Deregulation of miR-146a expression in a mouse model of pancreatic cancer affecting EGFR signaling.
Aberrant expression of microRNAs (miRNAs) plays important roles in the development and progression of pancreatic cancer (PC). Expression analysis of miR-146a in human PC tissues showed decreased expression in about 80% of samples compared to corresponding non-cancerous tissue. Moreover, expression of miR-146a in eight PC cell lines, and in pancreatic tissues obtained from transgenic mouse models of K-Ras (K), Pdx1-Cre (C), K-Ras;Pdx1-Cre (KC) and K-Ras;Pdx1-Cre;INK4a/Arf (KCI), showed down-regulation of miR-146a expression in KCI mice which was in part led to over-expression of its target gene, epidermal growth factor receptor (EGFR). Treatment of PC cells with CDF, a novel synthetic compound, led to re-expression of miR-146a, resulting in the down-regulation of EGFR expression. Moreover, re-expression of miR-146a by stable transfection or treatment with CDF in vivo (xenograft animal model) resulted in decreased tumor growth which was consistent with reduced EGFR, ERK1, ERK2, and K-Ras expression. Further knock-down of miR-146a in AsPC-1 cells led to the up-regulation of EGFR expression and showed increased clonogenic growth. In addition, knock-down of EGFR by EGFR siRNA transfection of parental AsPC-1 cells and AsPC-1 cells stably transfected with pre-miR-146a resulted in decreased invasive capacity, which was further confirmed by reduced luciferase activity in cells transfected with pMIR-Luc reporter vector containing miR-146a binding site. Collectively, these results suggest that the loss of expression of miR-146a is a fundamental mechanism for over-expression of EGFR signaling and that re-expression of miR-146a by CDF treatment could be useful in designing personalized strategy for the treatment of human PC.
Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, United States.
Shadan
S
Ali
Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, United States.
Aamir
A
Ahmad
Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, United States.
Amro
A
Aboukameel
Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, United States.
Alia
A
Ahmed
Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, United States.
Bin
B
Bao
Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, United States.
Sanjeev
S
Banerjee
Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, United States.
Philip A
PA
Philip
Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, United States; Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, United States. Electronic address: fsarkar@med.wayne.edu.
Fazlul H
FH
Sarkar
D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D003474:Curcumin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D015398:Signal Transduction; D047368:Tumor Burden
C542542:MIRN146 microRNA, human; D035683:MicroRNAs; C512478:EGFR protein, human; D066246:ErbB Receptors; D003474:Curcumin
CDF; EGFR; Pancreatic cancer; Xenograft mouse model; miR-146a