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胃黏膜癌变过程中LncRNAs的表达变化及其与幽门螺杆菌感染的关系
作者：张玉南  陈科  蔡晓刚  陈嘉伟  纪璘  王云飞  张小雪  董盛蓉  占强  安方梅 
单位：南京医科大学附属无锡人民医院 消化内科, 南京医科大学无锡医学中心, 国家消化系统疾病临床医学研究中心(西安)江苏分中心, 江苏 无锡 214023
关键词：长链非编码RNA 萎缩性胃炎 幽门螺杆菌 胃癌前病变 
分类号：R573.32
出版年·卷·期（页码）：2023·42·第五期（741-751）
摘要：

目的:探讨胃黏膜癌变过程中lncRNAs的表达谱变化及其与幽门螺杆菌(Hp)感染的关系,探索胃黏膜癌变的分子机制,为胃癌早期阻断和干预研究提供理论依据及靶点分子。方法:通过高通量测序(HiSeq)方法对慢性浅表性胃炎(CSG)、慢性萎缩性胃炎(CAG)、肠上皮化生(IM)、异型增生(Dys)以及胃癌(GC)中长链非编码RNA(LncRNAs)表达谱进行检测。生物信息学方法对差异表达的LncRNAs所调控的功能及信号通路分别进行基因本体(GO)和京都基因和基因组百科全书(KEGG)信号通路分析。通过RT-qPCR验证Lnc-XR_940570(XR_940570) 和Lnc-XR_001746081(XR_00 1746081)在胃黏膜癌病变临床标本中的表达及Hp不同感染状态时的表达。结果:与CSG组相比,CAG组中表达上调的LncRNAs有79个(上调倍数 ≥ 2,P<0.05),表达下调的LncRNAs有25个(下调倍数 ≤ -2,P<0.05),IM组中表达上调的LncRNAs有403个(上调倍数 ≥ 2,P<0.05),表达下调的LncRNAs有283个(下调倍数 ≤ -2,P<0.05),Dys组中表达上调的LncRNAs有219个(上调倍数 ≥ 2,P<0.05),表达下调的LncRNAs有159个(下调倍数 ≤ -2,P<0.05),GC组中表达上调的LncRNAs有1 276个(上调倍数 ≥ 2,P<0.05),表达下调的LncRNAs有904个(下调倍数 ≤ -2,P<0.05),在4个组中表达均有变化的LncRNAs有27个。对变化的27个LncRNAs进行生物信息学GO和KEGG分析发现,上调的LncRNAs主要调控代谢通路、消化吸收等,下调的LncRNAs主要调控肿瘤、胃酸分泌、cAMP信号通路、Wnt信号通路、神经活性配体-受体相互作用等。qRT-PCR验证显示,XR_001746081和XR_940570在CAG组中表达较CSG组上调,且在合并Hp感染的CAG组中差异更为显著。结论:胃黏膜从慢性炎症到癌变过程中LncRNAs 的表达谱发生显著变化。异常表达的LncRNAs调控肿瘤、胃酸分泌、代谢通路等。XR_001746081和XR_940570可能在Hp感染后胃黏膜由浅表性胃炎发展为萎缩性胃炎中起到关键调控作用。

Objective: To indentify the relationship between the expression profile of long non-coding RNAs(LncRNAs)and Helicobacter pylori(Hp) infection in the process of gastric epithelial carcinogenesis, to explore the molecular mechanism of gastric precancerous lesions, and to provide theoretical basis and target molecules for early blockade and intervention of gastric cancer. Methods: The aberrant expression profiles of LncRNAs in different gastric epithelial precancerous lesions were explored by microarray analysis. Gene ontology(GO) and kyoto encyclopedia of genes and genomes(KEGG) pathway analysis of aberrantly expressed LncRNAs were performed to identify the related biological functions and pathologic pathways. The expression changes of target LncRNAs were validated by quantitative real-time polymerase chain reaction(qRT-PCR) to confirm the microarray data in different gastric epithelial precancerous lesions with different Hp infection status. Results: 79 up regulated LncRNAs and 25 down regulated LncRNAs were identified as aberrantly expressed transcripts(≥ 2 or ≤ -2 fold change, P<0.05) in CAG group compared to CSG group. 403 up regulated LncRNAs and 283 down regulated LncRNAs were identified as aberrantly expressed transcripts(≥ 2 or ≤ -2 fold change, P<0.05) in IM group compared to CSG group. 219 up regulated LncRNAs and 159 down regulated LncRNAs were identified as aberrantly expressed transcripts(≥ 2 or ≤ -2 fold change, P<0.05) in Dys group compared to CSG group. One thousand two hundred and seventy six up regulated LncRNAs and 904 down regulated lncRNAs were identified as aberrantly expressed transcripts(≥ 2 or ≤ -2 fold change, P<0.05) in GC group compared to CSG group. XR_001746081 and XR_940570 were up regulated in CAG group compared to CSG group by qRT-PCR. The interactions of the differentially expressed genes in gastric epithelial precancerous conditions were investigated by gene ontology and KEGG pathways, showing that the up regulated LncRNAs were involved in many biological processes, such as metabolic pathway and digestive processes, and the down regulated LncRNAs were involved in gastric acid secretion, cancer, cAMP signaling pathway. Additionally, two up-regulated LncRNAs(XR_001746081 and XR_940570) were verified in Hp-positive CAG samples compared with CSG by qRT-PCR. Conclusion: Our study provided a preliminary exploration of LncRNAs expression profiles in different gastric epithelial precancerous conditions by microarray. XR_001746081 and XR_940570 might play an important role in the pathological process of CSG to CAG with Hp infection.
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