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

Research output: Contribution to journalArticlepeer-review

41 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)3770-3784
Number of pages15
JournalOncotarget
Volume5
Issue number11
DOIs
Publication statusPublished - 2014

Keywords

  • Bone metastasis
  • Epidermal growth factor receptor (EGFR)
  • KRAS
  • Prostate cancer
  • Tyrosine kinase inhibitors (TKIs) resistance
  • miR-203

ASJC Scopus subject areas

  • Oncology

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