Abstract
Resistance to TKI treatment is a major obstacle in effective treatment of NSCLC. Besides EGFR mutation status, the mechanisms involved are largely unknown. Some evidence supports a role for microRNA 21 in modulating drug sensitivity of chemotherapy but its role in NSCLC TKI resistance still remains unexplored. This study aimed to investigate whether NSCLC miR-21 mediated resistance to TKIs also results from Pten targeting. Here, we show miR-21 promotes cancer by negatively regulating Pten expression in human NSCLC tissues: high miR-21 expression levels were associated with shorter DFS in 47 NSCLC patients; high miR-21/low Pten expression levels indicated a poor TKI clinical response and shorter overall survival in another 46 NSCLC patients undergoing TKI treatment. In vitro assays showed that miR-21 was up-regulated concomitantly to down-regulation of Pten in pc-9/GR cells in comparison with pc-9 cells. Moreover, over-expression of miR-21 significantly decreased gefitinib sensitivity by down-regulating Pten expression and activating Akt and ERK pathways in pc-9 cells, while miR-21 knockdown dramatically restored gefitinib sensitivity of pc-9/GR cells by up-regulation of Pten expression and inactivation of AKT and ERK pathways, in vivo and in vitro. We propose alteration of miR-21/Pten expression as a novel mechanism for TKI resistance in NSCLC cancer. Our findings provide a new basis for using miR 21/Pten-based therapeutic strategies to reverse gefitinib resistance in NSCLC.
Highlights
Non-small cell lung cancer (NSCLC) is the leading cause of cancer related death worldwide. [1] in spite of advances in early detection of cancer, the majority of patients with NSCLC are diagnosed with advanced-stage disease, resulting in poor prognosis with a median survival of only 10–12 months. [2,3] The development of drugs that target the epidermal growth factor receptor (EGFR), such as EGFR-TKIs has improved the efficacy of NSCLC therapy
We found that Pten protein levels were significantly reduced in 34/47 (72.3%) tumor tissues compared with adjacent normal ones (Fig. 1B)
The results showed that patients with high miR-21 expression levels had a shorter disease free survival (DFS) compared with patients with low miR-21 expression (Fig. 1F)
Summary
Non-small cell lung cancer (NSCLC) is the leading cause of cancer related death worldwide. [1] in spite of advances in early detection of cancer, the majority of patients with NSCLC are diagnosed with advanced-stage disease, resulting in poor prognosis with a median survival of only 10–12 months. [2,3] The development of drugs that target the epidermal growth factor receptor (EGFR), such as EGFR-TKIs (gefitinib and erlotinib) has improved the efficacy of NSCLC therapy. [2,3] The development of drugs that target the epidermal growth factor receptor (EGFR), such as EGFR-TKIs (gefitinib and erlotinib) has improved the efficacy of NSCLC therapy. [3] EGFR-TKIs have been recommended as the first line therapy for NSCLC patients with EGFR mutations. We found that up-regulation of miR-21 and down-regulation of Pten in 47 NSCLC tumor tissues compared with their adjacent normal tissues, and that their expression levels negatively correlated. Our data showed a good correlation between high miR-21/low Pten expression levels and poor TKI sensitivity with short overall survival in 46 NSCLC patients undergoing TKI treatment. We hypothesized that alteration of miR-21-Pten expression modulates TKI sensitivity in lung cancer cells. Overexpression of miR-21 significantly decreased gefitinib sensitivity through down-regulation of Pten expression and activation of Akt and ERK pathways, while knockdown of miR-21 dramatically restored gefitinib sensitivity of pc-9/GR cells by up-regulating Pten expression and inactivating AKT and ERK signaling pathways, both in vivo and in vitro
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