Curcumin regulates miR-21 expression and inhibits invasion and metastasis in colorectal cancer.
Curcumin has promising potential in cancer prevention and therapy by interacting with proteins and modifying their expression and activity, which includes transcription factors, inflammatory cytokines and factors of cell survival, proliferation and angiogenesis. miR-21 is overexpressed in many tumours, promoting progression and metastasis. In the present study, we examined the potential of curcumin to regulate miR-21, tumour growth, invasion and in vivo metastasis in colorectal cancer. In Rko and HCT116 cells, we identified two new transcriptional start sites of the miR-21 gene and delineated its promoter region. PMA stimulation induced miR-21 expression via motifs bound with AP-1 (activator protein 1) transcription factors. Curcumin treatment reduced miR-21 promoter activity and expression in a dose-dependent manner by inhibiting AP-1 binding to the promoter, and induced the expression of the tumour suppressor Pdcd4 (programmed cell death protein 4), which is a target of miR-21. Curcumin-treated Rko and HCT116 cells were arrested in the G2/M phase with increasing concentrations. Furthermore, curcumin inhibited tumour growth, invasion and in vivo metastasis in the chicken-embryo-metastasis assay [CAM (chorionallantoic membrane) assay]. Additionally, curcumin significantly inhibited miR-21 expression in primary tumours generated in vivo in the CAM assay by Rko and HCT116 cells (P<0.00006 and P<0.035 respectively). Taken together, this is the first paper to show that curcumin inhibits the transcriptional regulation of miR-21 via AP-1, suppresses cell proliferation, tumour growth, invasion and in vivo metastasis, and stabilizes the expression of the tumour suppressor Pdcd4 in colorectal cancer.
Mudduluru
Giridhar
G
Department of Experimental Surgery, Mannheim Medical Faculty, Ruprecht-Karls-University Heidelberg, 68167 Mannheim, Germany.
George-William
Jonahunnatha N
JN
Muppala
Santoshi
S
Asangani
Irfan A
IA
Kumarswamy
Regalla
R
Nelson
Laura D
LD
Allgayer
Heike
H
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002642:Chick Embryo; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000556:secondary*; D003474:Curcumin / Q000494:pharmacology* / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D045325:HCT116 Cells; D006801:Humans; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics*; D009361:Neoplasm Invasiveness / Q000517:prevention & control*; D009362:Neoplasm Metastasis / Q000188:drug therapy; D016601:RNA-Binding Proteins / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; C114487:PDCD4 protein, human; D016601:RNA-Binding Proteins; D003474:Curcumin