非编码RNA在胃癌中的作用机制研究进展
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Roles of noncoding RNAs in gastric cancer: recent advances
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    摘要:

    胃癌是目前世界上恶性程度最高的肿瘤之一。近年来大量的研究证明非编码RNA在胃癌的发生、增殖、转移等生物过程中占据着重要地位,其中小RNA(miRNA)、环状RNA(circRNA)和长链非编码RNA(lncRNA)组成的非编码RNA调控网络涉及多种基因调控过程。目前对胃癌的诊断主要依赖于内镜检查,缺乏简单有效的筛查手段,针对晚期胃癌的治疗方法也十分有限。而非编码RNA的出现为胃癌的诊断和治疗提供了一个新的角度。miRNA可通过与mRNA结合导致mRNA的降解,从转录后水平上调节靶基因的表达。lncRNA、circRNA可竞争性与miRNA结合以拮抗miRNA的作用,从而间接调控基因的表达。肿瘤的产生可以认为是肿瘤细胞本身异常的生理特性、肿瘤微环境的形成及外部环境因素影响共同作用的结果。非编码RNA与胃癌细胞的增殖、凋亡、侵袭及转移密切相关。此外,非编码RNA还可参与细胞自噬调控过程,并影响肿瘤的干细胞特性及耐药性。肿瘤微环境包括肿瘤周围血管、间质细胞、免疫细胞、信号分子、细胞外基质等组成部分。一方面,非编码RNA可参与胃癌细胞诱导微环境形成的作用过程,例如诱导周围血管新生、免疫抑制;另一方面,非编码RNA可以外泌体形式参与微环境对胃癌细胞的作用,影响胃癌细胞的增殖、转移、耐药等生理过程。外部环境因素对诱导胃癌发生具有重要意义。幽门螺杆菌感染(HP)感染是导致胃癌的重要致病因素之一,非编码RNA与HP的致癌特性相关。氧化应激状态、EB病毒感染也可诱导胃癌发生,非编码RNA同样也参与这些机制。非编码RNA在胃癌中的重要地位使其可成为潜在的胃癌诊断分子标记物或治疗靶点。目前文献多报道的是以miRNA转录后调控基因作用为核心,circRNA、lncRNA为其上游调控分子的基因调控模式。lncRNA、circRNA均可竞争性结合miRNA,那么两者的调控关系仍未明确。circRNA在肿瘤中的作用是近年来才被初步认识的,在胃癌中的具体调控作用机制有待进一步研究。充分认识非编码RNA调控网络将有助于加深对肿瘤发生机制的理解,可为胃癌的临床诊疗提供新的思路和方法。非编码RNA在未来或可进一步用于细化对不同胃癌特征的描述,如同基因一样成为肿瘤的“身份证”,对精准医疗、个体化医疗的发展也具有重要意义。

    Abstract:

    Gastric cancer is one of the most malignant tumors in the world. In recent years, a number of studies have proved that noncoding RNAs play an important part in many biological processes in gastric cancer such as initiation, proliferation and metastasis. The regulatory network of nocoding RNAs consisting of the micro-RNAs (miRNAs), circular RNAs (circRNAs) and long noncoding RNAs (lncRNAs) are involved in the processes of regulating a variety of gene expressions. At present, the diagnosis of gastric cancer mainly depends on endoscopy, the simple and effective screening measures are still lacking, and the treatment modalities for advanced gastric cancer are also limited. Fortunately, the appearance of noncoding RNAs offers a new perspective for diagnosis and treatment of gastric cancer. The miRNAs can bind to the mRNAs to induce their degradation, and thereby regulate the expressions their target mRNAs at post-transcriptional level. The lncRNAs and circRNAs are able to antagonize the functions of miRNAs by competitively harboring miRNAs, and thereby indirectly regulate the gene expressions. Tumorigenesis can be regarded as the joint outcome of the abnormal features of tumor cells, the formation of tumor microenvironment and the influences of external environmental factors. The noncoding RNAs are closely related to the proliferation, apoptosis, invasion and metastasis of gastric cancer cells. Furthermore, the noncoding RNAs are associated with the autophagy and have great influence on stemness and drug resistance of gastric cancer cells. Tumor microenvironment is generally consisted of the components such as the tumor peripheral vasculature, mesenchymal cells, immune cells, signaling molecules and extracellular matrix. On the one hand, the noncoding RNAs are involved in the process of the formation of tumor microenvironment such as angiogenesis and immunosuppression induced by gastric cancer cells. On the other hand, the noncoding RNAs can function as exosomes to participate the action of microenvironment on gastric cancer cells, so as to affect the biological processes that include the proliferation, metastasis, drug resistance of gastric cancer cells. External environmental factors have great significance for inducing tumorigenesis of gastric cancer. Helicobacter pylori (HP) infection is one of the important causes for the occurrence of gastric cancer, and the noncoding RNAs considerably contribute to the oncogenic properties of the HP. In addition, oxidative stress and EB virus infection can also lead to tumorigenesis of gastric cancer, which are as well associated with the noncoding RNAs. The noncoding RNAs have potential to serve as diagnostic biomarker or therapeutic targets for gastric cancer owing to their essential roles in gastric cancer. The pattern of gene expression modulation shown by majority of current reports is post-transcriptional gene regulation by miRNAs serving as the central event with the lncRNAs or circRNAs as upstream regulators. Both lncRNAs and circRNAs competitively combine with the mRNAs but their reciprocal relationship is still unidentified. The actions of circRNAs in tumor are roughly recognized in recent years and their specific roles in gastric cancer remain to be further explored. Full understanding of the roles of noncoding RNAs in gastric cancer will not only help gain insights into the mechanism of tumorigenesis but may provide novel avenues for diagnosis and treatment gastric cancer. In the future, the noncoding RNAs may probably be used for description of different characteristics of gastric cancer after specification and subdivision, and become the “tumor identity cards” just as genes, which also has great significance for the development of precision medicine or personalized medicine.

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郑晋,苏婷婷,李永盛,王寿华,施伟斌.非编码RNA在胃癌中的作用机制研究进展[J].中国普通外科杂志,2021,30(4):471-481.
DOI:10.7659/j. issn.1005-6947.2021.04.012

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  • 收稿日期:2020-05-14
  • 最后修改日期:2021-04-25
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  • 在线发布日期: 2021-09-03