Alteration in Mir-21/PTEN Expression Modulates Gefitinib Resistance in Non-Small Cell Lung Cancer

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.

Emerging role of microRNA-21 in cancer

“…In addition to the well-known platinum-based chemotherapy for lung cancer, miR-21 has been shown to be involved in the resistance to the EGFR inhibitor. EGFR-tyrosine kinase inhibitor (TKI) has been regarded as an important treatment option for NSCLC and miR-21 overexpression was found to be associated with acquired resistance to EGFR-TKI (77,78). A pilot study using plasma miRNA profiles identified miR-21 to be involved in the primary resistance to EGFR-TKI in patients with advanced NSCLC with an activating EGFR mutation.…”

“…The application of this non-invasive approach may be considered for monitoring responses of lung cancer patients to EGFR-TKI treatment (79). Furthermore, the implication of miR-21 in chemotherapy resistance has been investigated for a wide range of solid cancer types, including pancreatic and prostate cancer, hepatoma, ovarian cancer, glioma, and head and neck, stomach and bladder cancer (Table I) (68)(69)(70)(71)75,(77)(78)(79)(80)(81)(82)(83)(84)(85)(86)(87)(88)(89)(90)(91)(92)(93)(94). These results support the clinical application of miR-21 inhibition in cancer treatments in the future.…”

Exosome‑mediated gefitinib resistance in lung cancer HCC827 cells via delivery of miR‑21

“…Additionally, the inhibition of miR-21 induced apoptosis in the PC9R cell line and inhibited miR-21, while miR-21 antisense oligo nucleotide (ASO) suppressed tumor growth in nude mice treated with EGFR-TKI (18). Shen et al (33) revealed that high miR-21 expression indicated a poor TKI clinical response and a shorter overall survival rate. miR-21 expression was upregulated in PC-9 gefitinib resistant cells (PC-9/GR) compared with PC-9 cells and miR-21 knockdown markedly restored gefitinib sensitivity in PC-9/GR cells (33).…”

“…Shen et al (33) revealed that high miR-21 expression indicated a poor TKI clinical response and a shorter overall survival rate. miR-21 expression was upregulated in PC-9 gefitinib resistant cells (PC-9/GR) compared with PC-9 cells and miR-21 knockdown markedly restored gefitinib sensitivity in PC-9/GR cells (33). Similar to previous studies, the results of the present investigation revealed that miR-21 expression was elevated in gefitinib-resistant lung cancer cells.…”

Role of microRNA-21 in atherogenesis.

“…MiR-21 has also been suggested to be regulated by reactive oxygen species-activated ERK/NF-B in arsenite-induced cell transformation [248]. Others have suggested that miR-21 is both a target and regulator of ERK/NF-B and JNK/c-jun axis [254]. My data show that LPS-induced ERK activation was diminished in miR-21-KO cells.…”