title: miR-223 enhances the sensitivity of non-small cell lung cancer cells to erlotinib by targeting the insulin-like growth factor-1 receptor.
abstract: Lung cancer is the leading cause of cancer-related fatalities worldwide, and non-small cell lung cancer (NSCLC) is the main pathological type. MicroRNAs (miRNAs or miRs) are a class of small non-coding RNAs, which are involved in tumor initiation and progression. miR‑223 is a tumor suppressor miRNA that has been reported in various types of cancer, including lung cancer. In the present study, to characterize the biological behavior of miR‑223 in NSCLC, we established an miR‑223 overexpression model in erlotinib-resistant PC‑9 (PC‑9/ER) cells by infection with lentivirus to induce the overexpression of miR‑223. As a result, miR‑223 enhanced the sensitivity of the PC‑9/ER cells to erlotinib by inducing apoptosis in vitro. Additionally, in vivo experiments were performed using nude mice which were injected with the cancer cells [either the PC‑9 (not resistant), PC‑9/ER, or the PC‑9/ER cells infected with miR‑223)]. We found that the tumor volumes were reduced in the rats injected with the cells infected with miR‑223. To further explore the underlying mechanisms, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis were used to identify the target molecules of miR‑223. miR‑223 was demonstrated to act as a local regulator of insulin-like growth factor-1 receptor (IGF-1R) in the acquired resistance to tyrosine kinase inhibitors (TKIs). Notably, the οverexpression of IGF-1R in NSCLC was downregulated by miR‑223, and the activation of Akt/S6, the downstream pathway, was also inhibited. The inhibition of IGF-1R by miR‑223 was attenuated by exogenous IGF-1 expression. Therefore, miR‑223 may regulate the acquired resistance of PC‑9/ER cells to erlotinib by targeting the IGF-1R/Akt/S6 signaling pathway. The overexpression of miR‑223 may partially reverse the acquired resistance to epidermal growth factor receptor-TKIs, thus, providing a potential therapeutic strategy for TKI-resistant NSCLC.
authors.affiliation: Cancer Institute of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China.
authors.forename: Feng-Yi
authors.initials: FY
authors.lastname: Zhao
authors.affiliation: Cancer Institute of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Han
authors.affiliation: Medical English Department, College of Basic Medicine, Third Military Medical University, Chongqing 400038, P.R. China.
authors.forename: Xie-Wan
authors.initials: XW
authors.lastname: Chen
authors.affiliation: Cancer Institute of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Wang
authors.affiliation: Cancer Institute of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China.
authors.forename: Xu-Dong
authors.initials: XD
authors.lastname: Wang
authors.affiliation: Cancer Institute of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China.
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Sun
authors.affiliation: Cancer Institute of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China.
authors.forename: Zheng-Tang
authors.initials: ZT
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D016086:Lentivirus / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000069347:Erlotinib Hydrochloride; D007334:Insulin-Like Growth Factor I; D035683:MicroRNAs; D051057:Proto-Oncogene Proteins c-akt; D017526:Receptor, IGF Type 1; C525067:MIR223, human