Liang Zong-Ying, Zhang Zhi-Min, Sun Guang-Rui, Zhao Bao-Shan, Xin Guo-Hua, Zhang Le
Department of Thoracic Surgery, The Affiliated Hospital of Chengde Medical University Chengde, Hebei, China.
Department of Education Division, The Affiliated Hospital of Chengde Medical University Chengde, Hebei, China.
Am J Cancer Res. 2023 Jun 15;13(6):2732-2750. eCollection 2023.
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 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.
耐药性是癌症患者治疗失败和治疗后疾病进展的主要原因。本研究旨在探讨IV期肺鳞状细胞癌（LSCC）对吉西他滨（GEM）联合顺铂（顺二氨二氯铂，DDP）化疗耐药的机制。它还研究了lncRNA ASBEL和lncRNA Erbb4-IR在LSCC恶性进展中的功能作用。使用qRT-PCR检测了lncRNA ASBEL、lncRNA Erbb4-IR、miR-21和LZTFL1 mRNA在人IV期LSCC组织和癌旁正常组织、人LSCC细胞和正常人支气管上皮细胞中的表达。此外，还使用蛋白质印迹法检测了LZTFL1蛋白水平。分别使用CCK-8、Transwell和流式细胞术检测法评估细胞增殖、细胞迁移和侵袭以及细胞周期进程和凋亡。根据治疗反应，将LSCC组织分为对GEM、DDP和GEM+DDP敏感/耐药。在转染实验后，进行MTT检测以评估人LSCC细胞对GEM、DDP和GEM+DDP的化疗耐药性。结果显示，lncRNA ASBEL、lncRNA Erbb4-IR和LZTFL1在人LSCC组织和细胞中表达下调，而miR-21表达上调。在IV期人LSCC组织中，miR-21水平与lncRNA ASBEL、lncRNA Erbb4-IR和LZTFL1 mRNA水平呈负相关。lncRNA ASBEL和lncRNA Erbb4-IR的过表达抑制细胞增殖、迁移和侵袭。它还阻止细胞进入细胞周期并加速细胞凋亡。这些作用是由miR-21/LZTFL1轴介导的，并降低了IV期人LSCC对GEM+DDP联合化疗的耐药性。这些发现表明，lncRNA ASBEL和lncRNA Erbb4-IR在IV期LSCC中起肿瘤抑制作用，并通过miR-21/LZTFL1轴减弱对GEM+DDP联合化疗的耐药性。因此，lncRNA ASBEL、lncRNA Erbb4-IR和LZTFL1可能成为增强GEM+DDP联合化疗治疗LSCC疗效的靶点。
