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Author Notes:

Correspondence to:Pu Zhang, e-mail: pxz122@swu.edu.cn; e-mail: pxz122@gmail.com

We thank Dr. Gentao Liu (Tongji University) and Dr. Gavin Robertson (Penn State College of Medicine) for helpful discussion.

P.Z., C.F. and Y.S. designed experiments. P.Z., C.H., C.F. and A.S. performed experiments. Y. H. conducted all statistical analyses. B.W. analyzed data. P.Z., C.F., Y.T., E.S. and Y.S. discussed the results and interpreted the data. P.Z. and C.F. wrote and revised the paper.

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Research Funding:

This study was funded by Fundamental Research Funds for the Central Universities (XDJK2014C176 to P.Z.), the Start-up Foundation of Southwest University (SWU114017 to P.Z.) and National Natural Science Foundation of China (NSFC) (NSFC-81402393 to P.Z.).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Oncology
  • Cell Biology
  • cordycepin
  • miR-33b
  • metastasis
  • cell migration
  • focal adhesion
  • EPITHELIAL-MESENCHYMAL TRANSITION
  • BREAST-CANCER CELLS
  • V600E B-RAF
  • MATRIX METALLOPROTEINASES
  • HEPATOCELLULAR-CARCINOMA
  • GENE-EXPRESSION
  • PROGRESSION
  • MICRORNAS
  • MIGRATION
  • PATHWAY

Cordycepin (3 '-deoxyadenosine) suppressed HMGA2, Twist1 and ZEB1-dependent melanoma invasion and metastasis by targeting miR-33b

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Journal Title:

Oncotarget

Volume:

Volume 6, Number 12

Publisher:

, Pages 9834-9853

Type of Work:

Article | Final Publisher PDF

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 cordycepininduced suppression of tumor metastasis and miR-33b/HMGA2/Twist1/ZEB1 axis plays critical roles in regulating melanoma dissemination.

Copyright information:

© 2015 Zhang et al.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 3.0 Unported License (http://creativecommons.org/licenses/by/3.0/).

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