Loss of EGFR signaling regulated miR-203 promotes prostate cancer bone metastasis and tyrosine kinase inhibitors resistance
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Impact Journals LLC
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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Bone metastasis, Epidermal growth factor receptor (egfr), Kras, Mir-203, Prostate cancer, Tyrosine kinase inhibitors (tkis) resistance, 3' untranslated regions, Animals, Base sequence, Bone neoplasms, Cell line, tumor, Down-regulation, Egf family of proteins, Epiregulin, Heterografts, Humans, Male, Mice, Mice, nude, Micrornas, Molecular sequence data, Neoplasm metastasis, Prostatic neoplasms, Protein kinase inhibitors, Proto-oncogene proteins, Ras proteins, Receptor, epidermal growth factor, Signal transduction, Transforming growth factor alpha, 4 (3 chloroanilino) 6,7 dimethoxyquinazoline, Antiapoptotic protein, Api5 protein, Birc2 protein, Canertinib, Epidermal growth factor receptor, Messenger rna, Microrna, Microrna 203, Protein, Protein tyrosine kinase inhibitor, Ras protein, Triap1 protein, Unclassified drug, 3' untranslated region, Areg protein, human, Egfr protein, human, Epidermal growth factor derivative, Ereg protein, human, Kras protein, human, Mirn203 microrna, human, Oncoprotein, Protein kinase inhibitor, Tgfa protein, human, Animal experiment, Animal model, Areg gene, Article, Cancer growth, Cancer resistance, Cell invasion, Controlled study, Down regulation, Drug sensitivity, Ereg gene, Gene expression, Human, Human cell, Metastasis, Mouse, Nonhuman, Oncogene k ras, Positive feedback, Tgfa gene, Tumor xenograft, Animal, Antagonists and inhibitors, Biosynthesis, Bone tumor, Enzymology, Genetics, Metabolism, Molecular genetics, Nucleotide sequence, Nude mouse, Pathology, Prostate tumor, Secondary, Tumor cell line, Xenograft