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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
MeSH terms
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3' Untranslated Regions
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Amphiregulin
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Animals
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Base Sequence
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Bone Neoplasms / enzymology
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Bone Neoplasms / genetics
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Bone Neoplasms / secondary*
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Cell Line, Tumor
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Down-Regulation
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EGF Family of Proteins / genetics
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EGF Family of Proteins / metabolism
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Epiregulin / genetics
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Epiregulin / metabolism
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ErbB Receptors / antagonists & inhibitors
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ErbB Receptors / metabolism*
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Heterografts
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Humans
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Male
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Mice
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Mice, Nude
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MicroRNAs / biosynthesis
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MicroRNAs / genetics
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MicroRNAs / metabolism*
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Molecular Sequence Data
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Neoplasm Metastasis
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Prostatic Neoplasms / genetics
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Prostatic Neoplasms / metabolism
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Prostatic Neoplasms / pathology*
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Protein Kinase Inhibitors / pharmacology
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Proto-Oncogene Proteins / biosynthesis
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins p21(ras)
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Signal Transduction
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Transforming Growth Factor alpha / genetics
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Transforming Growth Factor alpha / metabolism
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ras Proteins / biosynthesis
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ras Proteins / genetics
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ras Proteins / metabolism
Substances
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3' Untranslated Regions
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AREG protein, human
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Amphiregulin
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EGF Family of Proteins
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EREG protein, human
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Epiregulin
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KRAS protein, human
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MIRN203 microRNA, human
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MicroRNAs
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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TGFA protein, human
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Transforming Growth Factor alpha
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EGFR protein, human
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ErbB Receptors
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Proto-Oncogene Proteins p21(ras)
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ras Proteins