Loss of runt-related transcription factor 3 induces gemcitabine resistance in pancreatic cancer

Shigeru Horiguchi, Hidenori Shiraha, Teruya Nagahara, Jyunnro Kataoka, Masaya Iwamuro, Minoru Matsubara, Shinichi Nishina, Hironari Katou, Akinobu Takaki, Kazuhiro Nouso, Takehiro Tanaka, Koichi Ichimura, Takahito Yagi, Kazuhide Yamamoto

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Background & Aim: Runt-related transcription factor 3 (RUNX3) is a tumor suppressor gene that is expressed in gastric and other cancers including pancreatic cancer. However, the precise function of RUNX3 in pancreatic cancer has not been fully elucidated. In this study, we aimed to determine the effect of decreased RUNX3 expression in pancreatic cancer. Methods: This study included 36 patients with primary pancreatic cancer, who had undergone pancreaticoduodenectomy. All patients were treated with 1000mg/m2 gemcitabine after the surgery. The pancreatic cancer cell lines PANC-1, MIAPaCa-2, BxPC-3, SUIT-2, and KLM-1 were used for immunoblotting analysis of RUNX3 and multidrug resistance protein (MRP) expressions. Ectopic RUNX3 expression was achieved by cDNA transfection of the cells, and small interfering RNA (siRNA) against RUNX3 was used to knock down endogenous RUNX3. Cell growth in the presence of gemcitabine was assessed using the MTT assay. Results: Patients with RUNX3-positive and RUNX3-negative pancreatic cancer had a median survival of 1006 and 643 days, respectively. Exogenous RUNX3 expression reduced the expression of MRP1, MRP2, and MRP5 in endogenous RUNX3-negative cells, whereas RUNX3 siRNA increased the expressions of these genes in endogenous RUNX3-positive cells. Exogenous RUNX3 expression decreased gemcitabine IC50 in RUNX3-negative cells. Conclusion: Loss of RUNX3 expression contributes to gemcitabine resistance by inducing MRP expression, thereby resulting in poor patient survival.

Original languageEnglish
Pages (from-to)840-849
Number of pages10
JournalMolecular Oncology
Volume7
Issue number4
DOIs
Publication statusPublished - Aug 2013

Fingerprint

gemcitabine
Transcription Factor 3
Pancreatic Neoplasms
P-Glycoproteins
Small Interfering RNA
Pancreaticoduodenectomy
Survival
Tumor Suppressor Genes
Immunoblotting
Inhibitory Concentration 50
Stomach Neoplasms
Transfection
Complementary DNA
Gene Expression
Cell Line

Keywords

  • Adjuvant chemotherapy
  • Pancreaticoduodenectomy
  • Runt-related transcription factor 3 (RUNX3)
  • Survival

ASJC Scopus subject areas

  • Cancer Research
  • Genetics
  • Molecular Medicine

Cite this

Loss of runt-related transcription factor 3 induces gemcitabine resistance in pancreatic cancer. / Horiguchi, Shigeru; Shiraha, Hidenori; Nagahara, Teruya; Kataoka, Jyunnro; Iwamuro, Masaya; Matsubara, Minoru; Nishina, Shinichi; Katou, Hironari; Takaki, Akinobu; Nouso, Kazuhiro; Tanaka, Takehiro; Ichimura, Koichi; Yagi, Takahito; Yamamoto, Kazuhide.

In: Molecular Oncology, Vol. 7, No. 4, 08.2013, p. 840-849.

Research output: Contribution to journalArticle

Horiguchi, Shigeru ; Shiraha, Hidenori ; Nagahara, Teruya ; Kataoka, Jyunnro ; Iwamuro, Masaya ; Matsubara, Minoru ; Nishina, Shinichi ; Katou, Hironari ; Takaki, Akinobu ; Nouso, Kazuhiro ; Tanaka, Takehiro ; Ichimura, Koichi ; Yagi, Takahito ; Yamamoto, Kazuhide. / Loss of runt-related transcription factor 3 induces gemcitabine resistance in pancreatic cancer. In: Molecular Oncology. 2013 ; Vol. 7, No. 4. pp. 840-849.
@article{4a0a089b2f4c474c963262278b177d84,
title = "Loss of runt-related transcription factor 3 induces gemcitabine resistance in pancreatic cancer",
abstract = "Background & Aim: Runt-related transcription factor 3 (RUNX3) is a tumor suppressor gene that is expressed in gastric and other cancers including pancreatic cancer. However, the precise function of RUNX3 in pancreatic cancer has not been fully elucidated. In this study, we aimed to determine the effect of decreased RUNX3 expression in pancreatic cancer. Methods: This study included 36 patients with primary pancreatic cancer, who had undergone pancreaticoduodenectomy. All patients were treated with 1000mg/m2 gemcitabine after the surgery. The pancreatic cancer cell lines PANC-1, MIAPaCa-2, BxPC-3, SUIT-2, and KLM-1 were used for immunoblotting analysis of RUNX3 and multidrug resistance protein (MRP) expressions. Ectopic RUNX3 expression was achieved by cDNA transfection of the cells, and small interfering RNA (siRNA) against RUNX3 was used to knock down endogenous RUNX3. Cell growth in the presence of gemcitabine was assessed using the MTT assay. Results: Patients with RUNX3-positive and RUNX3-negative pancreatic cancer had a median survival of 1006 and 643 days, respectively. Exogenous RUNX3 expression reduced the expression of MRP1, MRP2, and MRP5 in endogenous RUNX3-negative cells, whereas RUNX3 siRNA increased the expressions of these genes in endogenous RUNX3-positive cells. Exogenous RUNX3 expression decreased gemcitabine IC50 in RUNX3-negative cells. Conclusion: Loss of RUNX3 expression contributes to gemcitabine resistance by inducing MRP expression, thereby resulting in poor patient survival.",
keywords = "Adjuvant chemotherapy, Pancreaticoduodenectomy, Runt-related transcription factor 3 (RUNX3), Survival",
author = "Shigeru Horiguchi and Hidenori Shiraha and Teruya Nagahara and Jyunnro Kataoka and Masaya Iwamuro and Minoru Matsubara and Shinichi Nishina and Hironari Katou and Akinobu Takaki and Kazuhiro Nouso and Takehiro Tanaka and Koichi Ichimura and Takahito Yagi and Kazuhide Yamamoto",
year = "2013",
month = "8",
doi = "10.1016/j.molonc.2013.04.004",
language = "English",
volume = "7",
pages = "840--849",
journal = "Molecular Oncology",
issn = "1574-7891",
publisher = "Elsevier",
number = "4",

