Micro-RNA-130a-3p Regulates Gemcitabine Resistance via PPARG in Cholangiocarcinoma

Kei Asukai, Koichi Kawamoto, Hidetoshi Eguchi, Masamitsu Konno, Ayumu Asai, Yoshifumi Iwagami, Daisaku Yamada, Tadafumi Asaoka, Takehiro Noda, Hiroshi Wada, Kunihito Gotoh, Naohiro Nishida, Taroh Satoh, Yuichiro Doki, Masaki Mori, Hideshi Ishii

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)2344-2352
Number of pages9
JournalAnnals of Surgical Oncology
Volume24
Issue number8
DOIs
Publication statusPublished - Aug 1 2017

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gemcitabine
Cholangiocarcinoma
MicroRNAs
pioglitazone
Peroxisome Proliferator-Activated Receptors
Laser Capture Microdissection
Microarray Analysis
Genes
Disease-Free Survival
Transfection

All Science Journal Classification (ASJC) codes

  • Surgery
  • Oncology

Cite this

Asukai, K., Kawamoto, K., Eguchi, H., Konno, M., Asai, A., Iwagami, Y., ... Ishii, H. (2017). Micro-RNA-130a-3p Regulates Gemcitabine Resistance via PPARG in Cholangiocarcinoma. Annals of Surgical Oncology, 24(8), 2344-2352. https://doi.org/10.1245/s10434-017-5871-x

Micro-RNA-130a-3p Regulates Gemcitabine Resistance via PPARG in Cholangiocarcinoma. / Asukai, Kei; Kawamoto, Koichi; Eguchi, Hidetoshi; Konno, Masamitsu; Asai, Ayumu; Iwagami, Yoshifumi; Yamada, Daisaku; Asaoka, Tadafumi; Noda, Takehiro; Wada, Hiroshi; Gotoh, Kunihito; Nishida, Naohiro; Satoh, Taroh; Doki, Yuichiro; Mori, Masaki; Ishii, Hideshi.

In: Annals of Surgical Oncology, Vol. 24, No. 8, 01.08.2017, p. 2344-2352.

Research output: Contribution to journalArticle

Asukai, K, Kawamoto, K, Eguchi, H, Konno, M, Asai, A, Iwagami, Y, Yamada, D, Asaoka, T, Noda, T, Wada, H, Gotoh, K, Nishida, N, Satoh, T, Doki, Y, Mori, M & Ishii, H 2017, 'Micro-RNA-130a-3p Regulates Gemcitabine Resistance via PPARG in Cholangiocarcinoma', Annals of Surgical Oncology, vol. 24, no. 8, pp. 2344-2352. https://doi.org/10.1245/s10434-017-5871-x
Asukai, Kei ; Kawamoto, Koichi ; Eguchi, Hidetoshi ; Konno, Masamitsu ; Asai, Ayumu ; Iwagami, Yoshifumi ; Yamada, Daisaku ; Asaoka, Tadafumi ; Noda, Takehiro ; Wada, Hiroshi ; Gotoh, Kunihito ; Nishida, Naohiro ; Satoh, Taroh ; Doki, Yuichiro ; Mori, Masaki ; Ishii, Hideshi. / Micro-RNA-130a-3p Regulates Gemcitabine Resistance via PPARG in Cholangiocarcinoma. In: Annals of Surgical Oncology. 2017 ; Vol. 24, No. 8. pp. 2344-2352.
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abstract = "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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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

PY - 2017/8/1

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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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