Bile acids increase levels of microRNAs 221 and 222, leading to degradation of CDX2 during esophageal carcinogenesis

Juntaro Matsuzaki, Hidekazu Suzuki, Hitoshi Tsugawa, Mitsuhiro Watanabe, Sharif Hossain, Eri Arai, Yoshimasa Saito, Shigeki Sekine, Toshihiro Akaike, Yae Kanai, Ken Ichi Mukaisho, Johan Auwerx, Toshifumi Hibi

研究成果: Article

45 引用 (Scopus)

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Background & Aims Bile reflux contributes to development of Barrett's esophagus (BE) and could be involved in its progression to esophageal adenocarcinoma (EAC). We investigated whether bile acids affect levels or functions of microRNAs (MIRs) 221 and 222, which bind to the 3′-UTR of p27Kip1 messenger RNA to inhibit its translation. Reduced p27Kip1 increases degradation of the transcription factor CDX2; levels of CDX2 have been reported to decrease during progression of BE to EAC. Methods We used quantitative reverse transcriptase polymerase chain reaction to compare levels of MIRs 221 and 222 and immunohistochemistry to compare levels of p27Kip1 and CDX2 proteins in areas of BE and EAC from each of 11 patients. We examined the effects of bile acid exposure on levels of MIRs 221 and 222 and CDX2 in EAC cells. We investigated the effects of inhibitors of MIRs 221 and 222 on growth of human EAC xenograft tumors in NOD/SCID/IL-2Rγnull mice. Results Levels of MIRs 221 and 222 increased and levels of p27Kip1 and CDX2 decreased in areas of EAC vs BE. Levels of MIRs 221 and 222 increased, along with activity of nuclear bile acid receptor/farnesoid X receptor (FXR), when cultured cells were exposed to bile acids. Incubation of cells with bile acids increased degradation of CDX2; this process was reduced when cells were also incubated with proteasome inhibitors. Overexpression of MIRs 221 and 222 reduced levels of p27Kip1 and CDX2, and knockdown of these MIRs increased levels of these proteins in cultured cells. Inhibitors of MIRs 221 and 222 increased levels of p27Kip1 and CDX2 in EAC cells and reduced growth of xenograft tumors in NOD/SCID/IL-2Rγnull mice. Conclusions We observed increased levels of MIRs 221 and 222 in human EAC tissues, compared with areas of BE from the same patient. We found that exposure of esophageal cells to bile acids activates FXR and increases levels of MIRs 221 and 222, reducing levels of p27Kip1 and promoting degradation of CDX2 by the proteasome. Our work opened the perspective of therapeutically targeting this pathway either via FXR antagonists or inhibitors of MIRs as a treatment option for BE and EAC.

元の言語English
ページ(範囲)1300-1311
ページ数12
ジャーナルGastroenterology
145
発行部数6
DOI
出版物ステータスPublished - 2013 12

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Bile Acids and Salts
MicroRNAs
Carcinogenesis
Adenocarcinoma
Barrett Esophagus
Heterografts
Cultured Cells
Bile Reflux
Cyclin-Dependent Kinase Inhibitor p27
Proteasome Inhibitors
3' Untranslated Regions
Proteasome Endopeptidase Complex
Growth
Reverse Transcriptase Polymerase Chain Reaction
Neoplasms
Immunohistochemistry
Messenger RNA

ASJC Scopus subject areas

  • Gastroenterology

これを引用

Bile acids increase levels of microRNAs 221 and 222, leading to degradation of CDX2 during esophageal carcinogenesis. / Matsuzaki, Juntaro; Suzuki, Hidekazu; Tsugawa, Hitoshi; Watanabe, Mitsuhiro; Hossain, Sharif; Arai, Eri; Saito, Yoshimasa; Sekine, Shigeki; Akaike, Toshihiro; Kanai, Yae; Mukaisho, Ken Ichi; Auwerx, Johan; Hibi, Toshifumi.

:: Gastroenterology, 巻 145, 番号 6, 12.2013, p. 1300-1311.

