COUP-TFII inhibits TGF-β-induced growth barrier to promote prostate tumorigenesis

Jun Qin, San Pin Wu, Chad J. Creighton, Fangyan Dai, Xin Xie, Chiang Min Cheng, Anna Frolov, Gustavo Ayala, Xia Lin, Xin Hua Feng, Michael M. Ittmann, Shaw-Jenq Tsai, Ming Jer Tsai, Sophia Y. Tsai

研究成果: Article

98 引文 (Scopus)

摘要

Mutations in phosphatase and tensin homologue (PTEN) or genomic alterations in the phosphatidylinositol-3-OH kinase-signalling pathway are the most common genetic alterations reported in human prostate cancer. However, the precise mechanism underlying how indolent tumours with PTEN alterations acquire metastatic potential remains poorly understood. Recent studies suggest that upregulation of transforming growth factor (TGF)-β signalling triggered by PTEN loss will form a growth barrier as a defence mechanism to constrain prostate cancer progression, underscoring that TGF-β signalling might represent a pre-invasive checkpoint to prevent PTEN-mediated prostate tumorigenesis. Here we show that COUP transcription factor II (COUP-TFII, also known as NR2F2), a member of the nuclear receptor superfamily, serves as a key regulator to inhibit SMAD4-dependent transcription, and consequently overrides the TGF-β-dependent checkpoint for PTEN-null indolent tumours. Overexpression of COUP-TFII in the mouse prostate epithelium cooperates with PTEN deletion to augment malignant progression and produce an aggressive metastasis-prone tumour. The functional counteraction between COUP-TFII and SMAD4 is reinforced by genetically engineered mouse models in which conditional loss of SMAD4 diminishes the inhibitory effects elicited by COUP-TFII ablation. The biological significance of COUP-TFII in prostate carcinogenesis is substantiated by patient sample analysis, in which COUP-TFII expression or activity is tightly correlated with tumour recurrence and disease progression, whereas it is inversely associated with TGF-β signalling. These findings reveal that the destruction of the TGF-β-dependent barrier by COUP-TFII is crucial for the progression of PTEN-mutant prostate cancer into a life-threatening disease, and supports COUP-TFII as a potential drug target for the intervention of metastatic human prostate cancer.

原文English
頁(從 - 到)236-240
頁數5
期刊Nature
493
發行號7431
DOIs
出版狀態Published - 2013 一月 10

指紋

Transforming Growth Factors
Phosphoric Monoester Hydrolases
Prostate
Carcinogenesis
Growth
Prostatic Neoplasms
COUP Transcription Factor II
Neoplasms
Cytoplasmic and Nuclear Receptors
Tensins
Phosphatidylinositol 3-Kinases
Disease Progression
Up-Regulation
Epithelium
Neoplasm Metastasis
Recurrence
Mutation
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • General

