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ERVK13-1/miR-873-5p/GNMT Axis Promotes Metastatic Potential in Human Bladder Cancer though Sarcosine Production
Shingo Kishi1,2, Shiori Mori1, Rina Fujiwara-Tani1
1Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Japan.
International Journal of Molecular Sciences
|November 25, 2023
Summary
N-methyl-glycine (sarcosine) promotes bladder cancer progression by increasing proliferation and invasion. Urinary sarcosine levels correlate with tumor invasion, suggesting its potential as a diagnostic marker.
Area of Science:
- Oncology
- Biochemistry
- Molecular Biology
Background:
- N-methyl-glycine (sarcosine) is implicated in promoting cancer metastasis.
- The role of sarcosine in bladder cancer progression and its underlying mechanisms remain largely unelucidated.
- Glycine N-methyltransferase (GNMT) is an enzyme involved in methyl metabolism and potentially cancer development.
Purpose of the Study:
- To investigate the role of sarcosine and GNMT in bladder cancer.
- To explore the relationship between sarcosine, GNMT, microRNA regulation, and bladder cancer phenotypes.
- To evaluate urinary sarcosine as a potential biomarker for bladder cancer muscle invasion.
Main Methods:
- Utilized invasive (T24) and non-invasive (RT4) bladder cancer cell lines.
- Administered S-adenosyl methionine (SAM) to induce sarcosine production.
- Assessed cell proliferation, invasion, apoptosis, sphere formation, and drug resistance.
- Investigated the expression of GNMT, miR-873-5p, and ERVK13-1.
- Performed xenograft tumor growth and lung metastasis assays in nude mice.
- Analyzed GNMT expression and urinary sarcosine levels in human bladder cancer tissues and urine samples.
Main Results:
- SAM treatment increased sarcosine production, promoting malignant phenotypes in T24 cells but not RT4 cells.
- In T24 cells, miR-873-5p was suppressed, and ERVK13-1 was increased, correlating with higher GNMT expression.
- ERVK13-1 knockdown suppressed tumor growth and metastasis in vivo, while miR-873-5p inhibition promoted it.
- Urinary sarcosine levels correlated with tumor weight in mice.
- Human bladder cancer tissues showed higher GNMT expression in muscle-invasive and metastatic cases.
- Urinary sarcosine concentrations were elevated in patients with muscle invasion.
Conclusions:
- Sarcosine, driven by GNMT, promotes bladder cancer progression, invasion, and drug resistance.
- A regulatory axis involving ERVK13-1, miR-873-5p, and GNMT influences bladder cancer malignancy.
- Urinary sarcosine shows promise as a non-invasive biomarker for detecting muscle invasion in bladder cancer, warranting further clinical validation.
