切换至 "中华医学电子期刊资源库"

中华肝脏外科手术学电子杂志 ›› 2021, Vol. 10 ›› Issue (03) : 331 -336. doi: 10.3877/cma.j.issn.2095-3232.2021.03.021

所属专题: 文献

基础研究

环状RNA circRTN4IP1在肝细胞癌中的生物信息学分析及其与预后的关系
魏英城1, 霍励耘1, 谭文亮1, 陈新明1, 陈亚进1, 商昌珍1,()   
  1. 1. 510120 广州,中山大学孙逸仙纪念医院肝胆外科
  • 收稿日期:2021-03-16 出版日期:2021-06-10
  • 通信作者: 商昌珍
  • 基金资助:
    国家自然科学基金(82072714,81972263); 中国博士后科学基金(2020M683088); 广东省自然科学基金(2018A030310118)

Bioinformatics analysis of circRTN4IP1 in hepatocellular carcinoma and its relationship with clinical prognosis

Yingcheng Wei1, Liyun Huo1, Wenliang Tan1, Xinming Chen1, Yajin Chen1, Changzhen Shang1,()   

  1. 1. Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
  • Received:2021-03-16 Published:2021-06-10
  • Corresponding author: Changzhen Shang
引用本文:

魏英城, 霍励耘, 谭文亮, 陈新明, 陈亚进, 商昌珍. 环状RNA circRTN4IP1在肝细胞癌中的生物信息学分析及其与预后的关系[J/OL]. 中华肝脏外科手术学电子杂志, 2021, 10(03): 331-336.

Yingcheng Wei, Liyun Huo, Wenliang Tan, Xinming Chen, Yajin Chen, Changzhen Shang. Bioinformatics analysis of circRTN4IP1 in hepatocellular carcinoma and its relationship with clinical prognosis[J/OL]. Chinese Journal of Hepatic Surgery(Electronic Edition), 2021, 10(03): 331-336.

目的

探讨环状RNA circRTN4IP1在肝细胞癌(HCC)中的表达及其与预后的关系。

方法

使用R软件的Limma包分析GEO数据集GSE 97332、GSE 94508、GSE 78520,联合筛选差异表达的环状RNA。通过CSCD网站预测circRTN4IP1结合的microRNA(miRNA),使用TargetScan、miRDB、miRTarBase数据库联合预测miRNA的靶基因,并对其进行基因本体(GO)功能和京都基因与基因组百科全书(KEGG)通路富集分析。应用STRING在线工具分析靶基因的功能和蛋白质相互作用(PPI)网络,筛选关键基因。采用Kaplan-Meier Plotter数据库分析其与预后的关系。收集2016年8月至2018年6月于中山大学孙逸仙纪念医院行手术切除的60例HCC患者癌组织及配对癌旁组织,荧光定量RT-PCR检测组织circRTN4IP1表达水平,并分析其与HCC患者临床病理特征和预后的关系。两组circRTN4IP1 mRNA相对表达量比较采用t检验,率的比较采用χ2检验。生存分析采用Kaplan-Meier法和Log-rank检验。

结果

GEO数据集分析筛选HCC中显著上调的circRTN4IP1,预测出其结合的60个miRNA及581个靶基因。GO和KEGG分析显示其靶基因主要参与转录、翻译、蛋白泛素化、细胞周期等生物学进程,以及p38MAPK、PI3K/AKT、FoxO及TGF-β/Smad等信号通路。共筛选出8个关键基因,其中UBE2D1、H2AFX、UBE2V1、LRRC41、POLR2D高表达的HCC患者总生存时间明显低于低表达患者(HR=1.61,1.93,1.72,1.88,1.51;P<0.05)。荧光定量RT-PCR结果显示,HCC癌组织中circRTN4IP1 mRNA平均相对表达量为0.759±0.020,明显高于癌旁组织的0.625±0.024 (t=8.385,P<0.05)。circRTN4IP1在HCC组织中的表达与AFP水平有关(χ2=4.267,P<0.05)。circRTN4IP1高表达组患者的无病生存明显差于低表达组(χ2=5.055,P<0.05)。

结论

circRTN4IP1在HCC中高表达,可能通过上调靶基因UBE2D1、H2AFX、UBE2V1、LRRC41、POLR2D参与调控HCC的发生、发展,是潜在的预后标志物及治疗靶点。

Objective

To explore the expression of circular RNA circRTN4IP1 in hepatocellular carcinoma (HCC) and its relationship with clinical prognosis.

Methods

GEO datasets of GSE 97332, GSE 94508 and GSE 78520 were analyzed using Limma package of R software, and the differentially-expressed circular RNAs were screened. The combining microRNAs (miRNAs) of circRTN4IP1 were predicted on CSCD website. The target genes of miRNA were jointly predicted through TargetScan, miRDB and miRTarBase databases and then subjected to gene ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. The function of target genes and protein-protein interaction (PPI) network were analyzed using STRING online tool, and the key genes were selected. The relationship between the genes and prognosis was analyzed by Kaplan-Meier Plotter database. The cancer tissues and paired adjacent tissues were collected from 60 HCC patients who underwent surgical resection in Sun Yat-sen Memorial Hospital of Sun Yat-sen University from August 2016 to June 2018. The expression level of circRTN4IP1 in the tissues was detected by fluorescence quantitative RT-PCR, and its relationship with the clinicopathological features and prognosis of HCC patients was analyzed. The relative expression levels of circRTN4IP1 mRNA were compared between two groups by t test, and the rate was statistically compared by Chi-square test. Survival analysis was performed with Kaplan-Meier method and Log-rank test.

