miR-146a suppresses invasion of pancreatic cancer cells.
The aggressive course of pancreatic cancer is believed to reflect its unusually invasive and metastatic nature, which is associated with epidermal growth factor receptor (EGFR) overexpression and NF-kappaB activation. MicroRNAs (miRNA) have been implicated in the regulation of various pathobiological processes in cancer, including metastasis in pancreatic cancer and in other human malignancies. In this study, we report lower expression of miR-146a in pancreatic cancer cells compared with normal human pancreatic duct epithelial cells. Reexpression of miR-146a inhibited the invasive capacity of pancreatic cancer cells with concomitant downregulation of EGFR and the NF-kappaB regulatory kinase interleukin 1 receptor-associated kinase 1 (IRAK-1). Cellular mechanism studies revealed crosstalk between EGFR, IRAK-1, IkappaBalpha, NF-kappaB, and MTA-2, a transcription factor that regulates metastasis. Treatment of pancreatic cancer cells with the natural products 3,3'-diinodolylmethane (DIM) or isoflavone, which increased miR-146a expression, caused a downregulation of EGFR, MTA-2, IRAK-1, and NF-kappaB, resulting in an inhibition of pancreatic cancer cell invasion. Our findings reveal DIM and isoflavone as nontoxic activators of a miRNA that can block pancreatic cancer cell invasion and metastasis, offering starting points to design novel anticancer agents.
Li
Yiwei
Y
Departments of Pathology and Internal Medicine, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
Vandenboom
Timothy G
TG
Wang
Zhiwei
Z
Kong
Dejuan
D
Ali
Shadan
S
Philip
Philip A
PA
Sarkar
Fazlul H
FH
D000970:Antineoplastic Agents / Q000494:pharmacology; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000473:pathology*; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018773:Genes, erbB-1 / Q000187:drug effects; D019833:Genistein / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D016328:NF-kappa B / Q000235:genetics; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D012097:Repressor Proteins / Q000235:genetics
C512018:1,1-bis(3'-indolyl)methane; D000970:Antineoplastic Agents; D007211:Indoles; C542542:MIRN146 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D019833:Genistein; C507768:IRAK1 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases; C120917:MTA2 protein, human; D006655:Histone Deacetylases; C016392:3,3'-diindolylmethane