Abstract
Cisplatin (CDDP) based chemotherapy is widely used as the first-line strategy in treating non-small cell lung cancer (NSCLC), especially lung squamous cell carcinoma (LUSC). However, secondary cisplatin resistance majorly undermines the cisplatin efficacy leading to a worse prognosis. In this respect, we have identified the role of the DLX6-AS1/miR-181a-5p/miR-382-5p/CELF1 axis in regulating cisplatin resistance of LUSC. qRT-PCR and Western blot analysis were applied to detect gene expression. Transwell assay was used to evaluate the migration and invasion ability of LUSC cells. CCK-8 assay was used to investigate the IC50 of LUSC cells. Flow cytometry was used to test cell apoptosis rate. RNA pull-down and Dual luciferase reporter gene assay were performed to evaluate the crosstalk. DLX6-AS1 was aberrantly high expressed in LUSC tissues and cell lines, and negatively correlated with miR-181a-5p and miR-382-5p expression. DLX6-AS1 expression was enhanced by H3K4me1 in cisplatin resistant LUSC cells. Besides, DLX6-AS1 knockdown led to impaired IC50 of cisplatin resistant LUSC cells. Furthermore, DLX6-AS1 interacted with miR-181a-5p and miR-382-5p to regulate CELF1 expression and thereby mediated the cisplatin sensitivity of cisplatin resistant LUSC cells. DLX6-AS1 induced by H3K4me1 played an important role in promoting secondary cisplatin resistance of LUSC through regulating the miR-181a-5p/miR-382-5p/CELF1 axis. Therefore, targeting DLX6-AS1 might be a novel way of reversing secondary cisplatin resistance in LUSC.
Highlights
Lung cancer, divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), is one of the most common malignancies and the most common cause of cancer death in the world, with almost 1.8 million newly diagnosed cases every y ear[1]
LncRNA TALC promotes the expression of O6-methylguanine DNA methyltransferase (MGMT) by competitively binding miR-20b to activate the c-MET/ STAT3/p300 axis, which leads to temozolomide (TMZ) resistance in glioblastoma[10]
Based on Gene Expression Profiling Interactive Analysis (GEPIA), we noticed that DLX6-AS1 was significantly differentially expressed in lung squamous cell carcinoma (LUSC) but not LUAD (Fig. 1a)
Summary
Lung cancer, divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), is one of the most common malignancies and the most common cause of cancer death in the world, with almost 1.8 million newly diagnosed cases every y ear[1]. At present, increasing evidence has shown that lncRNAs, which could act as competing endogenous RNA (ceRNA), play a crucial role in the occurrence and progression of malignant tumors via competitively binding to microRNAs (miRNAs) to regulate the expression of target mRNAs, and their aberrant expression are usually closely related to the proliferation, invasion, metastasis, and chemoresistance of tumor c ells[6,7,8]. Growing reports have indicated that DLX6-AS1 could interact with the target miRNAs to regulate the progression and treatment resistance of multiple cancers, including lung adenocarcinoma (LUAC)[12], ovarian cancer[13], hepatocellular cancer (HCC)14, glioma[15] and bladder c ancer[16]. The involvement of CELF1 in the acquired cisplatin resistance of LUSC remains unclear
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