Loss of EGFR signaling regulated miR-203 promotes prostate cancer bone metastasis and tyrosine kinase inhibitors resistance

Man Kit Siu, Wassim Abou-Kheir, Juan Juan Yin, Yung Sheng Chang, Ben Barrett, Florent Suau, Orla Casey, Wei Yu Chen, Lei Fang, Paul Hynes, Yao Yu Hsieh, Yen Nien Liu, Jiaoti Huang, Kathleen Kelly

研究成果: 雜誌貢獻文章

36 引文 (Scopus)

摘要

Activation of EGFR signaling pathway leads to prostate cancer bone metastasis; however, therapies targeting EGFR have demonstrated limited effectiveness and led to drug resistance. miR-203 levels are down-regulated in clinical samples of primary prostate cancer and further reduced in metastatic prostate cancer. Here we show that ectopic miR-203 expression displayed reduced bone metastasis and induced sensitivity to tyrosine kinase inhibitors (TKIs) treatment in a xenograft model. Our results demonstrate that the induction of bone metastasis and TKI resistance require miR-203 down regulation, activation of the EGFR pathway via altered expression of EGFR ligands (EREG and TGFA) and anti-apoptotic proteins (API5, BIRC2, and TRIAP1). Importantly, a sufficient reconstitution of invasiveness and resistance to TKIs treatment was observed in cells transfected with anti-miR-203. In prostate cancer patients, our data showed that miR-203 levels were inversely correlated with the expression of two EGFR ligands, EREG and TGFA, and an EGFR dependent gene signature. Our results support the existence of a miR-203, EGFR, TKIs resistance regulatory network in prostate cancer progression. We propose that the loss of miR-203 is a molecular link in the progression of prostate cancer metastasis and TKIs resistance characterized by high EGFR ligands output and anti-apoptotic proteins activation.
原文英語
頁(從 - 到)3770-3784
頁數15
期刊Oncotarget
5
發行號11
出版狀態已發佈 - 2014

指紋

Bone Neoplasms
Protein-Tyrosine Kinases
Prostatic Neoplasms
Neoplasm Metastasis
Apoptosis Regulatory Proteins
Ligands
erbB-1 Genes
Bone and Bones
Drug Resistance
Heterografts
Therapeutics
Down-Regulation

ASJC Scopus subject areas

  • Oncology
  • Medicine(all)

引用此文

Siu, M. K., Abou-Kheir, W., Yin, J. J., Chang, Y. S., Barrett, B., Suau, F., ... Kelly, K. (2014). Loss of EGFR signaling regulated miR-203 promotes prostate cancer bone metastasis and tyrosine kinase inhibitors resistance. Oncotarget, 5(11), 3770-3784.

Loss of EGFR signaling regulated miR-203 promotes prostate cancer bone metastasis and tyrosine kinase inhibitors resistance. / Siu, Man Kit; Abou-Kheir, Wassim; Yin, Juan Juan; Chang, Yung Sheng; Barrett, Ben; Suau, Florent; Casey, Orla; Chen, Wei Yu; Fang, Lei; Hynes, Paul; Hsieh, Yao Yu; Liu, Yen Nien; Huang, Jiaoti; Kelly, Kathleen.

於: Oncotarget, 卷 5, 編號 11, 2014, p. 3770-3784.

