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MicroRNA Blocks Tumor Suppressor Gene Activity in Prostate Cancer Cells

By BiotechDaily International staff writers
Posted on 22 Apr 2013
The microRNA miR-125b is highly expressed in human prostate cancer where it blocks the activity of tumor suppressor genes by repressing the protein product of the ink4a/ARF locus, p14ARF.

p14ARF is an alternate reading frame (ARF) product of the CDKN2A (cyclin-dependent kinase inhibitor 2A ) locus. Both p16INK4a and p14ARF are involved in cell cycle regulation. p14ARF inhibits Mdm2 (mouse double minute 2 homolog), thus promoting p53, which promotes p21 activation, which then binds and inactivates certain cyclin-CDK complexes, which would otherwise advance transcription of genes that would carry the cell through the G1/S checkpoint of the cell cycle. Loss of p14ARF by a homozygous mutation in the CDKN2A (INK4A) gene will lead to elevated levels in Mdm2 and, therefore, loss of p53 function and cell cycle control.

Investigators at the University of California, Davis (USA) worked with two prostate cancer cell lines, LNCaP (wild type-p53) and 22Rv1 (both wild type and mutant p53), as well as in the PC-346C prostate cancer xenograft model that lentivirally overexpressed miR-125b.

They reported in the April 9, 2013, online edition of the journal PLOS One that miR-125b modulated the p53 network by hindering the down-regulation of Mdm2, thereby affecting p53 and its target genes p21 and Puma to a degree sufficient to inhibit apoptosis. In contrast, treatment of prostate cancer cells with an inhibitor of miR-125b (anti-miR-125b) resulted in increased expression of p14ARF, decreased level of Mdm2, and induction of apoptosis.

Overexpression of miR-125b in p53-deficient PC3 cells induced down-regulation of p14ARF, which led to increased cell proliferation through a p53-independent manner. Therefore, the investigators concluded that miR-125b acted as an oncogene, which regulated p14ARF/Mdm2 signaling and stimulated proliferation of prostate cancer cells through a p53-dependent or p53-independent function.

“Our latest research demonstrates that elevated MiR-125b in prostate cancer cells is a mechanism that thwarts our efforts to eradicate the disease,” said senior author Dr. Ralph de Vere White, professor of urology at the University of California, Davis. “These latest findings reinforce our belief that miR-125b has potential as a therapeutic target for the management of patients with metastatic prostate cancer. We are pleased that these data build so successfully on our earlier studies of miR-125b and bring us closer to patient treatment.”

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University of California, Davis



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