基于整合生物信息学的肝内胆管癌关键通路和潜在生物标志物的鉴定及其诊断价值

刘波; 付婷婷; 郭晓冬; 何平; 王洪林

doi:10.16016/j.1000-5404.202011021

您当前的位置：

首页 >

文章列表页 >

基于整合生物信息学的肝内胆管癌关键通路和潜在生物标志物的鉴定及其诊断价值

基础医学 | 更新时间：2026-01-09

- 基于整合生物信息学的肝内胆管癌关键通路和潜在生物标志物的鉴定及其诊断价值
- Identification of key pathways and potential biomarkers for intrahepatic cholangiocarcinoma based on integrated bioinformatics and evaluation of their diagnostic value
- 第三军医大学学报 2021年43卷第10期页码：915-922
- 作者机构：
- 作者简介：
- 基金信息：
  
  四川省卫健委科研课题普及应用项目(18PJ568)
- DOI：10.16016/j.1000-5404.202011021
  中图分类号：
- 收稿：2020-11-04，
  
  纸质出版：2021-05-30
- 稿件说明：
移动端阅览
刘波, 付婷婷, 郭晓冬, 等. 基于整合生物信息学的肝内胆管癌关键通路和潜在生物标志物的鉴定及其诊断价值[J]. 第三军医大学学报, 2021,43(10):915-922.

Bo LIU, Tingting FU, Xiaodong GUO, et al. Identification of key pathways and potential biomarkers for intrahepatic cholangiocarcinoma based on integrated bioinformatics and evaluation of their diagnostic value[J]. Journal of Third Military Medical University, 2021, 43(10): 915-922.
刘波, 付婷婷, 郭晓冬, 等. 基于整合生物信息学的肝内胆管癌关键通路和潜在生物标志物的鉴定及其诊断价值[J]. 第三军医大学学报, 2021,43(10):915-922. DOI： 10.16016/j.1000-5404.202011021.

Bo LIU, Tingting FU, Xiaodong GUO, et al. Identification of key pathways and potential biomarkers for intrahepatic cholangiocarcinoma based on integrated bioinformatics and evaluation of their diagnostic value[J]. Journal of Third Military Medical University, 2021, 43(10): 915-922. DOI： 10.16016/j.1000-5404.202011021.

摘要

Abstract

Objective

To identify the key pathways and potential biomarkers with diagnotic value for the development of intrahepatic cholangiocarcinoma (ICC) by integrating bioinformatics analysis.

Methods

We downloaded 3 high-quality datasets of ICC gene microarray (GSE26566

GSE32879 and GSE45001) from Gene Expression Omnibus (GEO) and the high-throughput sequencing data of cholangiocarcinoma (CCA) from the Cancer Genome Atlas (TCGA) database. Differentially expressed genes (DEGs) were screened using the Limma package in R software; Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed with Cluster Profiler package. Protein-protein interaction (PPI) network analysis of DEGs was subsequently carried out using the Search Tool for the Retrieval of Interacting Genes (STRING) database and subsequently visualized with Cytoscape. In addition

the transcriptional expression of hub genes was further verified by Gene Expression Profiling Interactive Analysis (GEPIA)

and their diagnostic value was assessed by receiver operating characteristic (ROC) curve. Finally

the methylation level of the hub genes was determined using Diseasemeth 2.0.

Results

In total

382 DEGs were screened and validated

including 90 up-regulated and 292 down-regulated genes. The up-regulated genes were noticeably enriched in PI3K-Akt signaling pathway

while the down-regulated in the carbon metabolism pathway. A PPI network was constructed with 289 nodes

and 6 hub genes were identified by PPI analysis: PRSS23

LGALS1

VCAN

COL5A1

ITGB1 and EHHADH. ROC curve results showed that all the hub genes distinguished tumor tissues from non-tumorous tissues.

Conclusion

Six hub genes are identified by integrative bioinformatics analysis

which may be potential molecular biomarkers for early diagnosis of ICC.

