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Chinese Journal of Lung Cancer logoLink to Chinese Journal of Lung Cancer
. 2020 Dec 20;23(12):1095–1100. [Article in Chinese] doi: 10.3779/j.issn.1009-3419.2020.102.38

环状RNA在肺癌中的研究进展

Research Progress of Circular RNA in Lung Cancer

葛 祥伟 1, 张 智博 1, 智 晓玉 1, 汪 进良 1,*
PMCID: PMC7786223  PMID: 33357317

Abstract

肺癌是全球发病率和死亡率最高的恶性肿瘤，其较差的预后结局为患者带来了沉重的负担。目前肺癌诊疗面临的形势依然严峻，亟待探寻有效的治疗靶点及分子标志物。环状RNA（circular RNA, circRNA）是共价闭合的非编码RNA，因其保守性、稳定性、组织特异性等生物学特性而备受关注。诸多研究发现环状RNA通过吸附miRNA等多种机制参与肺癌的调控，并对肺癌的早期诊断、治疗及预后评价发挥重要作用。近年来，circRNA在肺癌的相关研究层出不穷。本文就目前circRNA在肺癌诊断、治疗以及预后方面的进展予以归纳总结。

Keywords: 环状RNA, 肺肿瘤, 诊断, 治疗, 预后

肺癌是目前世界范围内最常见的恶性肿瘤疾病，对人类生命健康造成严重威胁。据统计，2018年全球约有210万肺癌新增病例和180万肺癌死亡病例，发病率和死亡率居所有癌种中首位[1]。根据组织学分型，肺癌可以分为小细胞肺癌（small cell lung cancer, SCLC）和非小细胞肺癌（non-small cell lung cancer, NSCLC）两种，其中SCLC和NSCLC分别约占肺癌总数的15%和85%[2]。尽管临床诊断和治疗手段均有所改善，但由于诊断不及时、受益人群有限、患者耐药等原因，肺癌的5年生存率仍不乐观。另外，缺乏相对特异性的肿瘤标志物为肺癌的诊治及预后增添了挑战。因此，有必要深入研究肺癌分子机制以探寻肺癌潜在的生物标志物及治疗靶点。

环状RNA（circular RNA, circRNA）是一种特殊的内源性非编码RNA。早在20世纪70年代circRNA就被发现存在于RNA病毒中[3]。但介于当时技术的局限，circRNA被认为是剪接过程的副产物，因而并未受到广泛关注[4]。近些年随着高通量测序技术和生物信息学的发展，circRNA被大量发现并逐渐成为RNA领域的研究热点。目前，诸多研究证实circRNA能够参与肺癌发生发展过程的调控，并有望为肺癌的诊断、治疗及预后提供新思路[5, 6]。

1. circRNA的生物学特性及功能

circRNA是共价闭合的非编码RNA分子，在真核生物转录组中广泛存在。通常根据circRNA的来源将其分为：外显子circRNAs（ecRNAs）、内含子circRNA（ciRNAs）以及外显子-内含子circRNA（EIciRNAs）[7]。其中以外显子circRNAs最为常见。与线性RNA不同，circRNA没有5’端的帽子结构和3’端的多聚腺苷酸尾，能够抵抗核酸外切酶RNase R的降解，因而circRNA相较于线性RNA稳定性好且半衰期更长[8]。研究[9]还发现，circRNA表现出良好的物种保守性。另外，circRNA的表达具有组织特异性和发育阶段特异性，提示circRNA可能参与机体多种病理生理过程的调控[10]。

circRNA的功能研究多集中在以下几个方面：①作为分子海绵吸附miRNA。竞争性内源RNA（competing endogenous RNA, ceRNA）机制指出具有相同miRNA应答元件（miRNA response elements, MREs）的RNA能够竞争性结合miRNAs，从而相互调控影响彼此的表达[11]。目前，多数circRNA研究围绕miRNA分子海绵这一机制展开; ②通过结合RNA聚合酶II调控亲本基因的转录[12]; ③与RNA结合蛋白相互结合发挥生物学作用[9]; ④翻译蛋白。例如Yang等[13]发现Circ-FBXW7编码蛋白进而抑制胶质瘤发生。

