Research Papers:

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

Hai-Feng Zhang _, Abdulraheem Alshareef, Chengsheng Wu, Shang Li, Ji-Wei Jiao, Hui-Hui Cao, Raymond Lai, Li-Yan Xu and En-Min Li

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Oncotarget. 2015; 6:28949-28960. https://doi.org/10.18632/oncotarget.5027

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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

Correspondence to:

En-Min Li, e-mail: nmli@stu.edu.cn

Li-Yan Xu, e-mail: lyxu@stu.edu.cn

Raymond Lai, e-mail: rlai@ualberta.ca

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.

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