Down-regulation of miR-214 reverses erlotinib resistance in non-small-cell lung cancer through up-regulating LHX6 expression

Abstract

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are standard treatments for advanced non-small-cell lung cancer (NSCLC) patients. However, acquired resistance to EGFR-TKIs is widely detected across the world, and the exact mechanisms have not been fully demonstrated until now. This study aimed to examine the role of miR-214 in the acquired resistance to erlotinib in NSCLC, and elucidate the underlying mechanisms. qRT-PCR assay detected higher miR-214 expression in the plasma of NSCLC patients with acquired EGFR-TKI resistance than prior to EGFR-TKI therapy, and in the generated erlotinib-resistant HCC827 (HCC827/ER) cells than in HCC827 cells. Bioinformatics analysis and dual-luciferase reporter assay indentified LHX6 as a direct target gene of miR-214, and LHX6 expression was detected to be down-regulated in erlotinib-resistant HCC827 cells. Transwell invasion assay revealed that overexpressing LHX6 reversed the increase in the invasive ability of HCC827 cells induced by miR-214 overexpression, and the CRISPR-Cas9 system-mediated LHX6 knockdown reversed the reduction in the invasion of erlotinib-resistant HCC827 cells caused by miR-214 down-regulation. The results of the present study demonstrate that down-regulation of miR-214 may reverse acquired resistance to erlotinib in NSCLC through mediating its direct target gene LHX6 expression.

Inhibition of miR-214-3p Aids in Preventing Epithelial Ovarian Cancer Malignancy by Increasing the Expression of LHX6

“…This study also revealed that the inhibition of LHX6 in EOC cells is involved in resistance to platinum-based chemotherapy. This suggests that LHX6 may be a novel target for improving drug resistance in anticancer studies, along with a previous study that showed that down-regulation of LHX6 can induce resistance to chemotherapy in lung cancer [23].…”

“…LHX6 and FBXO32, analyzed in this study, were also expected to be targets of miR-214-3p. In gastric cancer, the inhibition of miR-214 up-regulates LHX6 and improves resistance to erlotinib [23]. Moreover, high FBXO32 expression was found to reflect higher five-year overall survival of patients with colorectal cancer [24].…”

LncRNA CASC2 inhibits autophagy and promotes apoptosis in non-small cell lung cancer cellsviaregulating the miR-214/TRIM16 axis

“…32 Our study demonstrated that miR-214 was aberrantly upregulated in NSCLC tissues and cells, consistently with the previous studies. 16,17 Rescue experiments demonstrated that CASC2 knockdown partially reversed miR-214 inhibition-mediated promotion of apoptosis and suppression of autophagy in NSCLC cells, suggesting that CASC2 knockdown exerted its function in NSCLC cells by upregulating miR-214. TRIM16 (also known as estrogen-responsive B-box protein, EBBP), a member of TRIM family, is identied as a positive transcriptional regulator of the retinoic acid receptor b2 in retinoid-treated cancer cells.…”

“…15 It has been previously demonstrated that miR-214 expression was elevated in lung cancer and promoted the progression of lung cancer by acting as an oncogene. 16,17 Recently, competing endogenous RNA (ceRNA) hypothesis suggests that lncRNAs could function as miRNA sponges to prevent miRNAs from binding to their regulatory targets, thus participating in the pathogenesis and development of cancers. 18 Nevertheless, whether CASC2 could interact with miR-214 to regulate the progression of NSCLC remains largely unknown.…”

MicroRNA-214 Prevents Pulmonary Angiogenesis and Alveolarization in Rat Models with Bronchopulmonary Dysplasia via PlGF-Dependent STAT3 Signaling Pathway

“…In lung cancer, miR-214-3p has been demonstrated to downregulate broblast growth factor receptor 1 and to provide bene cial effects to patients [8]. Also, downregulation of miR-214 could reverse the erlotinib resistance in non-small-cell lung cancer by upregulating its direct target gene LHX6 [9]. In our study, placental growth factor (PlGF) was predicted to the target gene of miR-214.…”