TY - JOUR
T1 - Micro-RNA-130a-3p Regulates Gemcitabine Resistance via PPARG in Cholangiocarcinoma
AU - Asukai, Kei
AU - Kawamoto, Koichi
AU - Eguchi, Hidetoshi
AU - Konno, Masamitsu
AU - Asai, Ayumu
AU - Iwagami, Yoshifumi
AU - Yamada, Daisaku
AU - Asaoka, Tadafumi
AU - Noda, Takehiro
AU - Wada, Hiroshi
AU - Gotoh, Kunihito
AU - Nishida, Naohiro
AU - Satoh, Taroh
AU - Doki, Yuichiro
AU - Mori, Masaki
AU - Ishii, Hideshi
N1 - Funding Information:
ACKNOWLEDGEMENT This work was supported in part by a Grant-In-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology; Grants-In-Aid, P-DIRECT and P-CREATE; a Grant-In-Aid from the Ministry of Health, Labor and Welfare; a grant from the National Institute of Biomedical Innovation; and a grant from the Osaka University Drug Discovery Funds. Institutional endowments were received partially from Taiho Pharmaceutical Co., Ltd; Evidence-Based Medical (EBM) Research Center, Unitech Co., Ltd; Chugai Co., Ltd; Yakult Honsha Co., Ltd; Ono Pharmaceutical Co., Ltd; and Merck Co., Ltd. These funders had no role in the main experimental equipments, supply expenses, study design, data collection and analysis, or decision to publish pertaining to this work, or preparation of the manuscript.
Funding Information:
This work was supported in part by a Grant-In-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology; Grants-In-Aid, P-DIRECT and P-CREATE; a Grant-In-Aid from the Ministry of Health, Labor and Welfare; a grant from the National Institute of Biomedical Innovation; and a grant from the Osaka University Drug Discovery Funds. Institutional endowments were received partially from Taiho Pharmaceutical Co., Ltd; Evidence-Based Medical (EBM) Research Center, Unitech Co., Ltd; Chugai Co., Ltd; Yakult Honsha Co., Ltd; Ono Pharmaceutical Co., Ltd; and Merck Co., Ltd. These funders had no role in the main experimental equipments, supply expenses, study design, data collection and analysis, or decision to publish pertaining to this work, or preparation of the manuscript. No potential conflict of interest to disclose.
Publisher Copyright:
© 2017, Society of Surgical Oncology.
PY - 2017/8/1
Y1 - 2017/8/1
N2 - Background: The prognosis of cholangiocarcinoma (CCA) is so poor that its chemoresistance needs to be reduced. In this study, we focused on the microRNAs (miRNAs) associated with gemcitabine resistance of CCA and assessed the clinical significance of miRNAs and their target genes. Methods: We performed miRNA microarray analysis for two CCA cell lines (CCLP-1 and MzChA-1) and their gemcitabine-resistant (GR) cells. An miR-130a-3p mimic was induced into CCA cells using lipofection, and we used pioglitazone as a peroxisome proliferator-activated receptor-γ (PPARγ) agonist in vitro. The expression of miR-130a-3p was studied in 27 intrahepatic CCA samples after laser capture microdissection (LCM) and by immunohistochemistry from patients who had undergone curative resection from March 2004 to November 2012 at Osaka University Hospital. Results: miR-130a-3p expression was upregulated in CCLP-1-GRs and MzChA-1-GRs significantly more than in their parental cells. Transfection of the miR-130a-3p mimic into CCA cells increased gemcitabine resistance, and we detected PPARG as a target gene of miR-130a-3p. Furthermore, pioglitazone had a synergistic effect with gemcitabine and alleviated gemcitabine resistance of CCA GR cells. Moreover, clinical examination revealed that for patients who underwent adjuvant gemcitabine therapy, those who were PPARγ positive had significantly longer disease-free survival than those who were PPARγ negative (n = 5 and 11, respectively; p = 0.027). Conclusions: Our data suggest that miR-130a-3p was associated with gemcitabine resistance in CCA through PPARG, and there is a possibility that pioglitazone can be used for the treatment of CCA.
AB - Background: The prognosis of cholangiocarcinoma (CCA) is so poor that its chemoresistance needs to be reduced. In this study, we focused on the microRNAs (miRNAs) associated with gemcitabine resistance of CCA and assessed the clinical significance of miRNAs and their target genes. Methods: We performed miRNA microarray analysis for two CCA cell lines (CCLP-1 and MzChA-1) and their gemcitabine-resistant (GR) cells. An miR-130a-3p mimic was induced into CCA cells using lipofection, and we used pioglitazone as a peroxisome proliferator-activated receptor-γ (PPARγ) agonist in vitro. The expression of miR-130a-3p was studied in 27 intrahepatic CCA samples after laser capture microdissection (LCM) and by immunohistochemistry from patients who had undergone curative resection from March 2004 to November 2012 at Osaka University Hospital. Results: miR-130a-3p expression was upregulated in CCLP-1-GRs and MzChA-1-GRs significantly more than in their parental cells. Transfection of the miR-130a-3p mimic into CCA cells increased gemcitabine resistance, and we detected PPARG as a target gene of miR-130a-3p. Furthermore, pioglitazone had a synergistic effect with gemcitabine and alleviated gemcitabine resistance of CCA GR cells. Moreover, clinical examination revealed that for patients who underwent adjuvant gemcitabine therapy, those who were PPARγ positive had significantly longer disease-free survival than those who were PPARγ negative (n = 5 and 11, respectively; p = 0.027). Conclusions: Our data suggest that miR-130a-3p was associated with gemcitabine resistance in CCA through PPARG, and there is a possibility that pioglitazone can be used for the treatment of CCA.
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U2 - 10.1245/s10434-017-5871-x
DO - 10.1245/s10434-017-5871-x
M3 - Article
C2 - 28560603
AN - SCOPUS:85019668879
SN - 1068-9265
VL - 24
SP - 2344
EP - 2352
JO - Annals of Surgical Oncology
JF - Annals of Surgical Oncology
IS - 8
ER -