lncRNA ASBEL and lncRNA Erbb4-IR reduce chemoresistance against gemcitabine and cisplatin in stage IV lung squamous cell carcinoma via the microRNA-21/LZTFL1 axis.

癌症研究 细胞周期 顺铂 细胞生长 吉西他滨 细胞凋亡 流式细胞术 细胞 小RNA 化学 生物 癌症 医学 分子生物学 内科学 化疗 基因 生物化学
作者
Zhongxin Liang,Zhimin Zhang,G G Sun,Baoshan Zhao,Guohua Xin,Le Zhang
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期刊:PubMed 卷期号:13 (6): 2732-2750
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Drug resistance is a major cause of treatment failure and post-treatment disease progression in patients with cancer. This study aimed to investigate the mechanisms of chemoresistance to gemcitabine (GEM) plus cisplatin (cis-diamminedichloroplatinum, DDP) combination therapy in stage IV lung squamous cell carcinoma (LSCC). It also examined the functional role of lncRNA ASBEL and lncRNA Erbb4-IR in the malignant progression of LSCC. The expression of lncRNA ASBEL, lncRNA Erbb4-IR, miR-21, and LZTFL1 mRNA was examined in human stage IV LSCC tissues and adjacent normal tissues, human LSCC cells and normal human bronchial epithelial cells using qRT-PCR. Furthermore, LZTFL1 protein levels were also examined using western blots. Cell proliferation, cell migration and invasion, and cell cycle progression and apoptosis were evaluated in vitro using the CCK-8, transwell, and flow cytometry assays, respectively. Based on the treatment response, LSCC tissues were classified as GEM-, DDP-, and GEM+DDP-sensitive/resistant. The MTT assay was performed to assess the chemoresistance of human LSCC cells to GEM, DDP, and GEM+DDP following transfection experiments. The results showed that lncRNA ASBEL, lncRNA Erbb4-IR, and LZTFL1 were down-regulated in human LSCC tissues and cells, whereas miR-21 was up-regulated. In stage IV human LSCC tissues, miR-21 levels were negatively correlated with those of lncRNA ASBEL, lncRNA Erbb4-IR, and LZTFL1 mRNA. The overexpression of lncRNA ASBEL and lncRNA Erbb4-IR inhibited cell proliferation, migration, and invasion. It also blocked cell cycle entry and accelerated apoptosis. These effects were mediated by the miR-21/LZTFL1 axis and reduced chemoresistance to GEM+DDP combination therapy in stage IV human LSCC. These findings indicate that lncRNA ASBEL and lncRNA Erbb4-IR function as tumor suppressors in stage IV LSCC and attenuate chemoresistance to GEM+DDP combination therapy via the miR-21/LZTFL1 axis. Hence, lncRNA ASBEL, lncRNA Erbb4-IR, and LZTFL1 may be targeted to enhance the efficacy of GEM+DDP combination chemotherapy against LSCC.

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