Wnt7a activates canonical Wnt signaling, promotes bladder cancer cell invasion, and is suppressed by miR-370-3p
| Autor: | Hongwen Zhu, Yu Dong, Bing Shen, Hongqian Guo, Meiqian Li, Junzun Li, Junlong Zhuang, Xiaojing Huang, Ruimin Huang, Hu Zhou, Jun Yan, Zemin Gao |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Epithelial-Mesenchymal Transition MMP10 Biochemistry Mass Spectrometry Metastasis Extracellular matrix 03 medical and health sciences 0302 clinical medicine Matrix Metalloproteinase 10 Cell Line Tumor microRNA medicine Humans Luciferase Genes Tumor Suppressor Neoplasm Invasiveness Neoplasm Metastasis Molecular Biology Wnt Signaling Pathway beta Catenin WNT Family Protein Chemistry fungi Wnt signaling pathway Cell Biology Oncogenes medicine.disease Prognosis Gene Expression Regulation Neoplastic Wnt Proteins MicroRNAs 030104 developmental biology WNT7A Urinary Bladder Neoplasms 030220 oncology & carcinogenesis Cancer research |
| Zdroj: | The Journal of biological chemistry. 293(18) |
| ISSN: | 1083-351X |
| Popis: | Once urinary bladder cancer (UBC) develops into muscle-invasive bladder cancer, its mortality rate increases dramatically. However, the molecular mechanisms of UBC invasion and metastasis remain largely unknown. Herein, using 5637 UBC cells, we generated two sublines with low (5637 NMI) and high (5637 HMI) invasive capabilities. Mass spectrum analyses revealed that the Wnt family protein Wnt7a is more highly expressed in 5637 HMI cells than in 5637 NMI cells. We also found that increased Wnt7a expression is associated with UBC metastasis and predicted worse clinical outcome in UBC patients. Wnt7a depletion in 5637 HMI and T24 cells reduced UBC cell invasion and decreased levels of active β-catenin and its downstream target genes involved in the epithelial-to-mesenchymal transition (EMT) and extracellular matrix (ECM) degradation. Consistently, treating 5637 NMI and J82 cells with recombinant Wnt7a induced cell invasion, EMT, and expression of ECM degradation–associated genes. Moreover, TOP/FOPflash luciferase assays indicated that Wnt7a activated canonical β-catenin signaling in UBC cells, and increased Wnt7a expression was associated with nuclear β-catenin in UBC samples. Wnt7a ablation suppressed matrix metalloproteinase 10 (MMP10) expression, and Wnt7a overexpression increased MMP10 promoter activity through two TCF/LEF promoter sites, confirming that Wnt7a-mediated MMP10 activation is mediated by the canonical Wnt/β-catenin pathway. Of note, the microRNA miR-370-3p directly repressed Wnt7a expression and thereby suppressed UBC cell invasion, which was partially restored by Wnt7a overexpression. Our results have identified an miR-370-3p/Wnt7a axis that controls UBC invasion through canonical Wnt/β-catenin signaling, which may offer prognostic and therapeutic opportunities. |
| Databáze: | OpenAIRE |
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