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Increased expression of miR-641 contributes to erlotinib resistance in non-small-cell lung cancer cells by targeting NF1.

ABSTRACT: Epidermal growth receptor (EGFR)-targeted tyrosine kinase inhibitors (TKIs) have emerged as first-line drugs for advanced non-small-cell lung cancer (NSCLC) patients with EFGR mutations. However, most patients with NSCLC show acquired resistance to EGFR-TKIs, and low expression of NF1 is a mechanism of EGFR-TKI resistance in lung cancer. However, the mechanism by which NF1 is downregulated in EGFR-TKI-resistant NSCLC is unclear. Here, we found the increased expression of miR-641 in NSCLC cells and human NSCLC samples with resistance to TKI compared to those with sensitive to TKI. In addition, our in vitro experiments show that overexpression of miR-641 induces TKI resistance in NSCLC cells. Furthermore, we identified that miR-641 activates ERK signaling by direct targeting of neurofibromatosis 1 (NF1) in NSCLC cells. Our data show that overexpression of NF1 or silencing of ERK can block miR-641-induced resistance of NSCLC cells to erlotinib treatment. Importantly, our animal experiments show that combination of miR-641 inhibition and erlotinib treatment can significantly inhibit erlotinib-resistant NSCLC growth, inhibit proliferation and induce apoptosis compared to single-drug treatment. Our findings suggest that increased expression of miR-641 significantly contributes to erlotinib resistance development in NSCLC cells through activating ERK signaling by targeting NF1 and that inhibition of miR-641 may reverse acquired resistance of NSCLC cells to erlotinib treatment.

SUBMITTER: Chen J

PROVIDER: S-EPMC5911582 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Increased expression of miR-641 contributes to erlotinib resistance in non-small-cell lung cancer cells by targeting NF1.

Chen Juan J Cui Jie-da JD Guo Xiao-Tong XT Cao Xia X Li Qing Q

Cancer medicine 20180301 4

Epidermal growth receptor (EGFR)-targeted tyrosine kinase inhibitors (TKIs) have emerged as first-line drugs for advanced non-small-cell lung cancer (NSCLC) patients with EFGR mutations. However, most patients with NSCLC show acquired resistance to EGFR-TKIs, and low expression of NF1 is a mechanism of EGFR-TKI resistance in lung cancer. However, the mechanism by which NF1 is downregulated in EGFR-TKI-resistant NSCLC is unclear. Here, we found the increased expression of miR-641 in NSCLC cells a ...[more]

PMID: 29493886

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Project description:BackgroundCisplatin (DDP) is the first-line chemotherapeutic drug for non-small cell lung cancer (NSCLC), and long-term DDP stimulation increased resistance of NSCLC cells to this drug by enriching cancer stem cells (CSCs), which contributed to recurrence and worse prognosis of NSCLC, but the molecular mechanisms are still not fully delineated.MethodsReal-Time qPCR and Western Blot analysis were conducted to examine gene expressions at mRNA and protein levels, respectively. Dual-luciferase reporter gene system was used to validate the targeting sites among circRNA CDR1as, miR-641 and HOXA9 mRNA. Cell growth was evaluated by CCK-8 assay, trypan blue staining assay and colony formation assay. The Annexin V-FITC/PI double staining method was employed to measure cell apoptosis ratio. Spheroid formation and flow cytometer assay was used to evaluate cell stemness. Xenograft mice models were established to measure tumorgenicity in vivo, and Ki67 expressions in mice tumor tissues were examined by immunohistochemistry (IHC).ResultsHere we identified a novel circRNA CDR1as/miR-641/Homeobox protein Hox-A9 (HOXA9) pathway regulated stemness and DDP chemoresistance in NSCLC. Mechanistically, circRNA CDR1as and HOXA9 were high-expressed, while miR-641 was low-expressed in DDP-resistant NSCLC cells, instead of their corresponding parental DDP-sensitive NSCLC cells. Additionally, we validated that circRNA CDR1as positively regulated HOXA9 in NSCLC cells by serving as an RNA sponge for miR-641, and knock-down of circRNA CDR1as increased the sensitivity of DDP-resistant NSCLC cells, which were reversed by downregulating miR-641 and upregulating HOXA9. Consistently, overexpression of circRNA CDR1as increased drug resistance of DDP-sensitive NSCLC cells by regulating miR-641/HOXA9 axis. In addition, the expression levels of stemness signatures (SOX2, OCT4 and Nanog) were higher in DDP-resistant NSCLC cells, which also tended to form spheres and enrich CD44+CD166+ population compared to their parental DDP-sensitive NSCLC cells, suggesting that CSCs were enriched in DDP-resistant NSCLC cells. Notably, knock-down of circRNA CDR1as inhibited stemness of DDP-resistant NSCLC cells by inhibiting HOXA9 through upregulating miR-641.ConclusionsTaken together, this study identified that circRNA CDR1as regulated stemness and DDP chemoresistance in NSCLC cells by targeting miR-641/HOXA9 axis.

Dataset Information

Increased expression of miR-641 contributes to erlotinib resistance in non-small-cell lung cancer cells by targeting NF1.

Publications

Increased expression of miR-641 contributes to erlotinib resistance in non-small-cell lung cancer cells by targeting NF1.

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