Results

Significantly up-regulated circRTN4IP1 in HCC was screened out by GEO datasets and its 60 combining miRNAs and 581 target genes were found. GO and KEGG analysis showed that the target genes were mainly involved in the transcription, translation, protein ubiquitination, cell cycle and other biological processes, as well as the p38MAPK, PI3K/AKT, FoxO and TGF-β/Smad signaling pathways. 8 key genes were selected. The overall survival of HCC patients with high expression of UBE2D1, H2AFX, UBE2V1, LRRC41 and POLR2D was significantly shorter than that of HCC patients with low expression of these genes (HR=1.61, 1.93, 1.72, 1.88, 1.51; P<0.05). Fluorescence quantitative RT-PCR demonstrated that the average relative expression of circRTN4IP1 mRNA in HCC tissues was 0.759±0.020, significantly higher than 0.625±0.024 in adjacent tissues (t=8.385, P<0.05). The expression level of circRTN4IP1 was significantly correlated with the AFP level in HCC tissues (χ2=4.267, P<0.05). The disease-free survival of patients with high circRTN4IP1 expression was significantly worse compared with their counterparts with low circRTN4IP1 expression (χ2=5.055, P<0.05).

Conclusions

circRTN4IP1 is highly expressed in HCC patients, which participates in regulating the incidence and development of HCC probably by up-regulating the target genes of UBE2D1, H2AFX, UBE2V1, LRRC41 and POLR2D. circRTN4IP1 is a potential prognostic marker and therapeutic target.

