MicroRNA-33b, upregulated by EF24, a curcumin analog, suppresses the epithelial-to-mesenchymal transition (EMT) and migratory potential of melanoma cells by targeting HMGA2.
Diphenyl difluoroketone (EF24), a curcumin analog, exhibits potent anti-tumor activities by arresting cell cycle and inducing apoptosis. However, the efficacy and modes of action of EF24 on melanoma metastasis remain elusive. In this study, we found that at non-cytotoxic concentrations, EF24 suppressed cell motility and epithelial-to-mesenchymal Transition (EMT) of melanoma cell lines, Lu1205 and A375. EF24 also suppressed HMGA2 expression at mRNA and protein levels. miR-33b directly bound to HMGA2 3' untranslated region (3'-UTR) to suppress its expression as measured by dual-luciferase assay. EF24 increased expression of E-cadherin and decreased STAT3 phosphorylation and expression of the mesenchymal markers, vimentin and N-cadherin. miR-33b inhibition or HMGA2 overexpression reverted EF24-mediated suppression of EMT phenotypes. In addition, EF24 modulated the HMGA2-dependent actin stress fiber formation, focal adhesion assembly and FAK, Src and RhoA activation by targeting miR-33b. Thus, the results suggest that EF24 suppresses melanoma metastasis via upregulating miR-33b and concomitantly reducing HMGA2 expression. The observed activities of EF24 support its further evaluation as an anti-metastatic agent in melanoma therapy.
Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University),Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, People's Republic of China; Department of Bioengineering, Pennsylvania State University, University Park, PA 16801, United States. Electronic address: pxz122@swu.edu.cn.
Pu
P
Zhang
Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University),Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, People's Republic of China.
Huiyuan
H
Bai
Shanghai Pulmonary Hospital, Tongji University School of Medicine, 507 Zhengmin Rd, Shanghai 200433, People's Republic of China.
Gentao
G
Liu
Shanghai Pulmonary Hospital, Tongji University School of Medicine, 507 Zhengmin Rd, Shanghai 200433, People's Republic of China.
Heyong
H
Wang
Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University),Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, People's Republic of China.
Feng
F
Chen
Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University),Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, People's Republic of China.
Baoshun
B
Zhang
Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University),Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, People's Republic of China.
Panying
P
Zeng
Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University),Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, People's Republic of China.
Chengxiang
C
Wu
Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University),Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, People's Republic of China.
Cong
C
Peng
Institute of Pathology, Third Military Medical University, Chongqing 400038, People's Republic of China; Division of Hematology/Oncology, Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, United States.
Changjin
C
Huang
Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University),Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, People's Republic of China.
Yang
Y
Song
Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University),Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, People's Republic of China.
Erqun
E
Song
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001597:Benzylidene Compounds / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D003474:Curcumin / Q000031:analogs & derivatives*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects* / Q000502:physiology; D005455:Fluorescent Antibody Technique; D025743:HMGA2 Protein / Q000187:drug effects*; D006801:Humans; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D035683:MicroRNAs / Q000187:drug effects* / Q000502:physiology; D010881:Piperidones / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation / Q000187:drug effects
C524042:3,5-bis(2-fluorobenzylidene)piperidin-4-one; D000970:Antineoplastic Agents; D001597:Benzylidene Compounds; D025743:HMGA2 Protein; C550416:MIRN33a microRNA, human; D035683:MicroRNAs; D010881:Piperidones; D003474:Curcumin
Cancer migration; EF24; EMT; HMGA2; Melanoma; miR-33b