenic pathways. Furthermore, the overexpression of OMD in bladder cancer cells strongly inhibited the anchorage-independent growth and tumorigenicity in mouse xenograft studies. On the other hand, we found that in the bladder epithelia, the knockout mice of OMD and/or PRELP gene caused partial EMT and a loss of tight junctions of the umbrella cells and resulted in formation of a bladder carcinoma in situ-like structure by spontaneous breakdowns of the umbrella cell layer. Furthermore, the ontological analysis of the expression profiling of an OMD knockout mouse bladder demonstrated very high similarity with those obtained from human bladder cancers. Our data indicate that OMD and PRELP are endogenous inhibitors of cancer initiation and progression by controlling EMT. OMD and/or PRELP may have potential for the treatment of bladder cancer. |
| topic |
OMD PRELP tumor suppression gene bladder cancer initiation tight junction partial EMT |
| url |
https://www.mdpi.com/2072-6694/12/11/3362 |
| work_keys_str_mv |
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doaj-06031738d23742d7b87b785ae7131c702020-11-25T03:59:06ZengMDPI AGCancers2072-66942020-11-01123362336210.3390/cancers12113362Two Secreted Proteoglycans, Activators of Urothelial Cell–Cell Adhesion, Negatively Contribute to Bladder Cancer Initiation and ProgressionVasiliki Papadaki0Ken Asada1Julie K. Watson2Toshiya Tamura3Alex Leung4Jack Hopkins5Margaret Dellett6Noriaki Sasai7Hongorzul Davaapil8Serena Nik-Zainal9Rebecca Longbottom10Makoto Nakakido11Ryo Torii12Abhi Veerakumarasivam13Syuzo Kaneko14Mandeep S. Sagoo15Gillian Murphy16Akihisa Mitani17Kohei Tsumoto18John D. Kelly19Ryuji Hamamoto20Shin-ichi Ohnuma21UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UKDivision of Molecular Modification and Cancer Biology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, JapanDepartment of Oncology, The Hutchison/MRC Research Centre, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UKUCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UKUCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UKUCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UKUCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UKUCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UKUCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UKMRC Cancer Unit University of Cambridge Hutchison/MRC Research Centre Box 197, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UKUCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UKUCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UKDepartment of Mechanical Engineering, University College London, Torrington Place, London WC1E 7JE, UKDepartment of Oncology, The Hutchison/MRC Research Centre, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UKDivision of Molecular Modification and Cancer Biology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, JapanUCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UKDepartment of Oncology, The Hutchison/MRC Research Centre, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UKDepartment of Respiratory Medicine, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, JapanInstitute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, JapanDepartment of Oncology, The Hutchison/MRC Research Centre, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UKDivision of Molecular Modification and Cancer Biology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, JapanUCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UKOsteomodulin (OMD) and proline/arginine-rich end leucine repeat protein (PRELP) are secreted extracellular matrix proteins belonging to the small leucine-rich proteoglycans family. We found that OMD and PRELP were specifically expressed in umbrella cells in bladder epithelia, and their expression levels were dramatically downregulated in all bladder cancers from very early stages and various epithelial cancers. Our in vitro studies including gene expression profiling using bladder cancer cell lines revealed that OMD or PRELP application suppressed the cancer progression by inhibiting TGF-β and EGF pathways, which reversed epithelial–mesenchymal transition (EMT), activated cell–cell adhesion, and inhibited various oncogenic pathways. Furthermore, the overexpression of OMD in bladder cancer cells strongly inhibited the anchorage-independent growth and tumorigenicity in mouse xenograft studies. On the other hand, we found that in the bladder epithelia, the knockout mice of OMD and/or PRELP gene caused partial EMT and a loss of tight junctions of the umbrella cells and resulted in formation of a bladder carcinoma in situ-like structure by spontaneous breakdowns of the umbrella cell layer. Furthermore, the ontological analysis of the expression profiling of an OMD knockout mouse bladder demonstrated very high similarity with those obtained from human bladder cancers. Our data indicate that OMD and PRELP are endogenous inhibitors of cancer initiation and progression by controlling EMT. OMD and/or PRELP may have potential for the treatment of bladder cancer.https://www.mdpi.com/2072-6694/12/11/3362OMDPRELPtumor suppression genebladder cancer initiationtight junctionpartial EMT |