Journal
INTERNATIONAL JOURNAL OF ONCOLOGY
Volume 48, Issue 5, Pages 1855-1867Publisher
SPANDIDOS PUBL LTD
DOI: 10.3892/ijo.2016.3401
Keywords
EGFR-TKI sigma; miR-223; erlotinib; non-small cell lung cancer; lung cancer stem-like cells
Categories
Funding
- National Natural Science Foundation of China [81172070, 81071786]
- National High Technology Research and Development Program of China [2008AA02Z104]
Ask authors/readers for more resources
Acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, is a critical issue for the treatment of EGFR mutant-positive non-small cell lung cancer (NSCLC). Recent evidence supports the role of microRNA-223 (miR-223) in modulating chemotherapeutic drug sensitivity, but its role in the resistance to EGFR-TKIs in NSCLC remains unclear. To this end, we investigated the involvement of miR-223 in erlotinib resistance, using two pairs of TKI-sensitive or resistant cell lines, PC9 vs PC9/ER, and HCC827 vs HCC827/ER, as well as PC9/CD133(+), which are lung cancer stem-like cells derived from PC9 cells. Downregulation of miR-223 expression in PC9/ER and PC9/CD133(+) cells was detected, and the reverse correlation of miR-233 and insulin-like growth factor 1 receptor (IGF1R) in these cells was also revealed. Next, levels of IGF1R mRNA and p-Akt were significantly reduced in miR-223 stably transfected PC9/ER and PC9/CD133(+) cells. However, the sensitivity of PC9/ER and PC9/CD133(+) cells to erlotinib was partially restored, after overexpression of miR-223 in those cells. Similar results were also observed in vivo. Furthermore, miR-223-mediated inhibition of the IGF1R/PI3K/Akt signaling pathway may have been reversed by the agonist of IGF1R in miR-223 transfected cells. Our findings indicated that downregulation of miR-223, which can induce activation of the IGF1R/phosphatidylinositol 3-kinase (PI3K)/Akt pathway in PC9/ER and PC9/CD133(+) cells, may be responsible for the resistance of PC9/ER and PC9/CD133(+) cells to erlotinib, suggesting that miR-223 is a potential therapeutic target for overcoming EGFR-TKIs resistance.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available