Circadian gene ARNTL initiates circGUCY1A2 transcription to suppress non-small cell lung cancer progression via miR-200c-3p/PTEN signaling.
Circadian gene ARNTL initiates circGUCY1A2 transcription to suppress non-small cell lung cancer progression via miR-200c-3p/PTEN signaling.
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DOI：
10.1186/s13046-023-02791-1
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发表时间：
2023-09-04
影响因子：
11.3
通讯作者：
Duan, Chaojun
中科院分区：
文献类型：
--
作者：
Zhao, Deze;Dong, Yeping;Duan, Minghao;He, Dan;Xie, Qun;Peng, Wei;Cui, Weifang;Jiang, Junjie;Cheng, Yuanda;Zhang, Heng;Tang, Faqing;Zhang, Chunfang;Gao, Yang;Duan, Chaojun
作为内源性稳定非编码 RNA 的一个亚类，环状 RNA 因其作为肿瘤治疗的潜力而开始受到重视。然而，circRNA 在非小细胞肺癌 (NSCLC) 中发挥保护作用的功能和机制在很大程度上仍不清楚。在肺腺癌标本中探讨了 circGUCY1A2 的预后作用。利用过表达和敲低质粒评估circGUCY1A2对NSCLC细胞增殖和凋亡功效的影响。利用荧光素酶报告系统证明circGUCY1A2可以与miRNA结合。采用芯片PCR证明circGUCY1A2可以被转录因子ARNTL启动。建立皮下致瘤移植模型以验证体内研究结果。在非小细胞肺癌（NSCLC）中，circGUCY1A2的表达显着降低（P<0.001），并且与肿瘤大小呈负相关（P<0.05）。 CircGUCY1A2上调促进细胞凋亡并抑制裸鼠皮下致瘤移植物的细胞增殖和生长（P < 0.01）。此外，肿瘤内注射 pLCDH-circGUCY1A2 可抑制患者来源的 NSCLC 异种移植模型 (PDX) 中的肿瘤生长。机制研究表明，circGUCY1A2可以作为海绵竞争性结合miR-200c-3p，促进PTEN表达，从而抑制PI3K/AKT通路。此外，我们发现在NSCLC中减少并延长患者总生存期的昼夜节律基因ARNTL可以与circGUCY1A2的启动子结合，从而增加其表达。该研究首次证明ARNTL可以通过circGUCY1A2/miR-200c-3p/PTEN轴抑制肺腺癌的发展，这一发现为肺腺癌的治疗提供了潜在的靶点和治疗途径。在线版本包含可在 10.1186/s13046-023-02791-1 获取的补充材料。
As a subclass of endogenous stable noncoding RNAs, circular RNAs are beginning to be appreciated for their potential as tumor therapeutics. However, the functions and mechanisms by which circRNAs exert protective functions in non-small cell lung cancer (NSCLC) remain largely elusive. The prognostic role of circGUCY1A2 was explored in lung adenocarcinoma specimens. The overexpressed and knockdown plasmids were used to evaluate the effect of circGUCY1A2 on NSCLC cell proliferation and apoptosis efficacy. Luciferase reporter system is used to prove that circGUCY1A2 could bind to miRNA. Chip-PCR was used to prove that circGUCY1A2 could be initiated by transcription factors ARNTL. Subcutaneous tumorigenicity grafts models were established to validate findings in vivo. The expression of circGUCY1A2 were significantly reduced (P < 0.001) and negatively correlated with tumor size (P < 0.05) in non-small cell lung cancer (NSCLC). CircGUCY1A2 upregulation promoted apoptosis and inhibits cell proliferation and growth of subcutaneous tumorigenicity grafts in nude mice (P < 0.01). In addition, intra-tumor injection of pLCDH-circGUCY1A2 inhibited tumor growth in patient-derived NSCLC xenograft models (PDX). Mechanism studies showed that circGUCY1A2 could act as a sponge to competitively bind miR-200c-3p, promote PTEN expression, and thereby inhibit PI3K/AKT pathway. In addition, we found that the circadian gene ARNTL, which was reduced in NSCLC and prolonged the overall survival of patients, could bind to the promoter of circGUCY1A2, thereby increasing its expression. This study is an original demonstration that ARNTL can inhibit the development of lung adenocarcinoma through the circGUCY1A2/miR-200c-3p/PTEN axis, and this finding provides potential targets and therapeutic approaches for the treatment of lung adenocarcinoma. The online version contains supplementary material available at 10.1186/s13046-023-02791-1.
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