ERVK13-1/miR-873-5p/GNMT Axis Promotes Metastatic Potential in Human Bladder Cancer though Sarcosine Production
N-methyl-glycine (sarcosine) is known to promote metastatic potential in some cancers; however, its effects on bladder cancer are unclear. T24 cells derived from invasive cancer highly expressed GNMT, and S-adenosyl methionine (SAM) treatment increased sarcosine production, promoting proliferation,...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
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MDPI AG
2023-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/22/16367 |
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| author | Shingo Kishi Shiori Mori Rina Fujiwara-Tani Ruiko Ogata Rika Sasaki Ayaka Ikemoto Kei Goto Takamitsu Sasaki Makito Miyake Satoru Sasagawa Masashi Kawaichi Yi Luo Ujjal Kumar Bhawal Kiyohide Fujimoto Hidemitsu Nakagawa Hiroki Kuniyasu |
| author_facet | Shingo Kishi Shiori Mori Rina Fujiwara-Tani Ruiko Ogata Rika Sasaki Ayaka Ikemoto Kei Goto Takamitsu Sasaki Makito Miyake Satoru Sasagawa Masashi Kawaichi Yi Luo Ujjal Kumar Bhawal Kiyohide Fujimoto Hidemitsu Nakagawa Hiroki Kuniyasu |
| author_sort | Shingo Kishi |
| collection | DOAJ |
| description | N-methyl-glycine (sarcosine) is known to promote metastatic potential in some cancers; however, its effects on bladder cancer are unclear. T24 cells derived from invasive cancer highly expressed GNMT, and S-adenosyl methionine (SAM) treatment increased sarcosine production, promoting proliferation, invasion, anti-apoptotic survival, sphere formation, and drug resistance. In contrast, RT4 cells derived from non-invasive cancers expressed low GNMT, and SAM treatment did not produce sarcosine and did not promote malignant phenotypes. In T24 cells, the expression of miR-873-5p, which suppresses GNMT expression, was suppressed, and the expression of ERVK13-1, which sponges miR-873-5p, was increased. The growth of subcutaneous tumors, lung metastasis, and intratumoral GNMT expression in SAM-treated nude mice was suppressed in T24 cells with ERVK13-1 knockdown but promoted in RT4 cells treated with miR-873-5p inhibitor. An increase in mouse urinary sarcosine levels was observed to correlate with tumor weight. Immunostaining of 86 human bladder cancer cases showed that GNMT expression was higher in cases with muscle invasion and metastasis. Additionally, urinary sarcosine concentrations increased in cases of muscle invasion. Notably, urinary sarcosine concentration may serve as a marker for muscle invasion in bladder cancer; however, further investigation is necessitated. |
| first_indexed | 2024-03-09T16:44:57Z |
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| id | doaj.art-607bbfb552ad4f5b93eb5a1e83c8f4c4 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T16:44:57Z |
| publishDate | 2023-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-607bbfb552ad4f5b93eb5a1e83c8f4c42023-11-24T14:47:19ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-11-0124221636710.3390/ijms242216367ERVK13-1/miR-873-5p/GNMT Axis Promotes Metastatic Potential in Human Bladder Cancer though Sarcosine ProductionShingo Kishi0Shiori Mori1Rina Fujiwara-Tani2Ruiko Ogata3Rika Sasaki4Ayaka Ikemoto5Kei Goto6Takamitsu Sasaki7Makito Miyake8Satoru Sasagawa9Masashi Kawaichi10Yi Luo11Ujjal Kumar Bhawal12Kiyohide Fujimoto13Hidemitsu Nakagawa14Hiroki Kuniyasu15Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, JapanDepartment of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, JapanDepartment of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, JapanDepartment of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, JapanDepartment of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, JapanDepartment