}

TY - JOUR

T1 - Loss of runt-related transcription factor 3 induces gemcitabine resistance in pancreatic cancer

AU - Horiguchi, Shigeru

AU - Shiraha, Hidenori

AU - Nagahara, Teruya

AU - Kataoka, Jyunnro

AU - Iwamuro, Masaya

AU - Matsubara, Minoru

AU - Nishina, Shinichi

AU - Katou, Hironari

AU - Takaki, Akinobu

AU - Nouso, Kazuhiro

AU - Tanaka, Takehiro

AU - Ichimura, Koichi

AU - Yagi, Takahito

AU - Yamamoto, Kazuhide

PY - 2013/8

Y1 - 2013/8

N2 - Background & Aim: Runt-related transcription factor 3 (RUNX3) is a tumor suppressor gene that is expressed in gastric and other cancers including pancreatic cancer. However, the precise function of RUNX3 in pancreatic cancer has not been fully elucidated. In this study, we aimed to determine the effect of decreased RUNX3 expression in pancreatic cancer. Methods: This study included 36 patients with primary pancreatic cancer, who had undergone pancreaticoduodenectomy. All patients were treated with 1000mg/m2 gemcitabine after the surgery. The pancreatic cancer cell lines PANC-1, MIAPaCa-2, BxPC-3, SUIT-2, and KLM-1 were used for immunoblotting analysis of RUNX3 and multidrug resistance protein (MRP) expressions. Ectopic RUNX3 expression was achieved by cDNA transfection of the cells, and small interfering RNA (siRNA) against RUNX3 was used to knock down endogenous RUNX3. Cell growth in the presence of gemcitabine was assessed using the MTT assay. Results: Patients with RUNX3-positive and RUNX3-negative pancreatic cancer had a median survival of 1006 and 643 days, respectively. Exogenous RUNX3 expression reduced the expression of MRP1, MRP2, and MRP5 in endogenous RUNX3-negative cells, whereas RUNX3 siRNA increased the expressions of these genes in endogenous RUNX3-positive cells. Exogenous RUNX3 expression decreased gemcitabine IC50 in RUNX3-negative cells. Conclusion: Loss of RUNX3 expression contributes to gemcitabine resistance by inducing MRP expression, thereby resulting in poor patient survival.

AB - Background & Aim: Runt-related transcription factor 3 (RUNX3) is a tumor suppressor gene that is expressed in gastric and other cancers including pancreatic cancer. However, the precise function of RUNX3 in pancreatic cancer has not been fully elucidated. In this study, we aimed to determine the effect of decreased RUNX3 expression in pancreatic cancer. Methods: This study included 36 patients with primary pancreatic cancer, who had undergone pancreaticoduodenectomy. All patients were treated with 1000mg/m2 gemcitabine after the surgery. The pancreatic cancer cell lines PANC-1, MIAPaCa-2, BxPC-3, SUIT-2, and KLM-1 were used for immunoblotting analysis of RUNX3 and multidrug resistance protein (MRP) expressions. Ectopic RUNX3 expression was achieved by cDNA transfection of the cells, and small interfering RNA (siRNA) against RUNX3 was used to knock down endogenous RUNX3. Cell growth in the presence of gemcitabine was assessed using the MTT assay. Results: Patients with RUNX3-positive and RUNX3-negative pancreatic cancer had a median survival of 1006 and 643 days, respectively. Exogenous RUNX3 expression reduced the expression of MRP1, MRP2, and MRP5 in endogenous RUNX3-negative cells, whereas RUNX3 siRNA increased the expressions of these genes in endogenous RUNX3-positive cells. Exogenous RUNX3 expression decreased gemcitabine IC50 in RUNX3-negative cells. Conclusion: Loss of RUNX3 expression contributes to gemcitabine resistance by inducing MRP expression, thereby resulting in poor patient survival.

KW - Adjuvant chemotherapy

KW - Pancreaticoduodenectomy

KW - Runt-related transcription factor 3 (RUNX3)

KW - Survival

UR - http://www.scopus.com/inward/record.url?scp=84880737291&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84880737291&partnerID=8YFLogxK

U2 - 10.1016/j.molonc.2013.04.004

DO - 10.1016/j.molonc.2013.04.004

M3 - Article

VL - 7

SP - 840

EP - 849

JO - Molecular Oncology

JF - Molecular Oncology

SN - 1574-7891

IS - 4

ER -