2. circRNA与肺癌的诊断

早期且准确的诊断对肺癌的治疗至关重要。尽管已有多种诊断方法应用于临床，但由于费用、准确度以及患者接受程度等原因，当前的手段仍有改进空间。因此对肺癌诊断标志物的探索依然很有必要。circRNA具有保守性、稳定性、特异性等优势，因而具有成为肺癌新兴标志物的潜能[14]。一项针对中国肺癌人群的meta分析汇集了8项关于肺癌组织和血液中circRNA诊断效能的研究显示，纳入的circRNA总灵敏度和特异度分别为0.77和0.76，总受试者工作特征曲线（receiver operating characteristic curve, ROC）的曲线下面积（area under curve, AUC）为0.78，提示circRNA在中国肺癌人群中具有诊断潜能[15]。

2.1. 肺癌组织circRNA的诊断价值

Wang等[16]发现，在区分NSCLC和正常组织方面，hsa_circ_0077837和hsa_circ_0001821的AUC分别为0.921和0.863，展现了这两种circRNA对肺癌的诊断价值。Liu等[17]证实hsa_circ_11780在NSCLC组织和细胞系中表达均显著下降，且低表达hsa_circ_11780的患者出现较大肿瘤（> 3 cm）、远处转移和较差生存预后的风险更大。Zhao等[18]对61对配对的肺癌和癌旁组织进行分析，发现hsa_circ_0037515和hsa_circ_0037516在NSCLC中低表达，二者的AUC分别为0.81和0.82，同样表现出较好的诊断能力。而联合hsa_circ_0037515和hsa_circ_0037516后的总AUC提升至0.90，提示肺癌组织circRNA联合诊断的重要性。

2.2. 血液circRNA的诊断价值

相比于传统活检，液体活检具有操作简单、侵入性小、成本低等优点，因此研究前景广阔。目前已有文献初步证实血浆circRNA具有较好的诊断能力，如circRNA-002178[19]、circMAN1A2[20]等。Chen等[21]通过高通量测序技术以识别肺腺癌（lung adenocarcinoma, LUAD）患者血浆外泌体中差异表达的circRNA。与对照组相比，105个circRNA表达升高，78个circRNA表达降低。进一步研究发现，hsa_circ_0001492和hsa_circ_0001346在LUAD早期即表达明显上调，而对照组血浆几乎检测不到，提示hsa_circ_0001492和hsa_circ_0001346可能成为早期LUAD诊断候选标记物。

Liu等[22]检测分析hsa_circ_0005962和hsa_circ_0086414在LUAD患者血浆中差异表达。二者联合诊断AUC达到0.81，提示双circRNA可能作为诊断LUAD的非侵入性生物标志物。另外，血液circRNA可能与肿瘤进展有关，LUAD患者术后hsa_circ_0005962表达较术前明显下降。而hsa_circ_0086414的表达水平与表皮生长因子受体（epidermal growth factor receptor, EGFR）突变相关。与野生型患者相比，EFGR突变型患者hsa_circ_0086414高表达。该研究表现了血液circRNA多方面的应用价值。当然，为实现血液circRNA肺癌诊断的临床转化，尚需更大的样本量以及更为深入的机制探索。

3. circRNA与肺癌的治疗

既往研究发现circRNA能够作为调控分子促进或者抑制肺癌的发生发展，因而调控circRNA的表达水平对肺癌的恶性生物学行为具有重要意义。目前，多项研究依据circRNA的ceRNA机制进行肺癌恶性生物学行为的机制探索（表 1）。例如，Yao等[23]发现circGFRA1在肺癌细胞内表达升高，并通过circGFRA1/miR-188-3p/PI3K/AKT通路促进肺癌的恶性增殖。LIMK1作为一种丝苏氨酸蛋白激酶，通过影响肌动蛋白细胞骨架参与上皮间质转化（epithelial-mesenchymal transition, EMT），调控肿瘤进程[24]。Qin等[25]发现circ_0012673在肺癌组织和细胞系中高表达。circ_0012673海绵吸附miR-320a导致下游靶蛋白LIMK1表达升高，从而抑制肺癌细胞凋亡，促进其增殖、迁移和EMT进程。

表 1.

