Hypoxia-Induced PLOD2 is a Key Regulator in Epithelial-Mesenchymal Transition and Chemoresistance in Biliary Tract Cancer

Yuichiro Okumura, Takehiro Noda, Hidetoshi Eguchi, Takuya Sakamoto, Yoshifumi Iwagami, Daisaku Yamada, Tadafumi Asaoka, Hiroshi Wada, Koichi Kawamoto, Kunihito Gotoh, Shogo Kobayashi, Yutaka Takeda, Masahiro Tanemura, Koji Umeshita, Yuichiro Doki, Masaki Mori

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Background: The prognosis of biliary tract cancer (BTC) is unfavorable due to its chemoresistance. Hypoxia triggers epithelial-to-mesenchymal transition (EMT), which is closely related to drug resistance. In this study, we focused on the functional roles of procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2), a hypoxia-induced gene, in BTC, and assessed the clinical significance of PLOD2. Methods: The expression of PLOD2 under hypoxia was assessed in BTC cell lines. Gemcitabine-resistant (GR) BTC cell lines were transfected with small interfering RNA (siRNA) against PLOD2, and EMT markers and chemoresistance were evaluated. PLOD2 expression was also characterized using immunohistochemistry in BTC clinical specimens following resection. Patient survival was analyzed and the role of PLOD2 expression was examined. Results: The expression of PLOD2 was induced by hypoxia in vitro and was upregulated in BTC-GR cell lines, which had low expression of epithelial markers and high expression of mesenchymal markers. Downregulation of PLOD2 by siRNA resulted in improved chemoresistance, recovery of epithelial markers, and reduction of mesenchymal markers. In the resected BTC samples, PLOD2 expression was significantly correlated with lymph node metastasis (p = 0.037) and stage (p = 0.001). Recurrence-free survival (p = 0.011) and overall survival (p < 0.001) rates were significantly lower in patients with high expression of PLOD2. PLOD2 expression was an independent prognostic factor for overall survival (p = 0.019). Conclusions: The expression of PLOD2 influenced chemoresistance through EMT, and high expression of PLOD2 was a significant unfavorable prognostic factor in BTC patients. PLOD2 might be a potential therapeutic target for overcoming chemoresistance.

Original languageEnglish
Pages (from-to)3728-3737
Number of pages10
JournalAnnals of Surgical Oncology
Volume25
Issue number12
DOIs
Publication statusPublished - Nov 1 2018
Externally publishedYes

Fingerprint

2-Oxoglutarate 5-Dioxygenase Procollagen-Lysine
Biliary Tract Neoplasms
Epithelial-Mesenchymal Transition
gemcitabine
Survival
Hypoxia
Cell Line
Small Interfering RNA

All Science Journal Classification (ASJC) codes

  • Surgery
  • Oncology

Cite this

Hypoxia-Induced PLOD2 is a Key Regulator in Epithelial-Mesenchymal Transition and Chemoresistance in Biliary Tract Cancer. / Okumura, Yuichiro; Noda, Takehiro; Eguchi, Hidetoshi; Sakamoto, Takuya; Iwagami, Yoshifumi; Yamada, Daisaku; Asaoka, Tadafumi; Wada, Hiroshi; Kawamoto, Koichi; Gotoh, Kunihito; Kobayashi, Shogo; Takeda, Yutaka; Tanemura, Masahiro; Umeshita, Koji; Doki, Yuichiro; Mori, Masaki.

In: Annals of Surgical Oncology, Vol. 25, No. 12, 01.11.2018, p. 3728-3737.