研究成果: 雜誌貢獻文章

Siu, MK, Abou-Kheir, W, Yin, JJ, Chang, YS, Barrett, B, Suau, F, Casey, O, Chen, WY, Fang, L, Hynes, P, Hsieh, YY, Liu, YN, Huang, J & Kelly, K 2014, 'Loss of EGFR signaling regulated miR-203 promotes prostate cancer bone metastasis and tyrosine kinase inhibitors resistance', Oncotarget, 卷 5, 編號 11, 頁 3770-3784.
Siu, Man Kit ; Abou-Kheir, Wassim ; Yin, Juan Juan ; Chang, Yung Sheng ; Barrett, Ben ; Suau, Florent ; Casey, Orla ; Chen, Wei Yu ; Fang, Lei ; Hynes, Paul ; Hsieh, Yao Yu ; Liu, Yen Nien ; Huang, Jiaoti ; Kelly, Kathleen. / Loss of EGFR signaling regulated miR-203 promotes prostate cancer bone metastasis and tyrosine kinase inhibitors resistance. 於: Oncotarget. 2014 ; 卷 5, 編號 11. 頁 3770-3784.
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abstract = "Activation of EGFR signaling pathway leads to prostate cancer bone metastasis; however, therapies targeting EGFR have demonstrated limited effectiveness and led to drug resistance. miR-203 levels are down-regulated in clinical samples of primary prostate cancer and further reduced in metastatic prostate cancer. Here we show that ectopic miR-203 expression displayed reduced bone metastasis and induced sensitivity to tyrosine kinase inhibitors (TKIs) treatment in a xenograft model. Our results demonstrate that the induction of bone metastasis and TKI resistance require miR-203 down regulation, activation of the EGFR pathway via altered expression of EGFR ligands (EREG and TGFA) and anti-apoptotic proteins (API5, BIRC2, and TRIAP1). Importantly, a sufficient reconstitution of invasiveness and resistance to TKIs treatment was observed in cells transfected with anti-miR-203. In prostate cancer patients, our data showed that miR-203 levels were inversely correlated with the expression of two EGFR ligands, EREG and TGFA, and an EGFR dependent gene signature. Our results support the existence of a miR-203, EGFR, TKIs resistance regulatory network in prostate cancer progression. We propose that the loss of miR-203 is a molecular link in the progression of prostate cancer metastasis and TKIs resistance characterized by high EGFR ligands output and anti-apoptotic proteins activation.",
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T1 - Loss of EGFR signaling regulated miR-203 promotes prostate cancer bone metastasis and tyrosine kinase inhibitors resistance

AU - Siu, Man Kit

AU - Abou-Kheir, Wassim

AU - Yin, Juan Juan

AU - Chang, Yung Sheng

AU - Barrett, Ben

AU - Suau, Florent

AU - Casey, Orla

AU - Chen, Wei Yu

AU - Fang, Lei

AU - Hynes, Paul

AU - Hsieh, Yao Yu

AU - Liu, Yen Nien

AU - Huang, Jiaoti

AU - Kelly, Kathleen

PY - 2014

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N2 - Activation of EGFR signaling pathway leads to prostate cancer bone metastasis; however, therapies targeting EGFR have demonstrated limited effectiveness and led to drug resistance. miR-203 levels are down-regulated in clinical samples of primary prostate cancer and further reduced in metastatic prostate cancer. Here we show that ectopic miR-203 expression displayed reduced bone metastasis and induced sensitivity to tyrosine kinase inhibitors (TKIs) treatment in a xenograft model. Our results demonstrate that the induction of bone metastasis and TKI resistance require miR-203 down regulation, activation of the EGFR pathway via altered expression of EGFR ligands (EREG and TGFA) and anti-apoptotic proteins (API5, BIRC2, and TRIAP1). Importantly, a sufficient reconstitution of invasiveness and resistance to TKIs treatment was observed in cells transfected with anti-miR-203. In prostate cancer patients, our data showed that miR-203 levels were inversely correlated with the expression of two EGFR ligands, EREG and TGFA, and an EGFR dependent gene signature. Our results support the existence of a miR-203, EGFR, TKIs resistance regulatory network in prostate cancer progression. We propose that the loss of miR-203 is a molecular link in the progression of prostate cancer metastasis and TKIs resistance characterized by high EGFR ligands output and anti-apoptotic proteins activation.

AB - Activation of EGFR signaling pathway leads to prostate cancer bone metastasis; however, therapies targeting EGFR have demonstrated limited effectiveness and led to drug resistance. miR-203 levels are down-regulated in clinical samples of primary prostate cancer and further reduced in metastatic prostate cancer. Here we show that ectopic miR-203 expression displayed reduced bone metastasis and induced sensitivity to tyrosine kinase inhibitors (TKIs) treatment in a xenograft model. Our results demonstrate that the induction of bone metastasis and TKI resistance require miR-203 down regulation, activation of the EGFR pathway via altered expression of EGFR ligands (EREG and TGFA) and anti-apoptotic proteins (API5, BIRC2, and TRIAP1). Importantly, a sufficient reconstitution of invasiveness and resistance to TKIs treatment was observed in cells transfected with anti-miR-203. In prostate cancer patients, our data showed that miR-203 levels were inversely correlated with the expression of two EGFR ligands, EREG and TGFA, and an EGFR dependent gene signature. Our results support the existence of a miR-203, EGFR, TKIs resistance regulatory network in prostate cancer progression. We propose that the loss of miR-203 is a molecular link in the progression of prostate cancer metastasis and TKIs resistance characterized by high EGFR ligands output and anti-apoptotic proteins activation.

KW - Bone metastasis

KW - Epidermal growth factor receptor (EGFR)

KW - KRAS

KW - miR-203

KW - Prostate cancer

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