研究成果: Article

Matsuzaki, Juntaro ; Suzuki, Hidekazu ; Tsugawa, Hitoshi ; Watanabe, Mitsuhiro ; Hossain, Sharif ; Arai, Eri ; Saito, Yoshimasa ; Sekine, Shigeki ; Akaike, Toshihiro ; Kanai, Yae ; Mukaisho, Ken Ichi ; Auwerx, Johan ; Hibi, Toshifumi. / Bile acids increase levels of microRNAs 221 and 222, leading to degradation of CDX2 during esophageal carcinogenesis. :: Gastroenterology. 2013 ; 巻 145, 番号 6. pp. 1300-1311.
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title = "Bile acids increase levels of microRNAs 221 and 222, leading to degradation of CDX2 during esophageal carcinogenesis",
abstract = "Background & Aims Bile reflux contributes to development of Barrett's esophagus (BE) and could be involved in its progression to esophageal adenocarcinoma (EAC). We investigated whether bile acids affect levels or functions of microRNAs (MIRs) 221 and 222, which bind to the 3′-UTR of p27Kip1 messenger RNA to inhibit its translation. Reduced p27Kip1 increases degradation of the transcription factor CDX2; levels of CDX2 have been reported to decrease during progression of BE to EAC. Methods We used quantitative reverse transcriptase polymerase chain reaction to compare levels of MIRs 221 and 222 and immunohistochemistry to compare levels of p27Kip1 and CDX2 proteins in areas of BE and EAC from each of 11 patients. We examined the effects of bile acid exposure on levels of MIRs 221 and 222 and CDX2 in EAC cells. We investigated the effects of inhibitors of MIRs 221 and 222 on growth of human EAC xenograft tumors in NOD/SCID/IL-2Rγnull mice. Results Levels of MIRs 221 and 222 increased and levels of p27Kip1 and CDX2 decreased in areas of EAC vs BE. Levels of MIRs 221 and 222 increased, along with activity of nuclear bile acid receptor/farnesoid X receptor (FXR), when cultured cells were exposed to bile acids. Incubation of cells with bile acids increased degradation of CDX2; this process was reduced when cells were also incubated with proteasome inhibitors. Overexpression of MIRs 221 and 222 reduced levels of p27Kip1 and CDX2, and knockdown of these MIRs increased levels of these proteins in cultured cells. Inhibitors of MIRs 221 and 222 increased levels of p27Kip1 and CDX2 in EAC cells and reduced growth of xenograft tumors in NOD/SCID/IL-2Rγnull mice. Conclusions We observed increased levels of MIRs 221 and 222 in human EAC tissues, compared with areas of BE from the same patient. We found that exposure of esophageal cells to bile acids activates FXR and increases levels of MIRs 221 and 222, reducing levels of p27Kip1 and promoting degradation of CDX2 by the proteasome. Our work opened the perspective of therapeutically targeting this pathway either via FXR antagonists or inhibitors of MIRs as a treatment option for BE and EAC.",
keywords = "Cancer, Mouse Model, Post-Transcriptional Modification, Tumor Development",
author = "Juntaro Matsuzaki and Hidekazu Suzuki and Hitoshi Tsugawa and Mitsuhiro Watanabe and Sharif Hossain and Eri Arai and Yoshimasa Saito and Shigeki Sekine and Toshihiro Akaike and Yae Kanai and Mukaisho, {Ken Ichi} and Johan Auwerx and Toshifumi Hibi",
year = "2013",
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language = "English",
volume = "145",
pages = "1300--1311",
journal = "Gastroenterology",
issn = "0016-5085",
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TY - JOUR

T1 - Bile acids increase levels of microRNAs 221 and 222, leading to degradation of CDX2 during esophageal carcinogenesis

