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Hsa-miR-425-5p promotes tumor growth and metastasis by activating the CTNND1-mediated β-catenin pathway and EMT in colorectal cancer.

ABSTRACT: Colorectal cancer (CRC) is a common malignancy with high mortality. However, the roles of miR-425-5p and its underlying mechanism in CRC remain unknown. Here, RT-qPCR confirmed that miR-425-5p expression was increased by miR-425-5p mimic in SW480 cells and decreased by miR-425-5p inhibitor in LOVO cells. CCK-8, flow cytometry, wound healing and transwell assays revealed that the increased miR-425-5p promoted cell viability, cell cycle entry, migration and invasion in CRC. Besides, miR-425-5p overexpression induced epithelial-mesenchymal transition (EMT) with upregulation of Fibronectin, N-cadherin, Vimentin, and downregulation of E-cadherin. Moreover, miR-425-5p overexpression induced c-myc, Cyclin D1 and MMP7 levels, and promoted β-catenin translocation to the nucleus. Knockdown of miR-425-5p exerted opposite effects. Luciferase reporter assay indicated that miR-425-5p directly targeted CTNND1. Overexpression of miR-425-5p repressed CTNND1 expression at mRNA and protein levels. Silencing of CTNND1 had the inhibitory effect of miR-425-5p inhibitor on cell proliferation, migration, invasion, EMT, and the activation of β-catenin signaling pathway. Furthermore, miR-425-5p promoted tumor growth and metastasis in vivo. In conclusion, miR-425-5p may promote tumorigenesis and metastasis through activating CTNND1-mediated β-catenin pathway, which may provide therapeutic targets for human CRC.

SUBMITTER: Liu D

PROVIDER: S-EPMC7469528 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Sulforaphane is a common antioxidant selectively abundant in cruciferous plants, which exhibits effective anti-cancer actions in control of tumorigenesis or progression of various cancers. A recent study has shown that sulforaphane attenuates the EGFR signaling pathway in non-small cell lung cancer (NSCLC), suggesting its potential anti-metastatic effects. In this study we assessed the involvement of sulforaphane and miR-616-5p in epithelial-mesenchymal transition (EMT) and NSCLC metastasis. Sulforaphane suppressed the cell proliferation in human NSCLC cell lines H1299, 95C and 95D with IC50 values of 9.52±1.23, 9.04±1.90 and 17.35±2.03 μmol/L, respectively. At low concentrations (1-5 μmol/L), sulforaphane dose-dependently inhibited the migration and invasion of 95D and H1299 cells with relatively high metastatic potential. The anti-metastatic action of sulforaphane was confirmed in 95D and H1299 cell xenografts in vivo. In fresh NSCLC tissue samples from 179 patients, miR-616-5p levels were upregulated in late-stage NSCLCs, and strongly correlated with risk of NSCLC recurrence and metastasis. Consistent with the clinic observation, miR-616-5p levels in the 3 NSCLC cell lines were correlated with their metastatic ability, and were decreased by sulforaphane treatment. Silencing miR-616-5p markedly suppressed the migration and invasion of 95D cells in vitro and NSCLC metastasis in vivo. Further studies revealed that miR-616-5p directly targeted GSK3β and decreased its expression, whereas sulforaphane decreased miR-616-5p levels by histone modification, and followed by inactivation of the GSK3β/β-catenin signaling pathway and inhibition of EMT, which was characterized by loss of epithelial markers and acquisition of a mesenchymal phenotype in NSCLC cells. Our findings suggest that sulforaphane is a potential adjuvant chemotherapeutic agent for the prevention of NSCLC recurrence and metastasis, and miR-616-5p can be clinically utilized as a biomarker or therapeutic target to inhibit metastasis.

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Hsa-miR-425-5p promotes tumor growth and metastasis by activating the CTNND1-mediated β-catenin pathway and EMT in colorectal cancer.

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