4.3 Article

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

Journal

ONCOTARGET
Volume 5, Issue 11, Pages 3770-3784

Publisher

IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.1994

Keywords

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

Funding

  1. NIH, National Cancer Institute, Center for Cancer Research, USA
  2. Taipei Medical University [TMU101-AE3-Y21]
  3. Wan Fang Hospital [DOH101-TD-C-111-008]
  4. National Health Research Institutes of Taiwan [NHRI-EX103-10308BC]

Ask authors/readers for more resources

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.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.3
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available