AU - Matsuzaki, Juntaro

AU - Suzuki, Hidekazu

AU - Tsugawa, Hitoshi

AU - Watanabe, Mitsuhiro

AU - Hossain, Sharif

AU - Arai, Eri

AU - Saito, Yoshimasa

AU - Sekine, Shigeki

AU - Akaike, Toshihiro

AU - Kanai, Yae

AU - Mukaisho, Ken Ichi

AU - Auwerx, Johan

AU - Hibi, Toshifumi

PY - 2013/12

Y1 - 2013/12

N2 - Background & Aims Bile reflux contributes to development of Barrett's esophagus (BE) and could be involved in its progression to esophageal adenocarcinoma (EAC). We investigated whether bile acids affect levels or functions of microRNAs (MIRs) 221 and 222, which bind to the 3′-UTR of p27Kip1 messenger RNA to inhibit its translation. Reduced p27Kip1 increases degradation of the transcription factor CDX2; levels of CDX2 have been reported to decrease during progression of BE to EAC. Methods We used quantitative reverse transcriptase polymerase chain reaction to compare levels of MIRs 221 and 222 and immunohistochemistry to compare levels of p27Kip1 and CDX2 proteins in areas of BE and EAC from each of 11 patients. We examined the effects of bile acid exposure on levels of MIRs 221 and 222 and CDX2 in EAC cells. We investigated the effects of inhibitors of MIRs 221 and 222 on growth of human EAC xenograft tumors in NOD/SCID/IL-2Rγnull mice. Results Levels of MIRs 221 and 222 increased and levels of p27Kip1 and CDX2 decreased in areas of EAC vs BE. Levels of MIRs 221 and 222 increased, along with activity of nuclear bile acid receptor/farnesoid X receptor (FXR), when cultured cells were exposed to bile acids. Incubation of cells with bile acids increased degradation of CDX2; this process was reduced when cells were also incubated with proteasome inhibitors. Overexpression of MIRs 221 and 222 reduced levels of p27Kip1 and CDX2, and knockdown of these MIRs increased levels of these proteins in cultured cells. Inhibitors of MIRs 221 and 222 increased levels of p27Kip1 and CDX2 in EAC cells and reduced growth of xenograft tumors in NOD/SCID/IL-2Rγnull mice. Conclusions We observed increased levels of MIRs 221 and 222 in human EAC tissues, compared with areas of BE from the same patient. We found that exposure of esophageal cells to bile acids activates FXR and increases levels of MIRs 221 and 222, reducing levels of p27Kip1 and promoting degradation of CDX2 by the proteasome. Our work opened the perspective of therapeutically targeting this pathway either via FXR antagonists or inhibitors of MIRs as a treatment option for BE and EAC.

AB - Background & Aims Bile reflux contributes to development of Barrett's esophagus (BE) and could be involved in its progression to esophageal adenocarcinoma (EAC). We investigated whether bile acids affect levels or functions of microRNAs (MIRs) 221 and 222, which bind to the 3′-UTR of p27Kip1 messenger RNA to inhibit its translation. Reduced p27Kip1 increases degradation of the transcription factor CDX2; levels of CDX2 have been reported to decrease during progression of BE to EAC. Methods We used quantitative reverse transcriptase polymerase chain reaction to compare levels of MIRs 221 and 222 and immunohistochemistry to compare levels of p27Kip1 and CDX2 proteins in areas of BE and EAC from each of 11 patients. We examined the effects of bile acid exposure on levels of MIRs 221 and 222 and CDX2 in EAC cells. We investigated the effects of inhibitors of MIRs 221 and 222 on growth of human EAC xenograft tumors in NOD/SCID/IL-2Rγnull mice. Results Levels of MIRs 221 and 222 increased and levels of p27Kip1 and CDX2 decreased in areas of EAC vs BE. Levels of MIRs 221 and 222 increased, along with activity of nuclear bile acid receptor/farnesoid X receptor (FXR), when cultured cells were exposed to bile acids. Incubation of cells with bile acids increased degradation of CDX2; this process was reduced when cells were also incubated with proteasome inhibitors. Overexpression of MIRs 221 and 222 reduced levels of p27Kip1 and CDX2, and knockdown of these MIRs increased levels of these proteins in cultured cells. Inhibitors of MIRs 221 and 222 increased levels of p27Kip1 and CDX2 in EAC cells and reduced growth of xenograft tumors in NOD/SCID/IL-2Rγnull mice. Conclusions We observed increased levels of MIRs 221 and 222 in human EAC tissues, compared with areas of BE from the same patient. We found that exposure of esophageal cells to bile acids activates FXR and increases levels of MIRs 221 and 222, reducing levels of p27Kip1 and promoting degradation of CDX2 by the proteasome. Our work opened the perspective of therapeutically targeting this pathway either via FXR antagonists or inhibitors of MIRs as a treatment option for BE and EAC.

KW - Cancer

KW - Mouse Model

KW - Post-Transcriptional Modification

KW - Tumor Development

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U2 - 10.1053/j.gastro.2013.08.008

DO - 10.1053/j.gastro.2013.08.008

M3 - Article

C2 - 23933602

AN - SCOPUS:84888250297

VL - 145

SP - 1300

EP - 1311

JO - Gastroenterology

JF - Gastroenterology

SN - 0016-5085

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