关键词

Keywords

references

BEAL E W TUMIN D MORIS D Cohort contributions to trends in the incidence and mortality of intrahepatic cholangiocarcinoma Hepatobiliary Surg Nutr 2018 7 4 270 276 10.21037/hbsn.2018.03.16 BEAL E W, TUMIN D, MORIS D, et al . Cohort contrib utions to trends in the incidence and mortality of intrahepatic cholangiocarcinoma[J ] . Hepatobiliary Surg Nutr, 2018, 7(4): 270-276. DOI: 10.21037/hbsn.2018.03.16.

EL-DIWANY R PAWLIK T M EJAZ A Intrahepatic cholangiocarcinoma Surg Oncol Clin N Am 2019 28 4 587 599 10.1016/j.soc.2019.06.002 EL-DIWANY R, PAWLIK T M, EJAZ A. Intrahepatic cholangiocarcinoma[J]. Surg Oncol Clin N Am, 2019, 28(4): 587-599. DOI: 10.1016/j.soc.2019.06.002.

RAZUMILAVA N GORES G J Cholangiocarcinoma Lancet 2014 383 9935 2168 2179 10.1016/S0140-6736(13)61903-0 RAZUMILAVA N, GORES G J. Cholangiocarcinoma[J]. Lancet, 2014, 383(9935): 2168-2179. DOI: 10.1016/S0140-6736(13)61903-0.

BANALES J M CARDINALE V CARPINO G Expert consensus document: Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA) Nat Rev Gastroenterol Hepatol 2016 13 5 261 280 10.1038/nrgastro.2016.51 BANALES J M, CARDINALE V, CARPINO G, et al . Expert consensus document: Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA)[J ] . Nat Rev Gastroenterol Hepatol, 2016, 13(5): 261-280. DOI: 10.1038/nrgastro.2016.51.

RAHNEMAI-AZAR A A WEISBROD A DILLHOFF M Intrahepatic cholangiocarcinoma: Molecular markers for diagnosis and prognosis Surg Oncol 2017 26 2 125 137 10.1016/j.suronc.2016.12.009 RAHNEMAI-AZAR A A, WEISBROD A, DILLHOFF M, et al . Intrahepatic cholangiocarcinoma: Molecular markers for diagnosis and prognosis[J ] . Surg Oncol, 2017, 26(2): 125-137. DOI: 10.1016/j.suronc.2016.12.009.

HUANG Q X CUI J Y MA H Screening of potential biomarkers for cholangiocarcinoma by integrated analysis of microarray data sets Cancer Gene Ther 2016 23 2/3 48 53 10.1038/cgt.2015.66 HUANG Q X, CUI J Y, MA H, et al . Screening of potential biomarkers for cholangiocarcinoma by integrated analysis of microarray data sets[J ] . Cancer Gene Ther, 2016, 23(2/3): 48-53. DOI: 10.1038/cgt.2015.66.

RITCHIE M E PHIPSON B WU D Limma Powers differential expression analyses for RNA-sequencing and microarray studies Nucleic Acids Res 2015 43 7 e47 10.1093/nar/gkv007 RITCHIE M E, PHIPSON B, WU D, et al . Limma Powers differential expression analyses for RNA-sequencing and microarray studies[J ] . Nucleic Acids Res, 2015, 43(7): e47. DOI: 10.1093/nar/gkv007.

BENJAMINI Y HOCHBERG Y Controlling the false discovery rate: a practical and powerful approach to multiple testing J Royal Stat Soc B 1995 57 1 289 300 10.1111/j.2517-6161.1995.tb02031.x BENJAMINI Y, HOCHBERG Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing[J]. J Royal Stat Soc B, 1995, 57(1): 289-300. DOI: 10.1111/j.2517-6161.1995.tb02031.x.

YU G C WANG L G HAN Y Y clusterProfiler: an R package for comparing biological themes among gene clusters OMICS 2012 16 5 284 287 10.1089/omi.2011.0118 YU G C, WANG L G, HAN Y Y, et al . clusterProfiler: an R package for comparing biological themes among gene clusters[J ] . OMICS, 2012, 16(5): 284-287. DOI: 10.1089/omi.2011.0118.