circRNA通过ceRNA机制作用于肺癌恶性生物学行为的总结

Summary of circRNA acting on malignant biological behaviors of lung cancer through ceRNA mechanis

circRNA Dysregulation Cell lines Function Sponge target Ref.
circRNA: circular RNA; EMT: epithelial-mesenchymal transition; ceRNA: competing endogenous RNA.
circGFRA1 Up A549, H838 Proliferation (+) miR-188-3p [23]
circ-0000211 Up A549, H1299, H1650 Migration (+), invasion (+) miR-622 [26]
circ-ABCB10 Up A549, H292 Proliferation (+), migration (+) miR-556-3p [27]
circ_0000326 Up A549, H1299 Proliferation (+), apoptosis (-), migration (+) miR-338-3p [28]
circ_0014130 Up PC-9, A549 Proliferation (+), apoptosis (-), invasion (+) miR-136-5p [29]
circ-SOX4 Up A549, SPC-A1 Proliferation (+), migration (+), invasion (+) miR-1270 [30]
circCCDC66 Up A549, H1299 Proliferation (+), apoptosis (-), migration (+), invasion (+) miR-33a-5p [31]
circ_0012673 Up A549, H23 Proliferation (+), apoptosis (-), migration (+), EMT (+) miR-320a [25]
circCDR1as Up A549, Calu-3 Proliferation(+), apoptosis (-), migration (+), invasion (+) miR-219a-5p [32]
circ_0058124 Up A549, H1975 Proliferation (+), apoptosis (-), migration (+), invasion (+) miR-1297 [33]
circ-MTO1 Down A549, SPC-A1 Proliferation (-) miR-17 [34]
cMras Down A549, H1299 Proliferation (-), migration (-) miR-567 [35]
circ-IGF1R Down PC9, A549 Migration (-), invasion (-) miR-1270 [36]
circCRIM1 Down A549, H1299, SPC-A1 Migration (-), invasion (-) miR-93, miR-182 [37]
circ_0007059 Down A549, H1975 Proliferation (-), EMT (-) miR-378 [38]
circ_11780 Down A549, H226 Proliferation (-), migration (-), invasion (-) miR-544a [17]
circ_0006427 Down SPC-A1, Calu-3 Proliferation (-), migration (-), invasion (-) miR-6783-3p [39]
circPTPRA Down H23, H1755, H522 Migration (-), invasion (-), EMT (-) miR-96-5p [40]
circSMARCA5 Down A549 Proliferation (-), migration (-), invasion (-) miR-19b-3p [41]
circ_0002483 Down A549, H1299 Proliferation (-), migration (-), invasion (-) miR-182-5p [42]
circ_0078767 Down A549, H23 Proliferation (-), apoptosis (+), invasion (-) miR-330-3p [43]
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3.1. circRNA与肺癌耐药

随着抗肿瘤药物的不断问世，为肺癌患者带来了更多希望，但是耐药问题依然是困扰临床治疗的一大难题。因此，亟待对肺癌耐药机制进行深入探索以探寻高效的生物标志物或治疗靶点。研究发现，部分circRNA能够参与肺癌的耐药进程（表 2）。Hong等[44]研究发现，circCPA4作为let-7的分子海绵，其下调可以影响程序性死亡配体1（programmed death-ligand 1, PD-L1）使其表达降低，进而抑制NSCLC细胞的生长、迁移和EMT过程。另外，NSCLC来源的含PD-L1的外泌体能够促进其干细胞特性，增强NSCLC细胞对顺铂的耐受性。Li等[42]报道circ_0002483能够降低miR-182-5p表达水平，解除其对靶分子GRB2、FOXO1、FOXO3的抑制，进而增强NSCLC对紫杉醇的敏感性。circRNA_103762在肺癌中高表达，通过抑制靶蛋白CHOP诱导肺癌的多药耐药[45]。

表 2.

肺癌circRNA对抗肿瘤药物敏感性影响的总结

Summary of the effects of circRNA on tumor drug sensitivity

CircRNA Cell lines Drugs Sensitivity Ref.
circAKT3 A549, H1299 Cisplatin Down-regulated [5]
circ-ABCB10 A549, H292 Cisplatin Down-regulated [27]
circZFR A549, H522 Cisplatin Down-regulated [46]
circ_0076305 A549, H1650 Cisplatin Down-regulated [47]
circ_0004015 A549, HCC827 Gefitinib Down-regulated [48]
circ_0003998 A549, H1299 Docetaxel Down-regulated [49]
circ_0002483 A549, H1299 Paclitaxel Up-regulated [42]
circ_0001946 A549 Cisplatin Up-regulated [50]
circESRP1 H69, H446 Cisplatin, etoposide Up-regulated [51]
circ-SMARCA5 H1299, H1437 Cisplatin, gemcitabine Up-regulated [52]
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3.2. circRNA与肺癌免疫治疗