图1 HCC组织差异表达的circRNA筛选
图2 circRTN4IP1下游预测靶基因的GO功能和KEGG通路富集分析
图3 circRTN4IP1下游预测靶基因PPI网络构建及关键基因筛选
图4 不同circRTN4IP1表达水平的肝细胞癌患者Kaplan-Meier生存曲线
[6]
Bachmayr-Heyda A, Reiner AT, Auer K, et al. Correlation of circular RNA abundance with proliferation--exemplified with colorectal and ovarian cancer, idiopathic lung fibrosis, and normal human tissues[J]. Sci Rep, 2015(5):8057.
[7]
Yao T, Chen Q, Fu L, et al. Circular RNAs: biogenesis, properties, roles, and their relationships with liver diseases[J]. Hepatol Res, 2017, 47(6):497-504.
[8]
Qin M, Liu G, Huo X, et al. Hsa_circ_0001649: a circular RNA and potential novel biomarker for hepatocellular carcinoma[J]. Cancer Biomark, 2016, 16(1):161-169.
[9]
Wei Y, Chen X, Liang C, et al. A noncoding regulatory RNAs network driven by circ-CDYL acts specifically in the early stages hepatocellular carcinoma[J]. Hepatology, 2020, 71(1):130-147.
[10]
Yang X, Song H, Zi Z, et al. Circ_0005075 promotes hepatocellular carcinoma progression by suppression of microRNA-335[J]. J Cell Physiol, 2019, 234(12):21937-21946.
[11]
Wang G, Liu W, Zou Y, et al. Three isoforms of exosomal circPTGR1 promote hepatocellular carcinoma metastasis via the miR449a-MET pathway[J]. EBioMedicine, 2019(40):432-445.
[12]
Xiong DD, Dang YW, Lin P, et al. A circRNA-miRNA-mRNA network identification for exploring underlying pathogenesis and therapy strategy of hepatocellular carcinoma[J]. J Transl Med, 2018, 16(1):220.
[13]
Li J, Huang Q, Long X, et al. CD147 reprograms fatty acid metabolism in hepatocellular carcinoma cells through Akt/mTOR/SREBP1c and P38/PPARα pathways[J]. J Hepatol, 2015, 63(6): 1378-1389.
[14]
Chen J, Gingold JA, Su X. Immunomodulatory TGF-β signaling in hepatocellular carcinoma[J]. Trends Mol Med, 2019, 25(11):1010-1023.
[15]
Khemlina G, Ikeda S, Kurzrock R. The biology of hepatocellular carcinoma: implications for genomic and immune therapies[J]. Mol Cancer, 2017, 16(1):149.
[16]
Hu WH, Hausmann ON, Yan MS, et al. Identification and characterization of a novel Nogo-interacting mitochondrial protein (NIMP)[J]. J Neurochem, 2002, 81(1):36-45.
[17]
Charif M, Nasca A, Thompson K, et al. Neurologic phenotypes associated with mutations in RTN4IP1 (OPA10) in children and young adults[J]. JAMA Neurol, 2018, 75(1):105-113.
[18]
Angebault C, Guichet PO, Talmat-Amar Y, et al. Recessive mutations in RTN4IP1 cause isolated and syndromic optic neuropathies[J]. Am J Hum Genet, 2015, 97(5):754-760.
[19]
Rahbari R, Kitano M, Zhang L, et al. RTN4IP1 is down-regulated in thyroid cancer and has tumor-suppressive function[J]. J Clin Endocrinol Metab, 2013, 98(3):E446-454.
[20]
Savci-Heijink CD, Halfwerk H, Koster J, et al. A specific gene expression signature for visceral organ metastasis in breast cancer[J]. BMC cancer, 2019, 19(1):333.
[1]
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020[J]. CA Cancer J Clin, 2020, 70(1):7-30.
[2]
Yu WB, Rao A, Vu V, et al. Management of centrally located hepatocellular carcinoma: update 2016[J]. World J Hepatol, 2017, 9(13):627-634.
[3]
朱思聪,谭文亮,商昌珍, 等. 分子靶向药物治疗肝细胞癌的临床应用进展[J]. 中华实验外科杂志, 2018, 35(9):1775-1777.
[4]
郭之野,黄飞舟. 中晚期肝细胞肝癌的靶向治疗:困境与希望[J]. 中国普通外科杂志, 2017, 26(1):109-115.
[5]
Chen S, Li T, Zhao Q, et al. Using circular RNA hsa_circ_0000190 as a new biomarker in the diagnosis of gastric cancer[J]. Clin Chim Acta, 2017(466):167-171.
[1] 李子禹, 卢信星, 李双喜, 陕飞. 食管胃结合部腺癌腹腔镜手术重建方式的选择[J/OL]. 中华普外科手术学杂志(电子版), 2025, 19(01): 5-8.
[2] 李乐平, 张荣华, 商亮. 腹腔镜食管胃结合部腺癌根治淋巴结清扫策略[J/OL]. 中华普外科手术学杂志(电子版), 2025, 19(01): 9-12.
[3] 许杰, 李亚俊, 韩军伟. 两种入路下腹腔镜根治性全胃切除术治疗超重胃癌的效果比较[J/OL]. 中华普外科手术学杂志(电子版), 2025, 19(01): 19-22.
[4] 李刘庆, 陈小翔, 吕成余. 全腹腔镜与腹腔镜辅助远端胃癌根治术治疗进展期胃癌的近中期随访比较[J/OL]. 中华普外科手术学杂志(电子版), 2025, 19(01): 23-26.
[5] 李华志, 曹广, 刘殿刚, 张雅静. 不同入路下行肝切除术治疗原发性肝细胞癌的临床对比[J/OL]. 中华普外科手术学杂志(电子版), 2025, 19(01): 52-55.
[6] 常小伟, 蔡瑜, 赵志勇, 张伟. 高强度聚焦超声消融术联合肝动脉化疗栓塞术治疗原发性肝细胞癌的效果及安全性分析[J/OL]. 中华普外科手术学杂志(电子版), 2025, 19(01): 56-59.
[7] 高杰红, 黎平平, 齐婧, 代引海. ETFA和CD34在乳腺癌中的表达及与临床病理参数和预后的关系研究[J/OL]. 中华普外科手术学杂志(电子版), 2025, 19(01): 64-67.
[8] 李代勤, 刘佩杰. 动态增强磁共振评估中晚期低位直肠癌同步放化疗后疗效及预后的价值[J/OL]. 中华普外科手术学杂志(电子版), 2025, 19(01): 100-103.
[9] 冯旺, 马振中, 汤林花. CT扫描三维重建在肝内胆管细胞癌腹腔镜肝切除术中的临床研究[J/OL]. 中华普外科手术学杂志(电子版), 2025, 19(01): 104-107.
[10] 陈浩, 王萌. 胃印戒细胞癌的临床病理特征及治疗选择的研究进展[J/OL]. 中华普外科手术学杂志(电子版), 2025, 19(01): 108-111.
[11] 燕速, 霍博文. 腹腔镜食管胃结合部腺癌根治性切除术[J/OL]. 中华普外科手术学杂志(电子版), 2025, 19(01): 13-13.
[12] 郭兵, 王万里, 何凯, 黄汉生. 腹腔镜下肝门部胆管癌根治术[J/OL]. 中华肝脏外科手术学电子杂志, 2025, 14(01): 143-143.
[13] 魏丽霞, 张安澜, 周宝勇, 李明. 腹腔镜下Ⅲb型肝门部胆管癌根治术[J/OL]. 中华肝脏外科手术学电子杂志, 2025, 14(01): 145-145.
[14] 王湛, 李文坤, 杨奕, 徐芳, 周敏思, 苏珈仪, 王亚丹, 吴静. 炎症指标在早发性结直肠肿瘤中的应用[J/OL]. 中华临床医师杂志(电子版), 2024, 18(09): 802-810.
[15] 刘琦, 王守凯, 王帅, 苏雨晴, 马壮, 陈海军, 司丕蕾. 乳腺癌肿瘤内微生物组的研究进展[J/OL]. 中华临床医师杂志(电子版), 2024, 18(09): 841-845.
阅读次数
全文


摘要