title: 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: Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China.|Department of Bioengineering, Pennsylvania State University, University Park, PA 16801, USA.
authors: Pu
authors: P
authors: Zhang
authors: Institute of Pathology, Third Military Medical University, Chongqing 400038, China.|Division of Hematology/Oncology, Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors: Changjin
authors: C
authors: Huang
authors: Department of Bioengineering, Pennsylvania State University, University Park, PA 16801, USA.
authors: Changliang
authors: C
authors: Fu
authors: Institute of Pathology, Third Military Medical University, Chongqing 400038, China.|Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
authors: Yang
authors: Y
authors: Tian
authors: Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA.
authors: Yijuan
authors: Y
authors: Hu
authors: College of Bioengineering, Chongqing University, Chongqing 400030, China.
authors: Bochu
authors: B
authors: Wang
authors: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, CA 92093, USA.
authors: Amy
authors: A
authors: Strasner
authors: Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China.
authors: Yang
authors: Y
authors: Song
authors: Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China.
authors: Erqun
authors: E
authors: Song
mesh_terms: D020413:3' Untranslated Regions; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D003599:Cytoskeleton / Q000378:metabolism; D003839:Deoxyadenosines / Q000494:pharmacology*; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D025743:HMGA2 Protein / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D008297:Male; D008545:Melanoma / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000378:metabolism*; D012878:Skin Neoplasms / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D051879:Twist-Related Protein 1 / Q000378:metabolism*; D014945:Wound Healing; D055815:Young Adult; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D020413:3' Untranslated Regions; D015820:Cadherins; D003839:Deoxyadenosines; D025743:HMGA2 Protein; D018398:Homeodomain Proteins; C550416:MIRN33a microRNA, human; D035683:MicroRNAs; D009687:Nuclear Proteins; C103173:TWIST1 protein, human; D014157:Transcription Factors; D051879:Twist-Related Protein 1; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; C058120:cordycepin
keywords: cell migration; cordycepin; focal adhesion; metastasis; miR-33b