miR-509-3-5p—lnc-RAB44-3:1对p21的调控及其在非小细胞肺癌发生发展过程中的作用

Non-coding RNAs play important roles in tumorigenesis and tumor development. But the underlying molecular mechanism is far from being elucidated and identification and functional characterization of these noncoding transcripts remained an emerging field. Our previous study found that: 1) miR-509-3-5p is a feasible suppressor for cancer by targeting PLK1. Meanwhile, the expression of p21 can be regulated by miR-509-3-5p but the mechanism is not known. 2) Further study found that long non-coding RNA lnc-RAB44-3:1 can down-regulate P21. 3) miR-509-3-5p directly inhibits lnc-RAB44-3:1 expression and their expression are negatively correlated at a statistical significance. Based on these results, combined with literature reports, we assume that Lnc-RAB44-3:1 is an important regulatory factor in expression of p21 during tumorigenesis and tumor development, whose expression is regulated by miR-509-3-5p. To test and verify the hypothesis, we will further focus on the regulation and mechanisms of miR-509-3-5p—lnc-RAB44-3:1 regulatory axis on the expression of p21, and explore the significance of this regulatory mechanism in the process of tumorigenesis. Our study will provide an in-depth understanding of miRNA–lncRNA regulatory network, which may provide a new clue for the tumorigenesis study of non-small cell lung cancer, and provide potentially therapeutic targets and experimental basis for the prevention and treatment of non-small cell ung cancer.

非编码RNA在肿瘤发生发展中发挥重要调控作用，但其分子机制远未得到阐明。我们前期研究发现：1) miR-509-3-5p可靶向抑制PLK1的表达而发挥抑癌作用，miR-509-3-5p也可调控p21表达，但其调控机制不清；2)长非编码RNA lnc-RAB44-3:1可下调p21表达；3) miR-509-3-5p可靶向抑制lnc-RAB44-3:1表达，二者表达呈负相关。基于这些结果并结合文献报道，我们假设：lnc-RAB44是调控肿瘤发生发展过程中p21表达的重要因子，其表达受miR-509-3-5p调控。本课题将在前期结果的基础上，进一步探讨这两种非编码RNA相互调控网络对p21表达的调控及其机制，揭示这一调控机制在肿瘤发生发展过程中的意义。我们的研究将会提供对miRNA–lncRNA调控网络的深入理解，为非小细胞肺癌的发生机制研究提供新的线索，也可能对肺癌的防治提供靶点和实验依据。

非编码RNA在肿瘤发生发展中发挥重要调控作用，我们前期研究发现 miR-509-3-5p可抑制肿瘤细胞生长并参与调控P21表达，而长链非编码RNA NONHSAT112228.2可下调p21的表达，但其具体调控机制尚不清楚。本研究中，我们首先进行生物信息学分析，发现miR-509-3-5p可能靶向调控NONHSAT112228.2，后者是与p21基因重叠的非编码基因转录生成的正义重叠lncRNA。荧光素酶报告基因及突变分析验证了miR-509-3-5p可以靶向NONHSAT112228.2的3'非翻译区的结合序列从而抑制其表达。在多种肿瘤细胞系中NONHSAT112228.2表达也与p21和miR-509-3-5p都呈负相关；过表达miR-509-3-5p以及基因敲减NONHSAT112228.2都可抑制肿瘤细胞增长、增殖和迁移。NONHSAT112228.2高表达伴有p21低表达，且与较低的生存率相关。综上所述，我们的研究发现了一条新的p21调控途径，即miR-509-3-5p靶向NONHSAT112228.2的3'非翻译区的结合序列，抑制其表达，进而影响p21的表达；miR-509-3-5p—NONHSAT112228.2调节轴可抑制肺癌细胞的增殖和迁移。探讨非编码RNA相互调控网络对p21表达的调控及其机制，将会提供对miRNA–lncRNA调控网络的深入理解，为非小细胞肺癌的发生机制研究提供新的线索，也可能对肺癌的防治提供靶点和实验依据。