SZKLARCZYK D FRANCESCHINI A WYDER S STRING v10: protein-protein interaction networks, integrated over the tree of life Nucleic Acids Res 2015 43 Database issue D447 D452 10.1093/nar/gku1003 SZKLARCZYK D, FRANCESCHINI A, WYDER S, et al . STRING v10: protein-protein interaction networks, integrated over the tree of life[J ] . Nucleic Acids Res, 2015, 43(Database issue): D447-D452. DOI: 10.1093/nar/gku1003.

SHANNON P MARKIEL A OZIER O Cytoscape: a software environment for integrated models of biomolecular interaction networks Genome Res 2003 13 11 2498 2504 10.1101/gr.1239303 SHANNON P, MARKIEL A, OZIER O, et al . Cytoscape: a software environment for integrated models of biomolecular interaction networks[J ] . Genome Res, 2003, 13(11): 2498-2504. DOI: 10.1101/gr.1239303.

TANG D YUAN Z X XUE X F High expression of Galectin-1 in pancreatic stellate cells plays a role in the development and maintenance of an immunosuppressive microenvironment in pancreatic cancer Int J Cancer 2012 130 10 2337 2348 10.1002/ijc.26290 TANG D, YUAN Z X, XUE X F, et al . High expression of Galectin-1 in pancreatic stellate cells plays a role in the development and maintenance of an immunosuppressive microenvironment in pancreatic cancer[J ] . Int J Cancer, 2012, 130(10): 2337-2348. DOI: 10.1002/ijc.26290.

ROBIN X TURCK N HAINARD A pROC: an open-source package for R and S+ to analyze and compare ROC curves BMC Bioinformatics 2011 12 77 10.1186/1471-2105-12-77 ROBIN X, TURCK N, HAINARD A, et al . pROC: an open-source package for R and S+ to analyze and compare ROC curves[J ] . BMC Bioinformatics, 2011, 12: 77. DOI: 10.1186/1471-2105-12-77.

XIONG Y C WEI Y J GU Y DiseaseMeth version 2.0: a major expansion and update of the human disease methylation database Nucleic Acids Res 2017 45 D1 D888 D895 10.1093/nar/gkw1123 XIONG Y C, WEI Y J, GU Y, et al . DiseaseMeth version 2.0: a major expansion and update of the human disease methylation database[J ] . Nucleic Acids Res, 2017, 45(D1): D888-D895. DOI: 10.1093/nar/gkw1123.

COX T R ERLER J T Remodeling and homeostasis of the extracellular matrix: implications for fibrotic diseases and cancer Dis Model Mech 2011 4 2 165 178 10.1242/dmm.004077 COX T R, ERLER J T. Remodeling and homeostasis of the extracellular matrix: implications for fibrotic diseases and cancer[J]. Dis Model Mech, 2011, 4(2): 165-178. DOI: 10.1242/dmm.004077.

PICKUP M W MOUW J K WEAVER V M The extracellular matrix modulates the hallmarks of cancer EMBO Rep 2014 15 12 1243 1253 10.15252/embr.201439246 PICKUP M W, MOUW J K, WEAVER V M. The extracellular matrix modulates the hallmarks of cancer[J]. EMBO Rep, 2014, 15(12): 1243-1253. DOI: 10.15252/embr.201439246.

JIANG J XU Y T REN H J MKRN2 inhibits migration and invasion of non-small-cell lung cancer by negatively regulating the PI3K/Akt pathway J Exp Clin Cancer Res 2018 37 1 189 10.1186/s13046-018-0855-7 JIANG J, XU Y T, REN H J, et al . MKRN2 inhibits migration and invasion of non-small-cell lung cancer by negatively regulating the PI3K/Akt pathway[J ] . J Exp Clin Cancer Res, 2018, 37(1): 189. DOI: 10.1186/s13046-018-0855-7.

SUN R J ZHAI R R MA C L Combination of aloin and metformin enhances the antitumor effect by inhibiting the growth and invasion and inducing apoptosis and autophagy in hepatocellular carcinoma through PI3K/AKT/mTOR pathway Cancer Med 2020 9 3 1141 1151 10.1002/cam4.2723 SUN R J, ZHAI R R, MA C L, et al . Combination of aloin and metformin enhances the antitumor effect by inhibiting the growth and invasion and inducing apoptosis and autophagy in hepatocellular carcinoma through PI3K/AKT/mTO R pathway[J ] . Cancer Med, 2020, 9(3): 1141-1151. DOI: 10.1002/cam4.2723.

