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- Title
miR-200b suppresses invasiveness and modulates the cytoskeletal and adhesive machinery in esophageal squamous cell carcinoma cells via targeting Kindlin-2.
- Authors
Zhang, Hai-Feng; Zhang, Kai; Liao, Lian-Di; Li, Li-Yan; Du, Ze-Peng; Wu, Bing-Li; Wu, Jian-Yi; Xu, Xiu-E; Zeng, Fa-Min; Chen, Bo; Cao, Hui-Hui; Zhu, Meng-Xiao; Dai, Li-Hua; Long, Lin; Wu, Zhi-Yong; Lai, Raymond; Xu, Li-Yan; Li, En-Min
- Abstract
Loss of miR-200b correlates with poor prognosis and aggressive clinical features in ESCC patients. The tumor suppressor effects of miR-200b in ESCC may be mediated by inhibition of Kindlin-2, a modulator of actin cytoskeleton, FA formation and cell invasiveness.To further our understanding of the pathobiology of esophageal squamous cell carcinoma (ESCC), we previously performed microRNA profiling that revealed downregulation of miR-200b in ESCC. Using quantitative real-time PCR applied to 88 patient samples, we confirmed that ESCC tumors expressed significantly lower levels of miR-200b compared with the respective adjacent benign tissues (P = 0.003). Importantly, downregulation of miR-200b significantly correlated with shortened survival (P = 0.025), lymph node metastasis (P = 0.002) and advanced clinical stage (P = 0.020) in ESCC patients. Quantitative mass spectrometry identified 57 putative miR-200b targets, including Kindlin-2, previously implicated in the regulation of tumor invasiveness and actin cytoskeleton in other cell types. Enforced expression of miR-200b mimic in ESCC cells led to a decrease of Kindlin-2 expression, whereas transfection of miR-200b inhibitor induced Kindlin-2 expression. Furthermore, transfection of miR-200b mimic or knockdown of Kindlin-2 in ESCC cells decreased cell protrusion and focal adhesion (FA) formation, reduced cell spreading and invasiveness/migration. Enforced expression of Kindlin-2 largely abrogated the inhibitory effects of miR-200b on ESCC cell invasiveness. Mechanistic studies revealed that Rho-family guanosine triphosphatases and FA kinase mediated the biological effects of the miR-200b—Kindlin-2 axis in ESCC cells. To conclude, loss of miR-200b, a frequent biochemical defect in ESCC, correlates with aggressive clinical features. The tumor suppressor effects of miR-200b may be due to its suppression of Kindlin-2, a novel target of miR-200b that modulates actin cytoskeleton, FA formation and the migratory/invasiveness properties of ESCC.
- Subjects
TREATMENT of esophageal cancer; MICRORNA; CANCER invasiveness; CYTOSKELETON; FOCAL adhesions; SQUAMOUS cell carcinoma; LYMPHATIC metastasis; PREVENTION
- Publication
Carcinogenesis, 2014, Vol 35, Issue 2, p292
- ISSN
0143-3334
- Publication type
Article
- DOI
10.1093/carcin/bgt320