Abstract
Metastasis is the major cause of bladder cancer death. 1,25D3, the active metabolite of vitamin D, has shown anti-metastasis activity in several cancer model systems. However, the role of 1,25D3 in migration and invasion in bladder cancer is unknown. To investigate whether 1,25D3 affects migration and invasion, four human bladder cell lines with different reported invasiveness were selected: low-invasive T24 and 253J cells and highly invasive 253J-BV and TCCSUP cells. All of the four bladder cancer cells express endogenous and inducible vitamin D receptor (VDR) as examined by immunoblot analysis. 1,25D3 had no effect on the proliferation of bladder cancer cells as assessed by MTT assay. In contrast, 1,25D3 suppressed migration and invasion in the more invasive 253J-BV and TCCSUP cells, but not in the low-invasive 253J and T24 cells using “wound” healing, chemotactic migration and Matrigel-based invasion assays. 1,25D3 promoted the expression of miR-101-3p and miR-126-3p in 253J-BV cells as examined by qRT-PCR. miR-101-3p inhibitor partially abrogated and pre-miR-101-3p further suppressed the inhibition of 1,25D3 on migration and invasion in 253J-BV cells. Further, 1,25D3 enhanced VDR recruitment to the promoter region of miR-101-3p using ChIP-qPCR assay. 1,25D3 enhanced the promoter activity of miR-101-3p as evaluated by luciferase reporter assay. Taken together, 1,25D3 suppresses bladder cancer cell migration and invasion in two invasive/migration competent lines but not in two less invasive/motile lines, which is partially through the induction of miR-101-3p expression at the transcriptional level.
Highlights
Bladder cancer is the fourth most commonly diagnosed cancer and the eighth leading cause of cancer death in men [1]
We and others have shown that that 1,25D3 potentiates the antitumor activity of the chemotherapeutic agents used most frequently in bladder cancer as well as many other classes of antineoplastic drugs; we have shown that this potentiation in human bladder cancer is mediated through the induction of p73 [12]
We demonstrated that 1,25D3 differentially regulates miRNA expression in a pair of human bladder cancer cells, low-tumorigenic and non-invasive 253J and highly-tumorigenic and invasive 253J-BV cells, using miRNA qPCR panels [37]
Summary
Bladder cancer is the fourth most commonly diagnosed cancer and the eighth leading cause of cancer death in men [1]. These findings are consistent with the hypothesis that 1,25D3 suppresses cell growth as well as inhibits cancer cell migration and invasion in multiple cancer types. The expression of miR-126-3p, miR-154-5p and miR-21-5p was positively correlated with 1,25D3 prostate tissue content [36] These data support the role of vitamin D in influencing the biology of tumor tissues. We investigate the effect of 1,25D3 on proliferation, migration and invasion in a panel of human bladder cancer cells. We demonstrated that 1,25D3 differentially regulates miRNA expression in a pair of human bladder cancer cells, low-tumorigenic and non-invasive 253J and highly-tumorigenic and invasive 253J-BV cells, using miRNA qPCR panels [37].
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