ZHANG H J TAO J SHENG L Twist2 promotes kidney cancer cell proliferation and invasion by regulating ITGA6 and CD44 expression in the ECM-receptor interaction pathway Onco Targets Ther 2016 9 1801 1812 10.2147/OTT.S96535 ZHANG H J, TAO J, SHENG L, et al . Twist2 promotes kidney cancer cell proliferation and invasion by regulating ITGA6 and CD44 expression in the ECM-receptor interaction pathway[J ] . Onco Targets Ther, 2016, 9: 1801-1812. DOI: 10.2147/OTT.S96535.

KONIECZNA A SZCZEPAN ŃSKA A SAWIUK K Enzymes of the central carbon metabolism: are they linkers between transcription, DNA replication, and carcinogenesis? Med Hypotheses 2015 84 1 58 67 10.1016/j.mehy.2014.11.016 KONIECZNA A, SZCZEPAN ŃSKA A, SAWIUK K, et al . Enzymes of the central carbon metabolism: are they linkers between transcription, DNA replication, and carcinogenesis?[J ] . Med Hypotheses, 2015, 84(1): 58-67. DOI: 10.1016/j.mehy.2014.11.016.

CURRIE E SCHULZE A ZECHNER R Cellular fatty acid metabolism and cancer Cell Metab 2013 18 2 153 161 10.1016/j.cmet.2013.05.017 CURRIE E, SCHULZE A, ZECHNER R, et al . Cellular fatty acid metabolism and cancer[J ] . Cell Metab, 2013, 18(2): 153-161. DOI: 10.1016/j.cmet.2013.05.017.

ZAJCHOWSKI D A BARTHOLDI M F GONG Y Identification of gene expression profiles that predict the aggressive behavior of breast cancer cells Cancer Res 2001 61 13 5168 5178 ZAJCHOWSKI D A, BARTHOLDI M F, GONG Y, et al . Identification of gene expression profiles that predict the aggressive behavior of breast cancer cells[J ] . Cancer Res, 2001, 61(13): 5168-5178.

JARZAB B WIENCH M FUJAREWICZ K Gene expression profile of papillary thyroid cancer: sources of variability and diagnostic implications Cancer Res 2005 65 4 1587 1597 10.1158/0008-5472.can-04-3078 JARZAB B, WIENCH M, FUJAREWICZ K, et al . Gene expression profile of papillary thyroid cancer: sources of variability and diagnostic implications[J ] . Cancer Res, 2005, 65(4): 1587-1597. DOI: 10.1158/0008-5472.can-04-3078.

JONES S ZHANG X S PARSONS D W Core signaling pathways in human pancreatic cancers revealed by global genomic analyses Science 2008 321 5897 1801 1806 10.1126/science.1164368 JONES S, ZHANG X S, PARSONS D W, et al . Core signaling pathways in human pancreatic cancers revealed by global genomic analyses[J ] . Science, 2008, 321(5897): 1801-1806. DOI: 10.1126/science.1164368.

HAN B YANG Y CHEN J PRSS23 knockdown inhibits gastric tumorigenesis through EIF2 signaling Pharmacol Res 2019 142 50 57 10.1016/j.phrs.2019.02.008 HAN B, YANG Y, CHEN J, et al . PRSS23 knockdown inhibits gastric tumorigenesis through EIF2 signaling[J ] . Pharmacol Res, 2019, 142: 50-57. DOI: 10.1016/j.phrs.2019.02.008.

EARL L A BI S G BAUM L G Galectin multimerization and lattice formation are regulated by linker region structure Glycobiology 2011 21 1 6 12 10.1093/glycob/cwq144 EARL L A, BI S G, BAUM L G. Galectin multimerization and lattice formation are regulated by linker region structure[J]. Glycobiology, 2011, 21(1): 6-12. DOI: 10.1093/glycob/cwq144.