引用此文

Qin, J., Wu, S. P., Creighton, C. J., Dai, F., Xie, X., Cheng, C. M., ... Tsai, S. Y. (2013). COUP-TFII inhibits TGF-β-induced growth barrier to promote prostate tumorigenesis. Nature, 493(7431), 236-240. https://doi.org/10.1038/nature11674
Qin, Jun ; Wu, San Pin ; Creighton, Chad J. ; Dai, Fangyan ; Xie, Xin ; Cheng, Chiang Min ; Frolov, Anna ; Ayala, Gustavo ; Lin, Xia ; Feng, Xin Hua ; Ittmann, Michael M. ; Tsai, Shaw-Jenq ; Tsai, Ming Jer ; Tsai, Sophia Y. / COUP-TFII inhibits TGF-β-induced growth barrier to promote prostate tumorigenesis. 於: Nature. 2013 ; 卷 493, 編號 7431. 頁 236-240.
@article{c260ad98ee7e485fb328907790e42bb7,
title = "COUP-TFII inhibits TGF-β-induced growth barrier to promote prostate tumorigenesis",
abstract = "Mutations in phosphatase and tensin homologue (PTEN) or genomic alterations in the phosphatidylinositol-3-OH kinase-signalling pathway are the most common genetic alterations reported in human prostate cancer. However, the precise mechanism underlying how indolent tumours with PTEN alterations acquire metastatic potential remains poorly understood. Recent studies suggest that upregulation of transforming growth factor (TGF)-β signalling triggered by PTEN loss will form a growth barrier as a defence mechanism to constrain prostate cancer progression, underscoring that TGF-β signalling might represent a pre-invasive checkpoint to prevent PTEN-mediated prostate tumorigenesis. Here we show that COUP transcription factor II (COUP-TFII, also known as NR2F2), a member of the nuclear receptor superfamily, serves as a key regulator to inhibit SMAD4-dependent transcription, and consequently overrides the TGF-β-dependent checkpoint for PTEN-null indolent tumours. Overexpression of COUP-TFII in the mouse prostate epithelium cooperates with PTEN deletion to augment malignant progression and produce an aggressive metastasis-prone tumour. The functional counteraction between COUP-TFII and SMAD4 is reinforced by genetically engineered mouse models in which conditional loss of SMAD4 diminishes the inhibitory effects elicited by COUP-TFII ablation. The biological significance of COUP-TFII in prostate carcinogenesis is substantiated by patient sample analysis, in which COUP-TFII expression or activity is tightly correlated with tumour recurrence and disease progression, whereas it is inversely associated with TGF-β signalling. These findings reveal that the destruction of the TGF-β-dependent barrier by COUP-TFII is crucial for the progression of PTEN-mutant prostate cancer into a life-threatening disease, and supports COUP-TFII as a potential drug target for the intervention of metastatic human prostate cancer.",
author = "Jun Qin and Wu, {San Pin} and Creighton, {Chad J.} and Fangyan Dai and Xin Xie and Cheng, {Chiang Min} and Anna Frolov and Gustavo Ayala and Xia Lin and Feng, {Xin Hua} and Ittmann, {Michael M.} and Shaw-Jenq Tsai and Tsai, {Ming Jer} and Tsai, {Sophia Y.}",
year = "2013",
month = "1",
day = "10",
doi = "10.1038/nature11674",
language = "English",
volume = "493",
pages = "236--240",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7431",

}

Qin, J, Wu, SP, Creighton, CJ, Dai, F, Xie, X, Cheng, CM, Frolov, A, Ayala, G, Lin, X, Feng, XH, Ittmann, MM, Tsai, S-J, Tsai, MJ & Tsai, SY 2013, 'COUP-TFII inhibits TGF-β-induced growth barrier to promote prostate tumorigenesis', Nature, 卷 493, 編號 7431, 頁 236-240. https://doi.org/10.1038/nature11674

COUP-TFII inhibits TGF-β-induced growth barrier to promote prostate tumorigenesis. / Qin, Jun; Wu, San Pin; Creighton, Chad J.; Dai, Fangyan; Xie, Xin; Cheng, Chiang Min; Frolov, Anna; Ayala, Gustavo; Lin, Xia; Feng, Xin Hua; Ittmann, Michael M.; Tsai, Shaw-Jenq; Tsai, Ming Jer; Tsai, Sophia Y.

於: Nature, 卷 493, 編號 7431, 10.01.2013, p. 236-240.

研究成果: Article

TY - JOUR

T1 - COUP-TFII inhibits TGF-β-induced growth barrier to promote prostate tumorigenesis

AU - Qin, Jun

AU - Wu, San Pin

AU - Creighton, Chad J.

AU - Dai, Fangyan

AU - Xie, Xin

AU - Cheng, Chiang Min

AU - Frolov, Anna

AU - Ayala, Gustavo

AU - Lin, Xia

AU - Feng, Xin Hua

AU - Ittmann, Michael M.

AU - Tsai, Shaw-Jenq

AU - Tsai, Ming Jer

AU - Tsai, Sophia Y.

