长链非编码RNA HOXC-AS2通过调控EZH2/p21、p27促进胃癌的恶性进展-现代医学

长链非编码RNA HOXC-AS2通过调控EZH2/p21、p27促进胃癌的恶性进展

单位：江苏大学附属人民医院普外科, 江苏镇江 212002

分类号：R735.2

出版年·卷·期（页码）：2025·53·第一期（1-10）

摘要：

目的: 探究长链非编码RNA(lncRNA) HOXC-AS2促进胃癌恶性进展的作用及其潜在的分子机制。方法: 使用癌症基因组图谱(TCGA)胃腺癌数据库筛选出胃癌中高表达的lncRNA HOXC-AS2。选择2018年9月至2021年10月于江苏大学附属人民医院行胃癌手术的98例患者为研究对象，实时荧光定量聚合酶链反应(qRT-PCR)检测胃癌组织及对应癌旁组织和胃癌细胞系中HOXC-AS2的表达情况；进行细胞功能试验以评估HOXC-AS2对胃癌细胞生长、迁移和侵袭能力的影响，基因集富集分析(GSEA)筛选在胃癌中与HOXC-AS2相关的信号通路；通过qRT-PCR和Western blotting以确认在胃癌细胞中敲低HOXC-AS2后下游基因变化情况； RNA免疫共沉淀(RIP)技术验证HOXC-AS2与转录因子的结合。结果: TCGA胃腺癌数据库中HOXC-AS2在胃癌组织中的表达相较于癌旁组织显著上调，qRT-PCR显示，lncRNA HOXC-AS2在胃癌组织的表达量较高并且其高表达与淋巴结转移及分期显著相关，胃癌细胞系中lncRNA HOXC-AS2表达上调；细胞功能实验显示，敲低HOXC-AS2后胃癌细胞增殖、迁移、侵袭能力受到抑制；GSEA筛选出的数据集主要与细胞周期、基因表观遗传及PRC2复合物等相关。qRT-PCR和Western blotting显示，敲低HOXC-AS2后EZH2表达量明显下降，同时p21和p27的表达量上升；RNA免疫共沉淀表明，HOXC-AS2可能通过与EZH2结合从而影响相关基因的表达。结论: lncRNA HOXC-AS2能结合转录因子EZH2，以表观遗传的方式抑制p21、p27的表达，促进胃癌的恶性进展。

Objective: To explore the role of lncRNA HOXC-AS2 in facilitating the malignant progression of gastric cancer and elucidate its underlying molecular mechanisms. Methods: The highly expressed lncRNA HOXC-AS2 in gastric cancer was identified by leveraging The Cancer Genome Atlas(TCGA) gastric adenocarcinoma database. A total of 98 patients who underwent gastric cancer surgery in the Affiliated People's Hospital of Jiangsu University from September 2018 to October 2021 were selected as the research subjects. The expression of HOXC-AS2 in gastric cancer tissues and corresponding adjacent tissues of the patients was detected by quantitative Real-time Polymerase Chain Reaction(qRT-PCR), and the same detection was carried out in gastric cancer cell lines. Cell function assays were performed to evaluate the impact of HOXC-AS2 on the growth, migration, and invasion abilities of gastric cancer cells. Gene Set Enrichment Analysis(GSEA) was employed to screen the signaling pathways associated with HOXC-AS2 in gastric cancer. The changes of downstream genes after HOXC-AS2 knockdown in gastric cancer cells were confirmed by qRT-PCR and Western blotting experiments. The binding between HOXC-AS2 and transcription factors was verified by RNA immunoprecipitation technology. Results: In the TCGA gastric adenocarcinoma database, the expression of HOXC-AS2 in gastric cancer tissues was significantly upregulated compared with that in adjacent tissues. QRT-PCR results demonstrated that lncRNA HOXC-AS2 exhibited a relatively high expression level in gastric cancer tissues, and its high expression was significantly correlated with lymph node metastasis and tumor stage. Moreover, the expression of lncRNA HOXC-AS2 was upregulated in gastric cancer cell lines. Cell function assays revealed that the proliferation, migration, and invasion abilities of gastric cancer cells were inhibited after HOXC-AS2 knockdown. The datasets screened by GSEA were mainly associated with cell cycle, gene epigenetics, and PRC2 complex. QRT-PCR and Western blotting results indicated that after HOXC-AS2 knockdown, the expression level of EZH2 was significantly decreased, while the expression levels of p21 and p27 were increased. RNA immunoprecipitation(RIP) demonstrated that HOXC-AS2 might affect the expression of related genes by binding to EZH2. Conclusion: LncRNA HOXC-AS2 can bind to the transcription factor EZH2, epigenetically suppress the expression of p21 and p27, and promote the malignant progression of gastric cancer.