ZHOU X F LI D WANG X G Galectin-1 is overexpressed in CD133+ human lung adenocarcinoma cells and promotes their growth and invasiveness Oncotarget 2015 6 5 3111 3122 10.18632/oncotarget.3076 ZHOU X F, LI D, WANG X G, et al . Galectin-1 is overexpressed in CD133+ human lung adenocarcinoma cells and promotes their growth and invasiveness[J ] . Oncotarget, 2015, 6(5): 3111-3122. DOI: 10.18632/oncotarget.3076.

LEUNG Z KO F C F TEY S K Galectin-1 promotes hepatocellular carcinoma and the combined therapeutic effect of OTX008 galectin-1 inhibitor and sorafenib in tumor cells J Exp Clin Cancer Res 2019 38 1 423 10.1186/s13046-019-1402-x LEUNG Z, KO F C F, TEY S K, et al . Galectin-1 promotes hepatocellular carcinoma and the combined therapeutic effect of OTX008 galectin-1 inhibitor and sorafenib in tumor cells[J ] . J Exp Clin Cancer Res, 2019, 38(1): 423. DOI: 10.1186/s13046-019-1402-x.

ZHANG P F LI K S SHEN Y H Galectin-1 induces hepatocellular carcinoma EMT and sorafenib resistance by activating FAK/PI3K/AKT signaling Cell Death Dis 2016 7 e2201 10.1038/cddis.2015.324 ZHANG P F, LI K S, SHEN Y H, et al . Galectin-1 induces hepatocellular carcinoma EMT and sorafenib resistance by activating FAK/PI3K/AKT signaling[J ] . Cell Death Dis, 2016, 7: e2201. DOI: 10.1038/cddis.2015.324.

FOULCER S J , DAY A J , APTE S S . Isolation and purification of versican and analysis of versican proteolysis glycosaminoglycans , 2015 ( 1229 ): 587 - 604 . DOI: 10.1007/978-1-4939-1714-3_46 . FOULCER S J, DAY A J, APTE S S. Isolation and purification of versican and analysis of versican proteolysis glycosaminoglycans, 2015(1229): 587-604. DOI: 10.1007/978-1-4939-1714-3_46.

LAPIERRE D P LEE D Y LI S Z The ability of versican to simultaneously cause apoptotic resistance and sensitivity Cancer Res 2007 67 10 4742 4750 10.1158/0008-5472.can-06-3610 LAPIERRE D P, LEE D Y, LI S Z, et al . The ability of versican to simultaneously cause apoptotic resistance and sensitivity[J ] . Cancer Res, 2007, 67(10): 4742-4750. DOI: 10.1158/0008-5472.can-06-3610.

ZHANG J J YANO H SASAKI T The pro-α1(V) collagen gene (Col5a1) is coordinately regulated by miR-29b with core promoter in cultured cells Connect Tissue Res 2018 59 3 263 273 10.1080/03008207.2017.1370465 ZHANG J J, YANO H, SASAKI T, et al . The pro-α1(V) collagen gene (Col5a1) is coordinately regulated by miR-29b with core promoter in cultured cells[J ] . Connect Tissue Res, 2018, 59(3): 263-273. DOI: 10.1080/03008207.2017.1370465.

FENG G MA H M HUANG H B Overexpression of COL5A1 promotes tumor progression and metastasis and correlates with poor survival of patients with clear cell renal cell carcinoma Cancer Manag Res 2019 11 1263 1274 10.2147/cmar.s188216 FENG G, MA H M, HUANG H B, et al . Overexpression of COL5A1 promotes tumor progression and metastasis and correlates with poor survival of patients with clear cell renal cell carcinoma[J ] . Cancer Manag Res, 2019, 11: 1263-1274. DOI: 10.2147/cmar.s188216.

HYNES R O Integrins: bidirectional, allosteric signaling machines Cell 2002 110 6 673 687 10.1016/s0092-8674(02)00971-6 HYNES R O. Integrins: bidirectional, allosteric signaling machines[J]. Cell, 2002, 110(6): 673-687. DOI: 10.1016/s0092-8674(02)00971-6.

