Loss of miR-200b promotes invasion via activating the Kindlin-2/integrin β1/AKT pathway in esophageal squamous cell carcinoma: An E-cadherin-independent mechanism
Metrics: PDF 1252 views | HTML 1167 views | ?
Hai-Feng Zhang1,3, Abdulraheem Alshareef3, Chengsheng Wu3, Shang Li4, Ji-Wei Jiao1, Hui-Hui Cao2, Raymond Lai3, Li-Yan Xu1,2, En-Min Li1
1The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong, China
2Institute of Oncologic Pathology, Shantou University Medical College, Shantou, Guangdong, China
3Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada
4College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang, China
En-Min Li, e-mail: email@example.com
Li-Yan Xu, e-mail: firstname.lastname@example.org
Raymond Lai, e-mail: email@example.com
Keywords: miR-200, E-cadherin, invasion, prognosis, esophageal squamous cell carcinoma
Received: May 04, 2015 Accepted: August 07, 2015 Published: August 20, 2015
Our previous studies have shown that loss of miR-200b enhances the invasiveness of esophageal squamous cell carcinoma (ESCC) cells. However, whether the miR-200-ZEB1/2-E-cadherin regulatory cascade, a master regulator of epithelial-to-mesenchymal transition (EMT), is involved in the regulation of ESCC invasion remains elusive. Here, we show that miR-200b represses ESCC cell invasion in vivo without altering the expression of E-cadherin and vimentin, two surrogate markers of EMT. However, an inverse correlation was observed between the expression levels of miR-200b and ZEB1/2 in both ESCC cell lines (n = 7, P < 0.05) and ESCC tumor samples (n = 88, P < 0.05). Methylation of E-cadherin gene was found to block the regulation of E-cadherin by the miR-200b-ZEB1/2 axis, indicating that an E-cadherin-independent mechanism can mediate the biological function of miR-200b in ESCC. We revealed that miR-200b suppresses the integrin β1-AKT pathway via targeting Kindlin-2 to mitigate ESCC cell invasiveness. In two independent cohorts of ESCC samples (n = 20 and n = 53, respectively), Kindlin-2 expression positively correlated with the activation status of both the integrin signaling pathway and the PI3K-AKT signaling pathway (both P < 0.01). These data highlight that suppression of the Kindlin-2-integrin β1-AKT regulatory axis is an alternative mechanism underlying the tumor suppressor function of miR-200b in ESCC.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.