Research Papers:
Cordycepin (3’-deoxyadenosine) suppressed HMGA2, Twist1 and ZEB1-dependent melanoma invasion and metastasis by targeting miR-33b
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Abstract
Pu Zhang1,4, Changjin Huang2,5, Changliang Fu4, Yang Tian2,6, Yijuan Hu8, Bochu Wang3, Amy Strasner7, Yang Song1, Erqun Song1
1Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China
2Institute of Pathology, Third Military Medical University, Chongqing 400038, China
3College of Bioengineering, Chongqing University, Chongqing 400030, China
4Department of Bioengineering, Pennsylvania State University, University Park, PA 16801, USA
5Division of Hematology/Oncology, Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
6Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA
7Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, CA 92093, USA
8Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA
Correspondence to:
Pu Zhang, e-mail: [email protected]; e-mail: [email protected]
Keywords: cordycepin, miR-33b, metastasis, cell migration, focal adhesion
Received: January 20, 2015 Accepted: February 14, 2015 Published: March 13, 2015
ABSTRACT
Malignant melanoma, the most deadly form of skin cancer, has a high propensity for metastatic spread and is notoriously chemotherapy-resistant. Cordycepin, the active component of Cordyceps spp., has been identified to have anti-metastatic effect on tumor progression and thus possesses pharmacological and therapeutic potentials. However, the mechanisms of anti-metastatic effects of cordycepin at cellular levels remain elusive. We analyzed the effect of cordycepin on human melanoma miRNA expression profiles by miRNAarray and found that miR-33b was upregulated in highly-metastatic melanoma cell lines following cordycepin exposure. Cordycepin-mediated miR-33b expression was dependent on LXR-RXR heterodimer activation. miR-33b directly binds to HMGA2, Twist1 and ZEB1 3’-UTR to suppress their expression. The negative correlations between miR-33b levels and HMGA2, Twist1 or ZEB1 expression were detected in 72 patient melanoma tissue samples. By targeting HMGA2 and Twist1, miR-33b attenuated melanoma migration and invasiveness upon cordycepin exposure. miR-33b knockdown or ZEB1 overexpression reverted cordycepin-mediated mesenchymal-epithelial transition (MET), triggering the expression of N-cadherin. In spontaneous metastasis models, cordycepin suppressed tumor metastasis without altering primary tumor growth. We showed for the first time that targeting miRNA by cordycepin indicates a new mechanism of cordycepin-induced suppression of tumor metastasis and miR-33b/HMGA2/Twist1/ZEB1 axis plays critical roles in regulating melanoma dissemination.
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