肿瘤细胞能够表达多种机制来逃避免疫系统的攻击，为自身的生长创造条件。程序性死亡受体1（programmed death protein 1, PD-1）是一种跨膜蛋白，已被发现几乎表达于各种类型的肿瘤细胞表面，并通过于PD-L1相互作用参与肿瘤的免疫逃逸机制[53]。近些年，以PD-1/PD-L1为靶点的免疫检查点抑制剂（immune checkpoint inhibitors, ICIs）为肺癌治疗提供了强大武器。Wang等[19]研究发现，circRNA-002178在肺腺癌组织中异常高表达，通过吸附miR-34促进肺癌细胞PD-L1的表达。同时，肺癌细胞能够分泌外泌体circRNA-002178并传递给T细胞，通过抑制miR-28-5p进而促进T细胞PD-1的表达。文献[54]证实，CXCR4参与细胞毒性T淋巴细胞耗竭、诱导抗PD-1药物耐药等过程。Zhang等[55]发现circFGFR1/miR-381-3p/CXCR4通路通过促进肺癌细胞对抗PD-1治疗药物的耐药进程，进而发挥免疫抑制效应。提示circRNA能够参与肿瘤免疫逃逸机制，相关通路抑制剂的联合使用有望提高临床疗效，为肿瘤的免疫疗法提供新的思路。

4. circRNA与肺癌的预后

肺癌患者的预后监测是评价临床诊疗效果的关键环节，对调整用药方案、改善患者生存时间有重要意义。研究证实，多种circRNA能够作为肺癌患者独立预后指标，与肺癌患者生存期紧密相关，如circSMARCA5[52]、circ_11780[17]、circCRIM1[37]。Liu等[17]对93例NSCLC患者肿瘤组织进行RT-qPCR检测发现hsa_circ_11780异常低表达，而低表达hsa_circ_11780的患者往往肿瘤更大，伴有远处转移以及更严重的肿瘤原发灶-淋巴结-转移（tumor-node-metastasis, TNM）分期。以Kaplan-Meier法进行生存分析表明低表达hsa_circ_11780的NSCLC患者总生存期（overall survival, OS）更短。circHIPK3来源于染色体11p13区的癌基因HIPK3的2号外显子。Chen等[6]发现敲低circHIPK3能够抑制NSCLC细胞株A549、H838和H1299增殖、迁移、侵袭能力，并诱导自噬的发生，而circHIPK3和linHIPK3对自噬的调控作用相互拮抗，circHIPK3:linHIPK3（C:L）比值能够反映肿瘤细胞的自噬水平。对于晚期NSCLC患者来说，高C:L比值（> 0.49）又是其低生存率的有效指标。这些结果提示自噬调节因子circHIPK3具有作为预后因子的潜在临床应用价值。

EGFR酪氨酸激酶抑制剂（EGFR-tyrosine kinase inhibitor, EGFR-TKIs）是EGFR敏感突变的NSCLC患者的重要治疗选择。Liu等[56]通过对使用EGFR-TKI吉非替尼后有效组与无效组NSCLC患者血浆circRNA测序，检测到1, 377个差异表达的circRNA。RT-qPCR检测证实hsa_circ_0109320与hsa_circ_0134501在吉非替尼有效组中高表达。进一步研究发现hsa_circ_0109320的高表达与患者更好的无进展生存期（progression-free survival, PFS）相关，提示hsa_circ_0109320可能是反映吉非替尼疗效的生物标志物。Fu等[57]发现hsa_circRNA_012515在NSCLC的组织、细胞尤其是吉非替尼耐药的细胞株中表达显著升高。另外，hsa_circRNA_012515表达上调与患者淋巴结转移、肿瘤分期及预后密切相关。高表达hsa_circRNA_012515的NSCLC患者其OS和PFS更短。研究者还发现与I期/II期NSCLC患者相比，hsa_circRNA_012515在III期/IV期患者中的表达水平更高。由此可见，hsa_circRNA_012515具有良好的临床相关性，可能是预测NSCLC患者不良预后的生物标志物。

