MiR-449c通过抑制c-Myc的表达抑制肺腺癌细胞的周期进程
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1.江南大学附属医院肿瘤内科;2.江苏省肿瘤医院肿瘤防治研究所

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江苏省卫计委科研项目(Z2018047)


MiR-449c inhibits the cell cycle progression of lung adenocarcinoma cells by inhibiting the expression of c-Myc
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Affiliation:

1.Department of Oncology,Affiliated Hospital of Jiangnan University;2.Research Center for Clinical Oncology,Jiangsu Cancer Hospital

Fund Project:

the Program of Jiangsu Commission of Health (Grant No. Z2018047).

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    摘要:

    目的:探讨miR-449c对肺腺癌发生发展的影响及可能的机制。方法:利用生物信息学分析鉴定高复发风险肺腺癌患者(无病生存期≤6个月)与低复发风险患者(无病生存期>60个月)之间差异表达的microRNA(miRNA)。靶基因预测及通路分析研究可能的机制。RT-PCR检测miR-449c在肺腺癌组织和细胞系中的表达。利用细胞转染实验在肺腺癌细胞系中过表达miR-449c和c-Myc。CCK8法测定细胞增殖活性。流式细胞术检测细胞周期及凋亡。蛋白质印迹分析检测相关蛋白表达水平。结果:生物信息学分析结果显示相比于低复发风险患者,肺腺癌高复发风险患者的miR-449c表达显著降低。miR-449c表达水平与肺腺癌患者临床分期和淋巴结转移显著相关,miR-449c低表达患者的预后显著差于高表达患者。通路和功能分析表明,miR-449c可能与细胞周期进程有关。与癌旁组织相比,miR-449c在肺腺癌组织中显著低表达;过表达miR-449c抑制了肺腺癌细胞增殖,导致细胞周期阻滞于G1期,下调了c-Myc及其下游细胞周期蛋白的表达。c-Myc过表达可抵消miR-449c对细胞周期蛋白的抑制,miR-449c过表达也可抵消c-Myc对细胞周期蛋白表达量的上调。结论:miR-449c低表达的肺腺癌患者预后较差,过表达miR-449c可以通过下调c-Myc调控细胞周期,抑制肺腺癌细胞增殖,提示miR-449c可能作为肺腺癌潜在治疗靶标之一。

    Abstract:

    Objective:The purpose of this study was to find out the effect and possible mechanism of miR-449c on the occurrence and development of lung adenocarcinoma. Methods:Bioinformatics analysis was used to identify the differentially expressed microRNAs between samples with lung adenocarcinoma patients at high risk of recurrence (disease-free survival ≤6 months) and samples with lung adenocarcinoma patients at low risk of recurrence (disease-free survival >60 months). Target gene prediction and pathway analysis were used to analysis possible mechanisms. RT-PCR was used to detect the expression of miR-449c in lung adenocarcinoma tissues and cell lines. miR-449c and c-Myc were overexpressed in lung adenocarcinoma cell lines by cell transfection experiments. Cell growth activity was determined by CCK-8. Cell cycle and apoptosis were detected by flow cytometry. Western blot analysis was used for relevant protein expression. Results:The results of bioinformatics analysis showed that the expression of miR-449c was significantly decreased in the group of lung adenocarcinoma patients at high risk of recurrence compared with the group of lung adenocarcinoma patients at low risk of recurrence. The expression of miR-449c was significantly correlated with the clinical stage and lymph node metastasis of patients with lung adenocarcinoma. The prognosis of patients with low miR-449c expression was significantly worse than that of patients with high miR-449c expression. Pathway and functional analysis indicated that miR-449c may be involved in cell cycle progression. Compared with normal tissues, miR-449c was significantly lower expressed in lung adenocarcinoma tissues. Overexpression of miR-449c inhibited lung adenocarcinoma cell proliferation, resulted in cell cycle arrest in G1 phase, and downregulated the expression of c-Myc and its downstream cyclins. Overexpression of c-Myc could counteract the inhibition of cyclin by miR-449c. Overexpression of miR-449c could also counteract the up-regulation of cyclin expression by c-Myc. Conclusion:Lung adenocarcinoma patients with low expression of miR-449c had a poor prognosis. Overexpression of miR-449c could regulate the lung adenocarcinoma cell cycle by downregulating c-Myc and inhibited the proliferation of lung adenocarcinoma cells. The results suggested that miR-449c may be one of the potential therapeutic targets for lung adenocarcinoma.

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  • 收稿日期:2022-03-01
  • 最后修改日期:2023-05-24
  • 录用日期:2023-10-25
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