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  • Title: MiR-106a-5p promotes 5-FU resistance and the metastasis of colorectal cancer by targeting TGFβR2.
    Author: Liu J, Huang Y, Wang H, Wu D.
    Journal: Int J Clin Exp Pathol; 2018; 11(12):5622-5634. PubMed ID: 31949649.
    Abstract:
    BACKGROUND: Colorectal cancer (CRC) is the third leading cause of cancer-related deaths. 5-Fluorouracil (5-FU)-based chemotherapy has always been the first-line treatment. However, development of 5-FU resistance seriously affects its curative effect. The aim of this study was to elucidate the molecular mechanisms of 5-FU resistance through miR-106a-5p in CRC. METHODS: Colorectal cancer tissues were collected to analyze miR-106a-5p and TGFβR2 expressions by qPCR. Functional experiments for evaluating cell survival and metastasis were conducted to observe the biological effects of miR-106a-5p and TGFβR2. The cell survival rate was calculated using an MTT assay; the metastasis was confirmed with a Transwell invasion assay and Western blotting, which we used to measure the expression levels of the epithelial-mesenchymal transition (EMT) markers E-cadherin and vimentin. The combination of miR-106a to TGFβR2 was predicted using Targetscan, and confirmed through the construction of the luciferase reporter plasmid pGL3-basic. The interplay between miR-106a-5p and TGFβR2 was tested with qPCR and Western blotting. A Spearman rank analysis was employed to verify the correlation of miR-106a-5p and TGFβR2 expressions. RESULTS: MiR-106a-5p was up-regulated and TGFβR2 was down-regulated in 5-FU resistant CRC tissues and HT-29 cells. MiR-106a-5p promoted cell survival and suppressed the apoptosis rate and caspase 3 activity. Additionally, cell invasion was promoted by miR-106a-5p overexpression in the HT-29 cells and was inhibited by miR-106a-5p knockdown in the 5-FU resistant HT-29 cells; miR-106a-5p overexpression contributed to migration by increasing vimentin expression and by decreasing E-cadherin expression in the HT-29 cells; miR-106a-5p functioned by directly binding to TGFβR2. The TGFβR2 knockdown conferred chemoresistance of 5-FU and metastasis in 5-FU resistant HT-29 cells, and TGFβR2 overexpression reduced cell survival, invasion numbers, vimentin expression, and increased the cell apoptosis rate and caspase 3 activity in 5-FU resistant HT-29 cells. Also, miR-106a-5p negatively regulated TGFβR2 in a linear correlation way in the CRC tissues. CONCLUSION: The up-regulation of miR-106a-5p contributes to the pathomechanism of colorectal cancer by promoting 5-FU resistance and metastasis via inhibiting target TGFβR2. Our findings provide new promising ways for the clinical application of the TGFβR2-miR-106a axis in clinical chemotherapy for 5-FU resistant colorectal cancer.
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