5. 展望

随着研究的不断深入，circRNA与肺癌的联系正在日益凸显。一方面，circRNA作为促癌或抑癌因子调控肺癌的增殖、转移、凋亡、自噬等生物学行为，调节化疗或靶向药物的敏感性以及免疫治疗疗效，为辅助临床治疗提供初步理论基础; 另一方面，组织或血液中circRNA的差异表达在肺癌的早期诊断及预后评估都展现了一定的相关性，有望成为肺癌潜在的生物标志物。但是目前circRNA研究尚处于早期阶段，多数研究者将重点置于miRNA海绵吸附功能探索，许多机制尚未阐明。其临床相关性研究也局限于少量样本，其转化价值有待商榷。相信未来circRNA领域将会有更多突破，为肺癌诊疗提供更多思路。

Funding Statement

本文受解放军总医院医疗大数据研发项目（No.2017MBD-013）资助

This paper was supported by the grant from People's Liberation Army General Hospital Medical Big Data R&D Projects (to Jinliang WANG)(No.2017MBD-013)

References

  • 1.Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424. doi: 10.3322/caac.21492. [DOI] [PubMed] [Google Scholar]
  • 2.Molina JR, Yang P, Cassivi SD, et al. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc. 2008;83(5):584–594. doi: 10.4065/83.5.584. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Sanger HL, Klotz G, Riesner D, et al. Viroids are single-stranded covalently closed circular RNA molecules existing as highly base-paired rod-like structures. Proc Natl Acad Sci U S A. 1976;73(11):3852–3856. doi: 10.1073/pnas.73.11.3852. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Cocquerelle C, Mascrez B, Hetuin D, et al. Mis-splicing yields circular RNA molecules. Faseb J. 1993;7(1):155–160. doi: 10.1096/fasebj.7.1.7678559. [DOI] [PubMed] [Google Scholar]
  • 5.Xu Y, Jiang T, Wu C, et al. CircAKT3 inhibits glycolysis balance in lung cancer cells by regulating miR-516b-5p/STAT3 to inhibit cisplatin sensitivity. Biotechnol Lett. 2020;42(7):1123–1135. doi: 10.1007/s10529-020-02846-9. [DOI] [PubMed] [Google Scholar]
  • 6.Chen X, Mao R, Su W, et al. Circular RNA circHIPK3 modulates autophagy via MIR124-3p-STAT3-PRKAA/AMPKalpha signaling in STK11 mutant lung cancer. Autophagy. 2020;16(4):659–671. doi: 10.1080/15548627.2019.1634945. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Mu YY, Xie FY. Research progress of circular RNA in lung cancer. Zhongguo Fei Ai Za Zhi. 2018;21(7):543–546. doi: 10.3779/j.issn.1009-3419.2018.07.07. [DOI] [PMC free article] [PubMed] [Google Scholar]; 穆 银玉, 谢 服役. 环状RNA与肺癌的研究进展. 中国肺癌杂志. 2018;21(7):543–546. doi: 10.3779/j.issn.1009-3419.2018.07.07. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Suzuki H, Tsukahara T. A view of pre-mRNA splicing from RNase R resistant RNAs. Int J Mol Sci. 2014;15(6):9331–9342. doi: 10.3390/ijms15069331. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Memczak S, Jens M, Elefsinioti A, et al. Circular RNAs are a large class of animal RNAs with regulatory potency. Nature. 2013;495(7441):333–338. doi: 10.1038/nature11928. [DOI] [PubMed] [Google Scholar]
  • 10.Xia S, Feng J, Lei L, et al. Comprehensive characterization of tissue-specific circular RNAs in the human and mouse genomes. Brief Bioinform. 2017;18(6):984–992. doi: 10.1093/bib/bbw081. [DOI] [PubMed] [Google Scholar]
  • 11.Salmena L, Poliseno L, Tay Y, et al. A ceRNA hypothesis: the rosetta stone of a hidden RNA language? Cell. 2011;146(3):353–358. doi: 10.1016/j.cell.2011.07.014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Li Z, Huang C, Bao C, et al. Exon-intron circular RNAs regulate transcription in the nucleus. Nat Struct Mol Biol. 2015;22(3):256–264. doi: 10.1038/nsmb.2959. [DOI] [PubMed] [Google Scholar]
  • 13.Yang Y, Gao X, Zhang M, et al. Novel role of FBXW7 circular RNA in repressing glioma tumorigenesis. J Natl Cancer Inst. 2018;110(3):304–315. doi: 10.1093/jnci/djx166. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Han B, Chao J, Yao H. Circular RNA and its mechanisms in disease: From the bench to the clinic. Pharmacol Ther. 2018;187:31–44. doi: 10.1016/j.pharmthera.2018.01.010. [DOI] [PubMed] [Google Scholar]
