miR-26a desensitizes non-small cell lung cancer cells to tyrosine kinase inhibitors by targeting PTPN13

Abstract

Epidermal growth factor receptor (EGFR)-targeted tyrosine kinase inhibitors (TKIs) have emerged as first-line drugs for non-small cell lung cancers (NSCLCs). However, the resistance to TKIs represents the key limitation for their therapeutic efficacy. We found that miR-26a was upregulated in gefitinib-refractory NSCLCs; miR-26a is downstream of EGFR signaling and directly targets and silences protein tyrosine phosphatase non-receptor type 13 (PTPN13) to maintain the activation of Src, a dephosphorylation substrate of PTPN13, thus reinforcing EGFR pathway in a regulatory circuit. miR-26a inhibition significantly improved NSCLC responses to gefitinib. These data revealed a novel mechanism of NSCLC resistance to TKI treatment.

Cefminox, a Dual Agonist of Prostacyclin Receptor and Peroxisome Proliferator-Activated Receptor-Gamma Identified by Virtual Screening, Has Therapeutic Efficacy against Hypoxia-Induced Pulmonary Hypertension in Rats

“…Two PPARγ-LBD crystal structures were retrieved from the Research Collaboratory for Structural Bioinformatics (RCSB) Protein DataBank ( http://www.rcsb.org ): an active form with binding to the full agonist rosiglitazone and coactivator peptide [entry code: 1FM6 (Gampe et al, 2000 ); defined herein as PPAR–full], and an active form with binding to the partial agonist (2S)-2-(biphenyl-4-yloxy)-3-phenylpropanoic acid (LRG) [entry code: 3B3K (Montanari et al, 2008 ); defined herein as PPAR–partial]. The coordinates for IP (accession number: NP_004387.1 ) were built with the MODELER module, with bovine rhodopsin (entry code: 1HZX; Teller et al, 2001 ) as a template (Stitham et al, 2003 ; Accelrys, 2011 ; Li et al, 2016 ; Xu et al, 2016 ). According to previously published protocols (Stitham et al, 2003 ; Pérez-Villa et al, 2015 ), each protein structure was first equilibrated by 100 ns explicit solvent molecular dynamics simulation using the GROMACS4.6.7 program (Pronk et al, 2013 ) and CHARMM27 force field (Brooks et al, 2009 ).…”

Molecular genetics and cellular events of K-Ras-driven tumorigenesis

“… 74 Recently, blebbishield emergency program is found to drive severe chromosomal instability by suppressing the expression of p53 during the transformation phase. 61 In addition, EGFR, a K-Ras target, induces the expression of miR-26a in non-small cell lung cancer, 75 and miR-26a promotes chromosomal instability and tumorigenesis in breast cancer cells. 76 …”

Genome-wide profiling of micro-RNA expression in gefitinib-resistant human lung adenocarcinoma using microarray for the identification of miR-149-5p modulation

“…Furthermore, miR-26a is a downstream of EGFR signaling, and miR-26a inhibition can considerably improve NSCLC responses to gefitinib. 9 In addition, miR-200a expression renders the cells more sensitive to gefitinib treatment. 18 These data revealed the novel mechanism of NSCLC resistance to TKI treatment.…”

“…Furthermore, the abnormal expression of miRNAs is widely investigated in numerous cancer types, including bladder cancer, 6 breast cancer, 7 gallbladder cancer, 8 and lung cancer. 9 Furthermore, miRNAs play a critical role in various cancer cellular processes, such as development, proliferation, apoptosis, migration, invasion, and drug resistance. 10 To identify the biological role of miRNAs in gefitinibresistant cells, we examined the genome-wide miRNA expression in the parental HCC827 cells and gefitinibresistant HCC827/GR-8-1 cells.…”