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

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.
Authors	Pu Zhang, Changjin Huang, Changliang Fu, Yang Tian, Yijuan Hu, Bochu Wang, Amy Strasner, Yang Song, Erqun Song
Journal	Oncotarget (Oncotarget) Vol. 6 Issue 12 Pg. 9834-53 ( 2015) ISSN: 1949-2553 [Electronic] United States
PMID	25868853 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	3' Untranslated Regions Cadherins Deoxyadenosines HMGA2 Protein Homeodomain Proteins MIRN33a microRNA, human MicroRNAs Nuclear Proteins TWIST1 protein, human Transcription Factors Twist-Related Protein 1 ZEB1 protein, human Zinc Finger E-box-Binding Homeobox 1 cordycepin
Topics	3' Untranslated Regions Adolescent Adult Aged Aged, 80 and over Animals Cadherins (metabolism) Cell Line, Tumor Cell Movement Cytoskeleton (metabolism) Deoxyadenosines (pharmacology) Epithelial-Mesenchymal Transition Female Gene Expression Regulation, Neoplastic HMGA2 Protein (metabolism) Homeodomain Proteins (metabolism) Humans Male Melanoma (metabolism) Mice Mice, Inbred BALB C Mice, Nude MicroRNAs (metabolism) Middle Aged Neoplasm Invasiveness Neoplasm Metastasis Neoplasm Transplantation Nuclear Proteins (metabolism) Skin Neoplasms (metabolism) Transcription Factors (metabolism) Twist-Related Protein 1 (metabolism) Wound Healing Young Adult Zinc Finger E-box-Binding Homeobox 1

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