PY - 2013/1/10

Y1 - 2013/1/10

N2 - Mutations in phosphatase and tensin homologue (PTEN) or genomic alterations in the phosphatidylinositol-3-OH kinase-signalling pathway are the most common genetic alterations reported in human prostate cancer. However, the precise mechanism underlying how indolent tumours with PTEN alterations acquire metastatic potential remains poorly understood. Recent studies suggest that upregulation of transforming growth factor (TGF)-β signalling triggered by PTEN loss will form a growth barrier as a defence mechanism to constrain prostate cancer progression, underscoring that TGF-β signalling might represent a pre-invasive checkpoint to prevent PTEN-mediated prostate tumorigenesis. Here we show that COUP transcription factor II (COUP-TFII, also known as NR2F2), a member of the nuclear receptor superfamily, serves as a key regulator to inhibit SMAD4-dependent transcription, and consequently overrides the TGF-β-dependent checkpoint for PTEN-null indolent tumours. Overexpression of COUP-TFII in the mouse prostate epithelium cooperates with PTEN deletion to augment malignant progression and produce an aggressive metastasis-prone tumour. The functional counteraction between COUP-TFII and SMAD4 is reinforced by genetically engineered mouse models in which conditional loss of SMAD4 diminishes the inhibitory effects elicited by COUP-TFII ablation. The biological significance of COUP-TFII in prostate carcinogenesis is substantiated by patient sample analysis, in which COUP-TFII expression or activity is tightly correlated with tumour recurrence and disease progression, whereas it is inversely associated with TGF-β signalling. These findings reveal that the destruction of the TGF-β-dependent barrier by COUP-TFII is crucial for the progression of PTEN-mutant prostate cancer into a life-threatening disease, and supports COUP-TFII as a potential drug target for the intervention of metastatic human prostate cancer.

AB - Mutations in phosphatase and tensin homologue (PTEN) or genomic alterations in the phosphatidylinositol-3-OH kinase-signalling pathway are the most common genetic alterations reported in human prostate cancer. However, the precise mechanism underlying how indolent tumours with PTEN alterations acquire metastatic potential remains poorly understood. Recent studies suggest that upregulation of transforming growth factor (TGF)-β signalling triggered by PTEN loss will form a growth barrier as a defence mechanism to constrain prostate cancer progression, underscoring that TGF-β signalling might represent a pre-invasive checkpoint to prevent PTEN-mediated prostate tumorigenesis. Here we show that COUP transcription factor II (COUP-TFII, also known as NR2F2), a member of the nuclear receptor superfamily, serves as a key regulator to inhibit SMAD4-dependent transcription, and consequently overrides the TGF-β-dependent checkpoint for PTEN-null indolent tumours. Overexpression of COUP-TFII in the mouse prostate epithelium cooperates with PTEN deletion to augment malignant progression and produce an aggressive metastasis-prone tumour. The functional counteraction between COUP-TFII and SMAD4 is reinforced by genetically engineered mouse models in which conditional loss of SMAD4 diminishes the inhibitory effects elicited by COUP-TFII ablation. The biological significance of COUP-TFII in prostate carcinogenesis is substantiated by patient sample analysis, in which COUP-TFII expression or activity is tightly correlated with tumour recurrence and disease progression, whereas it is inversely associated with TGF-β signalling. These findings reveal that the destruction of the TGF-β-dependent barrier by COUP-TFII is crucial for the progression of PTEN-mutant prostate cancer into a life-threatening disease, and supports COUP-TFII as a potential drug target for the intervention of metastatic human prostate cancer.

UR - http://www.scopus.com/inward/record.url?scp=84872161627&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84872161627&partnerID=8YFLogxK

U2 - 10.1038/nature11674

DO - 10.1038/nature11674

M3 - Article

C2 - 23201680

AN - SCOPUS:84872161627

VL - 493

SP - 236

EP - 240

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7431

ER -

Qin J, Wu SP, Creighton CJ, Dai F, Xie X, Cheng CM 等. COUP-TFII inhibits TGF-β-induced growth barrier to promote prostate tumorigenesis. Nature. 2013 1月 10;493(7431):236-240. https://doi.org/10.1038/nature11674