Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 20, Issue 4, Pages -Publisher
MDPI
DOI: 10.3390/ijms20040980
Keywords
metallothionein 3; bladder; tumorigenesis; NDRG1; MASPIN; hypoxia
Funding
- Taiwan Ministry of Science and Technology [MOST-107-2314-B-182A-017-MY3, MOST-105-2320-B-182-020-MY3]
- Chang Gung Memorial Hospital [CMRPD1F0141-3, CMRPG3H1251-2, CMRPG3F0801-3, CMRPD1I0111-3, CMRPG3H1321-2, CRRPD1F0041-3]
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Metallothioneins have been viewed as modulators in a number of biological regulations regarding cancerous development; however, the function of metallothionein 3 (MT3) in bladder cancer is unexplored. We determined the regulatory mechanisms and potential function of MT3 in bladder carcinoma cells. Real-Time Reverse Transcriptase-Polymerase Chain Reaction (RT-qPCR) assays revealed that TSGH-8301 cells expressed more MT3 levels than RT-4, HT1376, and T24 cells. Immunoblot and RT-qPCR assays showed that arsenic (AS(2)O(3)) treatments enhanced the gene expression of MT3. Hypoxia induced HIF-1, HIF-2, and MT3 expression; furthermore, HIF-2-knockdown attenuated hypoxic activation on MT3 expression. Ectopic overexpression of MT3 increased cell proliferation, invasion, and tumorigenesis significantly in T24 and HT1376 cells in vitro and in vivo; however, MT3-knockdown in TSGH-8301 cells had the reverse effect. Moreover, knockdown of MT3 enhanced arsenic-induced apoptosis determined by the Annexin V-FITC apoptosis assay. MT3-overexpression downregulated the gene expressions of N-myc downstream regulated gene 1 (NDRG1), N-myc downstream regulated gene 2 (NDRG2), and the mammary serine protease inhibitor (MASPIN) in HT1376 and T24 cells, whereas MT3-knockdown in TSGH-8301 cells had the opposite effect. The experiments indicated that MT3 is an arsenic- and hypoxia-upregulated oncogene that promotes cell growth and invasion of bladder carcinoma cells via downregulation of NDRG1, NDRG2, and MASPIN expressions.
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