Involvement of microRNA-181b in the gemcitabine resistance of pancreatic cancer cells.
OBJECTIVE
MicroRNAs (miRs) have been shown to regulate the sensitivity to several chemotherapeutic agents in various types of cancers. MiR-181b is one of such regulators, yet its importance in pancreatic cancer is not determined so far. The aim of this study was to investigate the relationship between microRNA (miR)-181b expression and gemcitabine resistance in pancreatic cancer cells.


METHODS
The effects of overexpression or knockdown of miR-181b on four pancreatic cancer cell lines exposed to gemcitabine were examined. The induction of apoptosis and the changes of the cylindromatosis (CYLD) protein were examined. Furthermore, the effect of small interference RNA for CYLD (siCYLD) on cell viability and the relationship between CYLD and nuclear factor kappa B (NF-κB) were investigated.


RESULTS
The expression of miR-181b was higher in BxPC3, Panc1 and PSN1 cells compared with MiaPaCa2 cells. Pre-miR-181b transfection into MiaPaCa2 cells increased their gemcitabine resistance, whereas anti-miR-181b transfection into the other pancreatic cancer cell lines reduced their resistance to gemcitabine and led to the induction of apoptosis. The protein levels of CYLD were increased by anti-miR-181b in Panc1 and PSN1 cells. Inhibition of CYLD increased the NF-κB activity and gemcitabine resistance in Panc1 and PSN1 cells.


CONCLUSIONS
The present study demonstrated that miR-181b was associated with the resistance of pancreatic cancer cells to gemcitabine, and verified that miR-181b enhances the activity of NF-κB by inhibiting CYLD, leading to the resistance to gemcitabine. Our results suggest that miR-181b is a potential target for decreasing gemcitabine resistance.
Department of Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Daisuke
D
Takiuchi
Hidetoshi
H
Eguchi
Hiroaki
H
Nagano
Yoshifumi
Y
Iwagami
Yoshito
Y
Tomimaru
Hiroshi
H
Wada
Koichi
K
Kawamoto
Shogo
S
Kobayashi
Shigeru
S
Marubashi
Masahiro
M
Tanemura
Masaki
M
Mori
Yuichiro
Y
Doki
D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000074749:Deubiquitinating Enzyme CYLD; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis / Q000502:physiology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D025521:Tumor Suppressor Proteins / Q000187:drug effects / Q000235:genetics; D000093542:Gemcitabine
C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D025521:Tumor Suppressor Proteins; D003841:Deoxycytidine; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD; D000093542:Gemcitabine
CYLD; Chemoresistance; Gemcitabine; NF-κB; Pancreatic cancer