Quantitatively Controlling Expression of miR-17∼92 Determines Colon Tumor Progression in a Mouse Tumor Model

The miRNA duster miR-17 similar to 92 targets mRNAs involved in distinct pathways that either promote or inhibit tumor progression. However, the cellular and molecular mechanisms underlying miR-17 similar to 92 cluster-mediated protumorigenic or anti-tumorigenic effects have not been studied. Herein, we determined that inhibition of colon cancer progression is dictated by quantitatively controlling expression of the miR-17 similar to 92 cluster. miR-19 in the context of the miR-17 similar to 92 cluster at medium Levels promoted tumor metastasis through induction of Wnt/beta-catenin mediated epithelialmesenchymal transition by targeting to the tumor-suppressor gene, PTEN. However, higher Levels of the miR-17 similar to 92 cluster switched from PTEN to oncogenes, including Ctnnb1 (beta-catenin) via miR-18a, which resulted in inhibition of tumor growth and metastasis. However, overexpression of Ctnnb1in tumor cells with high-level miR-17 similar to 92 did not lead to an increase in the Levels of beta-catenin protein, suggesting that other factors regulated by higher Levels of miR-17 similar to 92 might also contribute to inhibition of tumor growth and metastasis. Those unidentified factors may negatively regulate the production of beta-catenin protein. Collectively, the data presented in this study revealed that higher Levels of miR-17 similar to 92 were a critical negative regulator for activation of the Wnt/beta-catenin pathway and could have a potential therapeutic application.