  • 15.Xiao Z, Chen X, Lu X, et al. Accuracy evaluation of circular RNA in diagnosing lung cancer in a Chinese population. Dis Markers. 2019;2019:7485389. doi: 10.1155/2019/7485389. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Wang C, Tan S, Liu WR, et al. RNA-Seq profiling of circular RNA in human lung adenocarcinoma and squamous cell carcinoma. Mol Cancer. 2019;18(1):134. doi: 10.1186/s12943-019-1061-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Liu Y, Yang C, Cao C, et al. Hsa_circ_RNA_0011780 represses the proliferation and metastasis of non-small cell lung cancer by decreasing FBXW7 via targeting miR-544a. Onco Targets Ther. 2020;13:745–755. doi: 10.2147/OTT.S236162. [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]
  • 18.Zhao D, Liu H, Liu H, et al. Downregulated expression of hsa_circ_0037515 and hsa_circ_0037516 as novel biomarkers for non-small cell lung cancer. Am J Transl Res. 2020;12(1):162–170. [PMC free article] [PubMed] [Google Scholar]
  • 19.Wang J, Zhao X, Wang Y, et al. circRNA-002178 act as a ceRNA to promote PDL1/PD1 expression in lung adenocarcinoma. Cell Death Dis. 2020;11(1):32. doi: 10.1038/s41419-020-2230-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Fan CM, Wang JP, Tang YY, et al. circMAN1A2 could serve as a novel serum biomarker for malignant tumors. Cancer Sci. 2019;110(7):2180–2188. doi: 10.1111/cas.14034. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Chen F, Huang C, Wu Q, et al. Circular RNAs expression profiles in plasma exosomes from early-stage lung adenocarcinoma and the potential biomarkers. J Cell Biochem. 2020;121(3):2525–2533. doi: 10.1002/jcb.29475. [DOI] [PubMed] [Google Scholar]
  • 22.Liu XX, Yang YE, Liu X, et al. A two-circular RNA signature as a noninvasive diagnostic biomarker for lung adenocarcinoma. J Transl Med. 2019;17(1):50. doi: 10.1186/s12967-019-1800-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Yao J, Xu G, Zhu L, et al. circGFRA1 enhances NSCLC progression by sponging miR-188-3p. Onco Targets Ther. 2020;13:549–558. doi: 10.2147/ott.S230795. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Liao Q, Li R, Zhou R, et al. LIM kinase 1 interacts with myosin-9 and alpha-actinin-4 and promotes colorectal cancer progression. Br J Cancer. 2017;117(4):563–571. doi: 10.1038/bjc.2017.193. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Qin H, Liu J, Du ZH, et al. Circular RNA hsa_circ_0012673 facilitates lung cancer cell proliferation and invasion via miR-320a/LIMK18521 axis. Eur Rev Med Pharmacol Sci. 2020;24(4):1841–1852. doi: 10.26355/eurrev_202002_20362. [DOI] [PubMed] [Google Scholar]
  • 26.Feng D, Xu Y, Hu J, et al. A novel circular RNA, hsa-circ-0000211, promotes lung adenocarcinoma migration and invasion through sponging of hsa-miR-622 and modulating HIF1-alpha expression. Biochem Biophys Res Commun. 2020;521(2):395–401. doi: 10.1016/j.bbrc.2019.10.134. [DOI] [PubMed] [Google Scholar]
  • 27.Wu Z, Gong Q, Yu Y, et al. Knockdown of circ-ABCB10 promotes sensitivity of lung cancer cells to cisplatin via miR-556-3p/AK4 axis. BMC Pulm Med. 2020;20(1):10. doi: 10.1186/s12890-019-1035-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Xu Y, Yu J, Huang Z, et al. Circular RNA hsa_circ_0000326 acts as a miR-338-3p sponge to facilitate lung adenocarcinoma progression. J Exp Clin Cancer Res. 2020;39(1):57. doi: 10.1186/s13046-020-01556-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Geng Y, Bao Y, Zhang W, et al. Circular RNA hsa_circ_0014130 inhibits apoptosis in non-small cell lung cancer by sponging miR-136-5p and upregulating BCL2. Mol Cancer Res. 2020;18(5):748–756. doi: 10.1158/1541-7786.MCR-19-0998. [DOI] [PubMed] [Google Scholar]