参考文献：

[1] SIEGEL R L,MILLER K D,WAGLE N S,et al.Cancer statistics,2023[J].CA Cancer J Clin,2023,73(1):17-48.
[2] XIA C,DONG X,LI H,et al.Cancer statistics in China and United States,2022:profiles,trends,and determinants[J].Chin Med J,2022,135(5):584-590.
[3] THRIFT A P,WENKER T N,EL-SERAG H B.Global burden of gastric cancer:epidemiological trends,risk factors,screening and prevention[J].Nat Rev Clin Oncol,2023,20(5):338-349.
[4] WU L,QU X.Cancer biomarker detection:recent achievements and challenges[J].Chem Soc Rev,2015,44(10):2963-2997.
[5] 张玉南,陈科,蔡晓刚,等.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[J].东南大学学报(医学版),2023,42(5):741-751.
[6] LUO Y,ZHENG S,WU Q,et al.Long noncoding RNA(lncRNA) EIF3J-DT induces chemoresistance of gastric cancer via autophagy activation[J].Autophagy,2021,17(12):4083-4101.
[7] WU Q,MA J,WEI J,et al.lncRNA SNHG11 Promotes Gastric Cancer Progression by Activating the Wnt/β-Catenin Pathway and Oncogenic Autophagy[J].Mol Ther,2021,29(3):1258-1278.
[8] YIN C,LI J,LI S,et al.LncRNA-HOXC-AS2 regulates tumor-associated macrophage polarization through the STAT1/SOCS1 and STAT1/CIITA pathways to promote the progression of non-small cell lung cancer[J].Cell Signal,2024,115:111031.
[9] XIANG Y,HUANG G,WANG J,et al.lncRNA HOXC-AS2 promotes the progression of hypopharyngeal cancer by binding to the P62 protein mediating the autophagy process[J].Aging,2023,15(21):12476-96.
[10] YAN H,BU P.Non-coding RNA in cancer[J].Essays Biochem,2021,65(4):625-639.
[11] 曹砚杰,褚菲菲,吴慧丽,等.胃癌组织中LncRNA THOR的表达及其与患者预后的关系[J].东南大学学报(医学版),2023,42(1):92-97.
[12] DONG N,GUO J,HAN S,et al.Positive feedback loop of lncRNA HOXC-AS2/miR-876-5p/ZEB1 to regulate EMT in glioma[J].Onco Targets Ther,2019,12:7601-7609.
[13] GUO J,YE F,XIE W,et al.The HOXC-AS2/miR-876-5p/HKDC1 axis regulates endometrial cancer progression in a high glucose-related tumor microenvironment[J].Cancer Sci,2022,113(7):2297-2310.
[14] HERMAN A B,TSITSIPATIS D,GOROSPE M.Integrated lncRNA function upon genomic and epigenomic regulation[J].Mol Cell,2022,82(12):2252-2266.
[15] PEIXOTO P,CARTRON P F,SERANDOUR A A,et al.From 1957 to Nowadays:A Brief History of Epigenetics[J].Int J Mol Sci,2020,21(20):7571.
[16] ZHAO L,LI M,ZHANG S,et al.Plasma-Methylated SEPT9 for the Noninvasive Diagnosis of Gastric Cancer[J].J Clin Med,2022,11(21):6399.
[17] 陈馨宁,姜惠琴,杨轶慧,等.血浆Septin9基因甲基化状态和水平在胃癌患者诊断和预后评估中的应用价值[J].中国癌症杂志,2023,33(2):162-167.
[18] SUN L,ZHANG H,GAO P.Metabolic reprogramming and epigenetic modifications on the path to cancer[J].Protein Cell,2022,13(12):877-919.
[19] DOU R,HAN L,YANG C,et al.Upregulation of LINC00501 by H3K27 acetylation facilitates gastric cancer metastasis through activating epithelial-mesenchymal transition and angiogenesis[J].Clin Transl Med,2023,13(10):e1432.
[20] HOGG S J,BEAVIS P A,DAWSON M A,et al.Targeting the epigenetic regulation of antitumour immunity[J].Nat Rev Drug Discov,2020,19(11):776-800.
[21] DUAN R,DU W,GUO W.EZH2:a novel target for cancer treatment[J].J Hematol Oncol,2020,13(1):104.
[22] HUANG B,MU P,YU Y,et al.Inhibition of EZH2 and activation of ERRγ synergistically suppresses gastric cancer by inhibiting FOXM1 signaling pathway[J].Gastric Cancer,2021,24(1):72-84.
[23] HUME S,GROU C P,LASCAUX P,et al.The NUCKS1-SKP2-p21/p27 axis controls S phase entry[J].Nat Commun,2021,12(1):6959.
[24] JIE M,WU Y,GAO M,et al.CircMRPS35 suppresses gastric cancer progression via recruiting KAT7 to govern histone modification[J].Mol Cancer,2020,19(1):56.
[25] HE X,WANG J,CHEN J,et al.lncRNA UCA1 Predicts a Poor Prognosis and Regulates Cell Proliferation and Migration by Repressing p21 and SPRY1 Expression in GC[J].Mol Ther Nucleic Acids,2019,18:605-616.

服务与反馈：

【文章下载】【发表评论】【查看评论】【加入收藏】

提示：您还未登录，请登录！点此登录