Research output: Contribution to journalArticle

Okumura, Y, Noda, T, Eguchi, H, Sakamoto, T, Iwagami, Y, Yamada, D, Asaoka, T, Wada, H, Kawamoto, K, Gotoh, K, Kobayashi, S, Takeda, Y, Tanemura, M, Umeshita, K, Doki, Y & Mori, M 2018, 'Hypoxia-Induced PLOD2 is a Key Regulator in Epithelial-Mesenchymal Transition and Chemoresistance in Biliary Tract Cancer', Annals of Surgical Oncology, vol. 25, no. 12, pp. 3728-3737. https://doi.org/10.1245/s10434-018-6670-8
Okumura, Yuichiro ; Noda, Takehiro ; Eguchi, Hidetoshi ; Sakamoto, Takuya ; Iwagami, Yoshifumi ; Yamada, Daisaku ; Asaoka, Tadafumi ; Wada, Hiroshi ; Kawamoto, Koichi ; Gotoh, Kunihito ; Kobayashi, Shogo ; Takeda, Yutaka ; Tanemura, Masahiro ; Umeshita, Koji ; Doki, Yuichiro ; Mori, Masaki. / Hypoxia-Induced PLOD2 is a Key Regulator in Epithelial-Mesenchymal Transition and Chemoresistance in Biliary Tract Cancer. In: Annals of Surgical Oncology. 2018 ; Vol. 25, No. 12. pp. 3728-3737.
@article{ede378022afd43c4a8ac4619ea2b81e5,
title = "Hypoxia-Induced PLOD2 is a Key Regulator in Epithelial-Mesenchymal Transition and Chemoresistance in Biliary Tract Cancer",
abstract = "Background: The prognosis of biliary tract cancer (BTC) is unfavorable due to its chemoresistance. Hypoxia triggers epithelial-to-mesenchymal transition (EMT), which is closely related to drug resistance. In this study, we focused on the functional roles of procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2), a hypoxia-induced gene, in BTC, and assessed the clinical significance of PLOD2. Methods: The expression of PLOD2 under hypoxia was assessed in BTC cell lines. Gemcitabine-resistant (GR) BTC cell lines were transfected with small interfering RNA (siRNA) against PLOD2, and EMT markers and chemoresistance were evaluated. PLOD2 expression was also characterized using immunohistochemistry in BTC clinical specimens following resection. Patient survival was analyzed and the role of PLOD2 expression was examined. Results: The expression of PLOD2 was induced by hypoxia in vitro and was upregulated in BTC-GR cell lines, which had low expression of epithelial markers and high expression of mesenchymal markers. Downregulation of PLOD2 by siRNA resulted in improved chemoresistance, recovery of epithelial markers, and reduction of mesenchymal markers. In the resected BTC samples, PLOD2 expression was significantly correlated with lymph node metastasis (p = 0.037) and stage (p = 0.001). Recurrence-free survival (p = 0.011) and overall survival (p < 0.001) rates were significantly lower in patients with high expression of PLOD2. PLOD2 expression was an independent prognostic factor for overall survival (p = 0.019). Conclusions: The expression of PLOD2 influenced chemoresistance through EMT, and high expression of PLOD2 was a significant unfavorable prognostic factor in BTC patients. PLOD2 might be a potential therapeutic target for overcoming chemoresistance.",
author = "Yuichiro Okumura and Takehiro Noda and Hidetoshi Eguchi and Takuya Sakamoto and Yoshifumi Iwagami and Daisaku Yamada and Tadafumi Asaoka and Hiroshi Wada and Koichi Kawamoto and Kunihito Gotoh and Shogo Kobayashi and Yutaka Takeda and Masahiro Tanemura and Koji Umeshita and Yuichiro Doki and Masaki Mori",
year = "2018",
month = "11",
day = "1",
doi = "10.1245/s10434-018-6670-8",
language = "English",
volume = "25",
pages = "3728--3737",
journal = "Annals of Surgical Oncology",
issn = "1068-9265",
publisher = "Springer New York",
number = "12",

}

TY - JOUR

T1 - Hypoxia-Induced PLOD2 is a Key Regulator in Epithelial-Mesenchymal Transition and Chemoresistance in Biliary Tract Cancer

