Abstract
BackgroundEpidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) (e.g. gefitinib) currently remain the first-line treatment for patients with advanced non-small-cell lung cancer (NSCLC) with activating EGFR mutation. However, acquired resistance to gefitinib, which occurs frequently through unidentified mechanisms, significantly attenuate therapeutic effectiveness. Previous miRNA microarray analysis reveals that expression levels of a conserved oncomiR miR-762 are significantly upregulated in gefitinib-resistant NSCLC cells. We therefore aim to elucidate the role and underlying mechanisms of miR-762 during the pathogenesis of gefitinib resistance.MethodsmiR-762 expression in gefitinib-resistant NSCLC tissues and cells was evaluated using RT-qPCR. The potential regulation of miR-762 expression by IL-6 was studied using pharmacological and biochemical approaches. Effects of miR-762 manipulation on sensitivity to gefitinib was assessed using MTT, apoptotic ELISA and xenograft model. Finally, the posttranscriptional regulation of active BCR related protein (ABR) by miR-762 was determined using luciferase assay and site-directed mutagenesis.ResultsmiR-762 expression was upregulated in gefitinib-resistant NSCLC tissues and cells, and this upregulation predicted a poor post-chemotherapy prognosis in NSCLC patients. miR-762 upregulation, induced by IL-6 signaling, significantly enhanced cell survival and rendered NSCLC cells unresponsiveness to gefitinib-elicited cell death. We finally provided the evidence that the oncogenic effect of miR-762 was mediated mainly through posttranscriptional repression of ABR in gefitinib-resistant NSCLC cells.ConclusionsOur findings provide a rationale for future efforts testing miR-762 inhibition and ABR restoration co-treatment in patients with recurrent EGFR mutant NSCLC to therapeutically combat the heterogeneity of EGFR-TKIs resistance mechanisms.
Highlights
Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) currently remain the first-line treatment for patients with advanced non-small-cell lung cancer (NSCLC) with activating EGFR mutation
Upregulation of miR-762 is associated with gefitinib resistance in NSCLC cells To study the potential involvement of miR-762 in the regulation of chemosensitivity, we evaluated the expression profile of miR-762 in a bunch of NSCLC cells
Subsequent reverse transcription (RT)-Quantitative polymerase chain reaction (qPCR) analyses revealed that miR-762 expression levels correlated negatively to the sensitivity to gefitinib in NSCLC cells, with the lowest values being observed in PC-9 cells and a normal human lung epithelial cell line (NuLi-1) and the highest values being detected in NCI-H2347 cells (Fig. 1a)
Summary
Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) (e.g. gefitinib) currently remain the first-line treatment for patients with advanced non-small-cell lung cancer (NSCLC) with activating EGFR mutation. Given that the constitutive activation of epidermal growth factor receptor (EGFR) signaling pathway plays an essential role in the development and progression of advanced non-small cell lung cancer (NSCLC) whose tumors harbor EGFRactivating mutations [1], EGFR-tyrosine kinase inhibitors (TKIs) including gefitinib, erlotinib and afatinib, have become the standard of treatment for mutation-positive, advanced-stage non-squamous NSCLC [2]. Recent profiling and functional studies have demonstrated that a panel of miRNAs (miR-608, − 4513, − 497, −499a [3], −23a [4] and et al.) are aberrantly expressed in EGFR-TKIs-resistant NSCLC, and dysregulation of these miRNAs regulates fundamentally the pathogenesis of EGFR-TKIs resistance via modulation of multiple cancerous functions including deregulated cell proliferation/apoptosis, maintenance of cancer stem cells and activation of alternative signaling (HGF, Met, AXL and IGF-1R). The function of miR-762 (either as oncomiR or tumor suppressor miRNA) and its corresponding mechanisms in gefitinib resistance remain poorly understood
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