of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, JapanDepartment of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, JapanDepartment of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, JapanDepartment of Urology, Nara Medical University, Kashihara 634-8522, JapanResearch Institute, Tokushukai Nozaki Hospital, 2-10-50 Tanigawa, Daito 574-0074, JapanResearch Institute, Tokushukai Nozaki Hospital, 2-10-50 Tanigawa, Daito 574-0074, JapanJiangsu Province Key Laboratory of Neuroregeneration, Nantong University, 19 Qixiu Road, Nantong 226001, ChinaResearch Institute of Oral Science, Nihon University School of Dentistry at Matsudo, Matsudo 271-8587, JapanDepartment of Urology, Nara Medical University, Kashihara 634-8522, JapanResearch Institute, Tokushukai Nozaki Hospital, 2-10-50 Tanigawa, Daito 574-0074, JapanDepartment of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, JapanN-methyl-glycine (sarcosine) is known to promote metastatic potential in some cancers; however, its effects on bladder cancer are unclear. T24 cells derived from invasive cancer highly expressed GNMT, and S-adenosyl methionine (SAM) treatment increased sarcosine production, promoting proliferation, invasion, anti-apoptotic survival, sphere formation, and drug resistance. In contrast, RT4 cells derived from non-invasive cancers expressed low GNMT, and SAM treatment did not produce sarcosine and did not promote malignant phenotypes. In T24 cells, the expression of miR-873-5p, which suppresses GNMT expression, was suppressed, and the expression of ERVK13-1, which sponges miR-873-5p, was increased. The growth of subcutaneous tumors, lung metastasis, and intratumoral GNMT expression in SAM-treated nude mice was suppressed in T24 cells with ERVK13-1 knockdown but promoted in RT4 cells treated with miR-873-5p inhibitor. An increase in mouse urinary sarcosine levels was observed to correlate with tumor weight. Immunostaining of 86 human bladder cancer cases showed that GNMT expression was higher in cases with muscle invasion and metastasis. Additionally, urinary sarcosine concentrations increased in cases of muscle invasion. Notably, urinary sarcosine concentration may serve as a marker for muscle invasion in bladder cancer; however, further investigation is necessitated.https://www.mdpi.com/1422-0067/24/22/16367SAMGNMTsarcosinecancer metastasisbladder cancer |
| spellingShingle | Shingo Kishi Shiori Mori Rina Fujiwara-Tani Ruiko Ogata Rika Sasaki Ayaka Ikemoto Kei Goto Takamitsu Sasaki Makito Miyake Satoru Sasagawa Masashi Kawaichi Yi Luo Ujjal Kumar Bhawal Kiyohide Fujimoto Hidemitsu Nakagawa Hiroki Kuniyasu ERVK13-1/miR-873-5p/GNMT Axis Promotes Metastatic Potential in Human Bladder Cancer though Sarcosine Production International Journal of Molecular Sciences SAM GNMT sarcosine cancer metastasis bladder cancer |
| title | ERVK13-1/miR-873-5p/GNMT Axis Promotes Metastatic Potential in Human Bladder Cancer though Sarcosine Production |
| title_full | ERVK13-1/miR-873-5p/GNMT Axis Promotes Metastatic Potential in Human Bladder Cancer though Sarcosine Production |
| title_fullStr | ERVK13-1/miR-873-5p/GNMT Axis Promotes Metastatic Potential in Human Bladder Cancer though Sarcosine Production |
| title_full_unstemmed | ERVK13-1/miR-873-5p/GNMT Axis Promotes Metastatic Potential in Human Bladder Cancer though Sarcosine Production |
| title_short | ERVK13-1/miR-873-5p/GNMT Axis Promotes Metastatic Potential in Human Bladder Cancer though Sarcosine Production |
| title_sort | ervk13 1 mir 873 5p gnmt axis promotes metastatic potential in human bladder cancer though sarcosine production |
| topic | SAM GNMT sarcosine cancer metastasis bladder cancer |
| url | https://www.mdpi.com/1422-0067/24/22/16367 |
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