LIU M Y ZHANG Y Q YANG J X ZIP4 increases expression of transcription factor ZEB1 to promote integrin α3β1 signaling and inhibit expression of the gemcitabine transporter ENT1 in pancreatic cancer cells Gastroenterology 2020 158 3 679 692 10.1053/j.gastro.2019.10.038 LIU M Y, ZHANG Y Q, YANG J X, et al . ZIP4 increases expression of transcription factor ZEB1 to promote integrin α3β1 sign aling and inhibit expression of the gemcitabine transporter ENT1 in pancreatic cancer cells[J ] . Gastroenterology, 2020, 158(3): 679-692. e1. DOI: 10.1053/j.gastro.2019.10.038.

JIA Y Z QI C ZHANG Z Y Overexpression of peroxisome proliferator-activated receptor-alpha (PPARalpha)-regulated genes in liver in the absence of peroxisome proliferation in mice deficient in both L-and D-forms of enoyl-CoA hydratase/dehydrogenase enzymes of peroxisomal beta-oxidation system J Biol Chem 2003 278 47 47232 47239 10.1074/jbc.M306363200 JIA Y Z, QI C, ZHANG Z Y, et al . Overexpression of peroxisome proliferator-activated receptor-alpha (PPARalpha)-regulated genes in liver in the absence of peroxisome proliferation in mice deficient in both L-and D-forms of enoyl-CoA hydratase/dehydrogenase enzymes of peroxisomal beta-oxidation system[J ] . J Biol Chem, 2003, 278(47): 47232-47239. DOI: 10.1074/jbc.M306363200.

REKA A K GOSWAMI M T KRISHNAPURAM R Molecular cross-regulation between PPAR-γ and other signaling pathways: implications for lung cancer therapy Lung Cancer 2011 72 2 154 159 10.1016/j.lungcan.2011.01.019 REKA A K, GOSWAMI M T, KRISHNAPURAM R, et al . Molecular cross-regulation between PPAR-γ and other signaling pathways: implications for lung cancer therapy[J ] . Lung Cancer, 2011, 72(2): 154-159. DOI: 10.1016/j.lungcan.2011.01.019.

CHEN Y Z XUE J Y CHEN C M PPAR signaling pathway may be an important predictor of breast cancer response to neoadjuvant chemotherapy Cancer Chemother Pharmacol 2012 70 5 637 644 10.1007/s00280-012-1949-0 CHEN Y Z, XUE J Y, CHEN C M, et al . PPAR signaling pathway may be an important predictor of breast cancer response to neoadjuvant chemotherapy[J ] . Cancer Chemother Pharmacol, 2012, 70(5): 637-644. DOI: 10.1007/s00280-012-1949-0.

KONDO Y Epigenetic cross-talk between DNA methylation and histone modifications in human cancers Yonsei Med J 2009 50 4 455 463 10.3349/ymj.2009.50.4.455 KONDO Y. Epigenetic cross-talk between DNA methylation and histone modifications in human cancers[J]. Yonsei Med J, 2009, 50(4): 455-463. DOI: 10.3349/ymj.2009.50.4.455.

PESCHANSKY V J WAHLESTEDT C Non-coding RNAs as direct and indirect modulators of epigenetic regulation Epigenetics 2014 9 1 3 12 10.4161/epi.27473 PESCHANSKY V J, WAHLESTEDT C. Non-coding RNAs as direct and indirect modulators of epigenetic regulation[J]. Epigenetics, 2014, 9(1): 3-12. DOI: 10.4161/epi.27473.

浏览量

下载量

CSCD

文章被引用时，请邮件提醒。

提交

工具集

关联资源

基于普通转录组和单细胞转录组测序解析间质型胃癌复发风险相关的肿瘤细胞及微环境特征

血浆胰岛素样因子6水平与急性主动脉综合征发生风险及不良预后的相关性

转录因子LMO3对子宫内膜癌患者预后的影响

综合生物信息学分析鉴定与胃癌预后相关关键基因

8-自噬相关lncRNA模型在预测膀胱癌患者预后中的作用