AU - Okumura, Yuichiro

AU - Noda, Takehiro

AU - Eguchi, Hidetoshi

AU - Sakamoto, Takuya

AU - Iwagami, Yoshifumi

AU - Yamada, Daisaku

AU - Asaoka, Tadafumi

AU - Wada, Hiroshi

AU - Kawamoto, Koichi

AU - Gotoh, Kunihito

AU - Kobayashi, Shogo

AU - Takeda, Yutaka

AU - Tanemura, Masahiro

AU - Umeshita, Koji

AU - Doki, Yuichiro

AU - Mori, Masaki

PY - 2018/11/1

Y1 - 2018/11/1

N2 - Background: The prognosis of biliary tract cancer (BTC) is unfavorable due to its chemoresistance. Hypoxia triggers epithelial-to-mesenchymal transition (EMT), which is closely related to drug resistance. In this study, we focused on the functional roles of procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2), a hypoxia-induced gene, in BTC, and assessed the clinical significance of PLOD2. Methods: The expression of PLOD2 under hypoxia was assessed in BTC cell lines. Gemcitabine-resistant (GR) BTC cell lines were transfected with small interfering RNA (siRNA) against PLOD2, and EMT markers and chemoresistance were evaluated. PLOD2 expression was also characterized using immunohistochemistry in BTC clinical specimens following resection. Patient survival was analyzed and the role of PLOD2 expression was examined. Results: The expression of PLOD2 was induced by hypoxia in vitro and was upregulated in BTC-GR cell lines, which had low expression of epithelial markers and high expression of mesenchymal markers. Downregulation of PLOD2 by siRNA resulted in improved chemoresistance, recovery of epithelial markers, and reduction of mesenchymal markers. In the resected BTC samples, PLOD2 expression was significantly correlated with lymph node metastasis (p = 0.037) and stage (p = 0.001). Recurrence-free survival (p = 0.011) and overall survival (p < 0.001) rates were significantly lower in patients with high expression of PLOD2. PLOD2 expression was an independent prognostic factor for overall survival (p = 0.019). Conclusions: The expression of PLOD2 influenced chemoresistance through EMT, and high expression of PLOD2 was a significant unfavorable prognostic factor in BTC patients. PLOD2 might be a potential therapeutic target for overcoming chemoresistance.

AB - Background: The prognosis of biliary tract cancer (BTC) is unfavorable due to its chemoresistance. Hypoxia triggers epithelial-to-mesenchymal transition (EMT), which is closely related to drug resistance. In this study, we focused on the functional roles of procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2), a hypoxia-induced gene, in BTC, and assessed the clinical significance of PLOD2. Methods: The expression of PLOD2 under hypoxia was assessed in BTC cell lines. Gemcitabine-resistant (GR) BTC cell lines were transfected with small interfering RNA (siRNA) against PLOD2, and EMT markers and chemoresistance were evaluated. PLOD2 expression was also characterized using immunohistochemistry in BTC clinical specimens following resection. Patient survival was analyzed and the role of PLOD2 expression was examined. Results: The expression of PLOD2 was induced by hypoxia in vitro and was upregulated in BTC-GR cell lines, which had low expression of epithelial markers and high expression of mesenchymal markers. Downregulation of PLOD2 by siRNA resulted in improved chemoresistance, recovery of epithelial markers, and reduction of mesenchymal markers. In the resected BTC samples, PLOD2 expression was significantly correlated with lymph node metastasis (p = 0.037) and stage (p = 0.001). Recurrence-free survival (p = 0.011) and overall survival (p < 0.001) rates were significantly lower in patients with high expression of PLOD2. PLOD2 expression was an independent prognostic factor for overall survival (p = 0.019). Conclusions: The expression of PLOD2 influenced chemoresistance through EMT, and high expression of PLOD2 was a significant unfavorable prognostic factor in BTC patients. PLOD2 might be a potential therapeutic target for overcoming chemoresistance.

UR - http://www.scopus.com/inward/record.url?scp=85051428110&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85051428110&partnerID=8YFLogxK

U2 - 10.1245/s10434-018-6670-8

DO - 10.1245/s10434-018-6670-8

M3 - Article

C2 - 30105440

AN - SCOPUS:85051428110

VL - 25

SP - 3728

EP - 3737

JO - Annals of Surgical Oncology

JF - Annals of Surgical Oncology

SN - 1068-9265

IS - 12

ER -