  • 30.Gao N, Ye B. Circ-SOX4 drives the tumorigenesis and development of lung adenocarcinoma via sponging miR-1270 and modulating PLAGL2 to activate WNT signaling pathway. Cancer Cell Int. 2020;20:2. doi: 10.1186/s12935-019-1065-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Wang Y, Zhao W, Zhang S. STAT3-induced upregulation of circCCDC66 facilitates the progression of non-small cell lung cancer by targeting miR-33a-5p/KPNA4 axis. Biomed Pharmacother. 2020;126:110019. doi: 10.1016/j.biopha.2020.110019. [DOI] [PubMed] [Google Scholar]
  • 32.Li Y, Zhang J, Pan S, et al. CircRNA CDR1as knockdown inhibits progression of non-small-cell lung cancer by regulating miR-219a-5p/SOX5 axis. Thorac Cancer. 2020;11(3):537–548. doi: 10.1111/1759-7714.13274. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Li X, Zhang Q, Yang Z. Knockdown of hsa_circ_0058124 inhibits the proliferation of human lung cancer cells by up-regulation of miR-1297. Artif Cells Nanomed Biotechnol. 2020;48(1):584–593. doi: 10.1080/21691401.2020.1725537. [DOI] [PubMed] [Google Scholar]
  • 34.Zhang B, Chen M, Jiang N, et al. A regulatory circuit of circ-MTO1/miR-17/QKI-5 inhibits the proliferation of lung adenocarcinoma. Cancer Biol Ther. 2019;20(8):1127–1135. doi: 10.1080/15384047.2019.1598762. [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]
  • 35.Yu C, Tian F, Liu J, et al. Circular RNA cMras inhibits lung adenocarcinoma progression via modulating miR-567/PTPRG regulatory pathway. Cell Prolif. 2019;52(3):e12610. doi: 10.1111/cpr.12610. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Xu Z, Xiang W, Chen W, et al. Circ-IGF1R inhibits cell invasion and migration in non-small cell lung cancer. Thorac Cancer. 2020;11(4):875–887. doi: 10.1111/1759-7714.13329. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Wang L, Liang Y, Mao Q, et al. Circular RNA circCRIM1 inhibits invasion and metastasis in lung adenocarcinoma through the microRNA (miR)-182/miR-93-leukemia inhibitory factor receptor pathway. Cancer Sci. 2019;110(9):2960–2972. doi: 10.1111/cas.14131. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Gao S, Yu Y, Liu L, et al. Circular RNA hsa_circ_0007059 restrains proliferation and epithelial-mesenchymal transition in lung cancer cells via inhibiting microRNA-378. Life Sci. 2019;233:116692. doi: 10.1016/j.lfs.2019.116692. [DOI] [PubMed] [Google Scholar]
  • 39.Yao Y, Hua Q, Zhou Y. CircRNA has_circ_0006427 suppresses the progression of lung adenocarcinoma by regulating miR-6783-3p/DKK1 axis and inactivating Wnt/beta-catenin signaling pathway. Biochem Biophys Res Commun. 2019;508(1):37–45. doi: 10.1016/j.bbrc.2018.11.079. [DOI] [PubMed] [Google Scholar]
  • 40.Wei S, Zheng Y, Jiang Y, et al. The circRNA circPTPRA suppresses epithelial-mesenchymal transitioning and metastasis of NSCLC cells by sponging miR-96-5p. EBioMedicine. 2019;44:182–193. doi: 10.1016/j.ebiom.2019.05.032. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Wang Y, Li H, Lu H, et al. Circular RNA SMARCA5 inhibits the proliferation, migration, and invasion of non-small cell lung cancer by miR-19b-3p/HOXA9 axis. Onco Targets Ther. 2019;12:7055–7065. doi: 10.2147/ott.S216320. [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]
  • 42.Li X, Yang B, Ren H, et al. Hsa_circ_0002483 inhibited the progression and enhanced the Taxol sensitivity of non-small cell lung cancer by targeting miR-182-5p. Cell Death Dis. 2019;10(12):953. doi: 10.1038/s41419-019-2180-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Chen T, Yang Z, Liu C, et al. Circ_0078767 suppresses non-small-cell lung cancer by protecting RASSF1A expression via sponging miR-330-3p. Cell Prolif. 2019;52(2):e12548. doi: 10.1111/cpr.12548. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Hong W, Xue M, Jiang J, et al. Circular RNA circ-CPA4/ let-7 miRNA/PD-L1 axis regulates cell growth, stemness, drug resistance and immune evasion in non-small cell lung cancer (NSCLC) J Exp Clin Cancer Res. 2020;3(1):149. doi: 10.1186/s13046-020-01648-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Xiao G, Huang W, Zhan Y, et al. CircRNA_103762 promotes multidrug resistance in NSCLC by targeting DNA damage inducible transcript 3 (CHOP) J Clin Lab Anal. 2020;34(6):e23252. doi: 10.1002/jcla.23252. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Li H, Liu F, Qin W. Circ_0072083 interference enhances growth-inhibiting effects of cisplatin in non-small-cell lung cancer cells via miR-545-3p/CBLL1 axis. Cancer Cell Int. 2020;20:78. doi: 10.1186/s12935-020-1162-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Dong Y, Xu T, Zhong S, et al. Circ_0076305 regulates cisplatin resistance of non-small cell lung cancer via positively modulating STAT3 by sponging miR-296-5p. Life Sci. 2019;239:116984. doi: 10.1016/j.lfs.2019.116984. [DOI] [PubMed] [Google Scholar]
  • 48.Zhou Y, Zheng X, Xu B, et al. Circular RNA hsa_circ_0004015 regulates the proliferation, invasion, and TKI drug resistance of non-small cell lung cancer by miR-1183/PDPK1 signaling pathway. Biochem Biophys Res Commun. 2019;508(2):527–535. doi: 10.1016/j.bbrc.2018.11.157. [DOI] [PubMed] [Google Scholar]
  • 49.Yu W, Peng W, Sha H, et al. Hsa_circ_0003998 promotes chemoresistance via modulation of miR-326 in lung adenocarcinoma cells. Oncol Res. 2019;27(5):623–628. doi: 10.3727/096504018x15420734828058. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Huang MS, Liu JY, Xia XB, et al. Hsa_circ_0001946 inhibits lung cancer progression and mediates cisplatin sensitivity in non-small cell lung cancer via the nucleotide excision repair signaling pathway. Front Oncol. 2019;9:508. doi: 10.3389/fonc.2019.00508. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Huang W, Yang Y, Wu J, et al. Circular RNA cESRP1 sensitises small cell lung cancer cells to chemotherapy by sponging miR-93-5p to inhibit TGF-beta signalling. Cell Death Differ. 2019;27(5):1709–1727. doi: 10.1038/s41418-019-0455-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Tong S. Circular RNA SMARCA5 may serve as a tumor suppressor in non-small cell lung cancer. J Clin Lab Anal. 2020;34(5):e23195. doi: 10.1002/jcla.23195. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Jiang X, Wang J, Deng X, et al. Role of the tumor microenvironment in PD-L1/PD-1-mediated tumor immune escape. Mol Cancer. 2019;18(1):10. doi: 10.1186/s12943-018-0928-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Seo YD, Jiang X, Sullivan KM, et al. Mobilization of CD8(+) T cells via CXCR4 blockade facilitates PD-1 checkpoint therapy in human pancreatic cancer. Clin Cancer Res. 2019;25(13):3934–3945. doi: 10.1158/1078-0432.Ccr-19-0081. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Zhang PF, Pei X, Li KS, et al. Circular RNA circFGFR1 promotes progression and anti-PD-1 resistance by sponging miR-381-3p in non-small cell lung cancer cells. Mol Cancer. 2019;18(1):179. doi: 10.1186/s12943-019-1111-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Liu YT, Han XH, Xing PY, et al. Circular RNA profiling identified as a biomarker for predicting the efficacy of Gefitinib therapy for non-small cell lung cancer. J Thorac Dis. 2019;11(5):1779–1787. doi: 10.21037/jtd.2019.05.22. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Fu Y, Huang L, Tang H, et al. hsa_circRNA_012515 is highly expressed in NSCLC patients and affects its prognosis. Cancer Manag Res. 2020;12:1877–1886. doi: 10.2147/cmar.S245525. [DOI] [PMC free article] [PubMed] [Google Scholar]

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