Jin Lei, Ma Xuemei, Zhang Nan, Zhang Qian, Chen Xueming, Zhang Zhongtao, Ding Guoqian, Yu Hongzhi
Department of Vascular Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, People's Republic of China.
Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, People's Republic of China.
Cancer Manag Res. 2021 Nov 16;13:8599-8609. doi: 10.2147/CMAR.S332713. eCollection 2021.
This study aimed to explore the value of miR-181a-2-3p in cisplatin (DDP) treatment effectiveness prediction, and to reveal the function underlying the reversal of DDP resistance in patients with gastric cancer (GC).
miRNA expression dataset of three DDP-resistant GC cell lines and their DDP-sensitive parental cell lines obtained from GEO DataSets and GenBank, and functional miRNAs were annotated by bioinformatics analyses. Serum specimens and tumor samples were collected from 91 GC patients for understanding of the interrelation between chemotherapy response and miRNA expression. RT-qPCR validated these miRNAs at the transcriptional level in both gastric cancer cells and 91 gastric cancer patients. The correlation between the miRNAs expression and clinical parameters of the patients were analyzed. Receiver operating characteristics (ROC) analysis has been utilized to assess the diagnostic performance. The MTT and colony formation assays were performed to assess cell proliferation. Flow cytometry was conducted to detect cell apoptosis. DDP-resistant GC cells and their DDP-sensitive parental cells were transfected with miRNA mimic or inhibitor vector to overexpress or downregulate miRNA expression.
miR-181a-2-3p as a unique miRNA was found in the common differentially expressed-miRNAs (DE-miRNAs) after miRNA screening and validation from three DDP-resistant and DDP-sensitive gastric cancer cell lines. Clinical data analysis displayed that miR-181a-2-3p expression was apparently increased in larger tumor size (≥5 cm), higher T stage (T4), and chemotherapy resistance. miR-181a-2-3p (AUC=0.926, SE=0.028, 95% CI: 0.872-0.980, < 0.0001) differentiated chemosensitive GC patients from chemoresistant GC patients. miR-181a-2-3p presented a higher level in gastric cancer, and could serve as a valid biomarker to predict the overall survival of GC patients. Upregulation of miR-181a-2-3p rendered the apoptosis-inducing and anti-proliferative effects of DDP, while downregulating it decreased these effects.
miR-181a-2-3p can function as a therapeutic target and a tumor biomarker. Targeting oncogenic miR-181a-2-3p inhibits growth and suppresses cisplatin resistance of gastric cancer.
本研究旨在探讨miR-181a-2-3p在顺铂（DDP）治疗效果预测中的价值，并揭示其逆转胃癌（GC）患者DDP耐药的潜在机制。
从GEO数据集和GenBank获取三种DDP耐药GC细胞系及其DDP敏感亲本细胞系的miRNA表达数据集，并通过生物信息学分析注释功能性miRNA。收集91例GC患者的血清标本和肿瘤样本，以了解化疗反应与miRNA表达之间的相互关系。RT-qPCR在胃癌细胞和91例胃癌患者中验证了这些miRNA在转录水平的表达。分析了miRNA表达与患者临床参数之间的相关性。采用受试者工作特征（ROC）分析评估诊断性能。进行MTT和集落形成试验以评估细胞增殖。通过流式细胞术检测细胞凋亡。用miRNA模拟物或抑制剂载体转染DDP耐药GC细胞及其DDP敏感亲本细胞，以过表达或下调miRNA表达。
在对三种DDP耐药和DDP敏感胃癌细胞系进行miRNA筛选和验证后，发现miR-181a-2-3p是常见的差异表达miRNA（DE-miRNA）中的独特miRNA。临床数据分析显示，miR-181a-2-3p在肿瘤较大（≥5 cm）、T分期较高（T4）和化疗耐药的患者中表达明显增加。miR-181a-2-3p（AUC=0.926，SE=0.028，95%CI：0.872-0.980，<0.0001）可区分化疗敏感和化疗耐药的GC患者。miR-181a-2-3p在胃癌中呈现较高水平，可作为预测GC患者总生存期的有效生物标志物。上调miR-181a-2-3p可增强DDP的诱导凋亡和抗增殖作用，而下调则降低这些作用。
miR-181a-2-3p可作为治疗靶点和肿瘤生物标志物。靶向致癌性miR-181a-2-3p可抑制胃癌生长并抑制顺铂耐药。
