MicroRNA-330 acts as tumor suppressor and induces apoptosis of prostate cancer cells through E2F1-mediated suppression of Akt phosphorylation

Abstract

MicroRNAs (miRNAs) make up a novel class of gene regulators; they function as oncogenes or tumor suppressors by targeting tumor-suppressor genes or oncogenes. A recent study that analysed a large number of human cancer cell lines showed that miR-330 is a potential tumorsuppressor gene. However, the function and molecular mechanism of miR-330 in determining the aggressiveness of human prostate cancer has not been studied. Here, we show that miR-330 is significantly lower expressed in human prostate cancer cell lines than in nontumorigenic prostate epithelial cells. Bioinformatics analyses reveal a conserved target site for miR-330 in the 3 0 -untranslated region (UTR) of E2F1 at nucleotides 1018-1024. MiR-330 significantly suppressed the activity of a luciferase reporter containing the E2F1-3 0 -UTR in the cells. This activity could be abolished with the transfection of anti-miR-330 or mutated E2F1-3 0 -UTR. In addition, the expression level of miR-330 and E2F1 was inversely correlated in cell lines and prostate cancer specimens. After overexpressing of miR-330 in PC-3 cells, cell growth was suppressed by reducing E2F1-mediated Akt phosphorylation and thereby inducing apoptosis. Collectively, this is the first study to show that E2F1 is negatively regulated by miR-330 and also show that miR-330 induces apoptosis in prostate cancer cells through E2F1-mediated suppression of Akt phosphorylation.

Let-7/miR-98 regulate Fas and Fas-mediated apoptosis

“…22 miR-330 promotes apoptosis in prostate cancer cells through E2F1-mediated suppression of Akt phosphorylation. 23 The role of miRNAs in apoptosis is not fully understood, especially in Fas-mediated apoptosis pathway.…”

Post-Transcriptional Regulation of E2F Transcription Factors: Fine-Tuning DNA Repair, Cell Cycle Progression and Survival in Development & Disease

“…This demonstrates that miRNAs can function as tumor suppressors. A similar role has been suggested for miRNA-195 (Xu et al, 2009), miRNA-128 (Cui et al, 2010, miRNA-330-3p (Lee et al, 2009) and miRNA193a (Kozaki et al, 2008). Overexpression of miRNA-195 causes cell cycle arrest at the G1/S boundary, by interfering with the expression of cell cycle regulatory proteins, such E2F-3, Cyclin D1 and cyclindependent kinase 6 (CDK6).…”

Cząsteczki mikroRNA jako istotny składnik mechanizmów regulacji ekspresji genów związanych z nowotworami

“…Cząsteczka ta jest prawdopodobnie supresorem nowotworu dzięki zdolności wyciszania genów E2F1 (czynnik transkrypcyjny). Niska ekspresja miR-330 koreluje z wysokim poziomem E2F1 w komórkach nowotworowych, co może przyczyniać się do szybszego ich wzrostu w związku ze stymulacją transkrypcji genów zaangażowanych w ten proces [13]. Przy wymuszeniu ekspresji mikroRNA-330 w komórkach raka prostaty obserwowano zahamowanie wzrostu, co mogło być spowodowane redukcją ilości czynnika E2F1.…”

“…Zwiększenie poziomu ekspresji miR-330 związane jest także z indukcją apoptozy. Wnioskuje się zatem, że miR-330 jest supresorem nowotworu, którego ekspresja w przypadku raka prostaty zostaje obniżona [13].…”