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CN 22-1108/R
Volume 40 Issue 7
Jul.  2024
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Article Navigation >  Journal of Clinical Hepatology  > 2024  >  40(7): 1428-1437

Expression of Midkine in cholangiocarcinoma and its value in predicting prognosis based on bioinformatics analysis

DOI: 10.12449/JCH240722
  • 1.

    The PLA 307 Clinical College of Anhui Medical University，The Fifth Clinical Medical College of Anhui Medical University，Hefei 230032，China

  • 2.

    Senior Department of Hepatology，The Fifth Medical Center of Chinese PLA General Hospital，Beijing 100039，China

  • 3.

    Peking University 302 Clinical Medical School，Beijing 100039，China

  • 4.

    Senior Department of Oncology，The Fifth Medical Center of Chinese PLA General Hospital，Beijing 100071，China

Research funding:

National Science and Technology Major Project of China (2018ZX10725-506-002);

National Health Commission Medical and Health Science and Technology Development Research Center (WKZX2023CX020011);

Beijing Municipal Natural Science Foundation (7222172)

More Information
  • Corresponding author: ZENG Zhen， zengzhen1970@sina.com （ORCID： 0000-0002-1574-7196）
  • Received Date: 2024-02-01
  • Accepted Date: 2024-04-25
  • Published Date: 2024-07-25
    Abstract
  •   Objective  To investigate the expression of Midkine （MDK） in cholangiocarcinoma （CCA） and its value in predicting the prognosis of CCA， as well as the potential mechanism of the effect of MDK on the progression of CCA.  Methods  The data of CCA samples were obtained from TCGA database to analyze the difference in the expression of MDK between cancer tissue and paracancerous tissue and its association with clinical features， and the data collected from GEO database and 11 CCA patients who underwent surgical resection in The Fifth Medical Center of Chinese PLA General Hospital from June 2018 to September 2021 were used for validation. STRING and Cytoscape were used to construct a protein-protein interaction network， and gene ontology （GO） and Kyoto Encyclopedia of Genes and Genomes （KEGG） enrichment analyses were used to investigate the biological functions and tumor-related pathways involving MDK-related genes. In addition， TIMER and TISIDB databases were used to analyze the correlation between MDK expression and immune cell infiltration in CCA tissue. The independent-samples t test or the Mann-Whitney U test was used for comparison of continuous data between two groups， and the Fisher’s exact test was used for comparison of categorical data between two groups. The Kaplan-Meier method was used to plot survival curves， and the Log-rank test was used for comparison between groups. The Spearman correlation analysis was used to investigate the correlation between two variables.  Results  The expression level of MDK in cancer tissue and paracancerous tissue of CCA patients was compared based on TCGA database， and the results of the non-paired and paired analyses showed that the expression level of MDK in CCA tumor tissue was significantly higher than that in paracancerous tissue （P<0.001）. Transcriptome sequencing was performed for the tumor tissue and its corresponding paracancerous tissue from 11 CCA patients， and the results showed that the expression level of MDK in CCA tumor tissue was significantly higher than that in corresponding paracancerous tissue （P<0.01）. High expression of MDK was associated with lymph node metastasis （P=0.045） and vascular invasion （P=0.044）. Survival analysis showed that compared with the CCA patients with low MDK expression， the CCA patients with high MDK expression had significantly shorter overall survival time （χ2=5.30， P=0.028） and disease-specific survival time （χ2=6.25， P=0.019）. The GO and KEGG enrichment analyses showed that the 30 MDK-related genes were closely associated with ubiquitin-mediated proteolysis and affected the prognosis of CCA patients. The TIMER analysis showed that the expression level of MDK was positively correlated with the infiltration of B cells （r=0.356， P=0.035 6） and dendritic cells （r=0.409， P=0.014 7） in tumor microenvironment of CCA； the TISIDB analysis showed that the expression level of MDK was positively correlated with CXCL16 （r=0.465， P=0.004 67） and was negatively correlated with CXCL12 （r=-0.389， P=0.019 7） and CXCR5 （r=-0.393， P=0.018 5）， and it was also negatively correlated with the immune checkpoint regulators VTCN1 （r=-0.393， P=0.018 3）， LTA （r=-0.380， P=0.022 7）， and PVR （r=-0.350， P=0.037 3）.  Conclusion  High expression of MDK is associated with poor prognosis in CCA patients， and MDK has the potential of being used as a molecular marker for predicting the prognosis of CCA. MDK may promote the development and progression of CCA by regulating ubiquitin-mediated proteolysis and the infiltration of B cells and dendritic cells.

     

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    • References(30)
  • [1]
    GRETEN TF, SCHWABE R, BARDEESY N, et al. Immunology and immunotherapy of cholangiocarcinoma[J]. Nat Rev Gastroenterol Hepatol, 2023, 20( 6): 349- 365. DOI: 10.1038/s41575-022-00741-4.
    [2]
    BANALES JM, MARIN JJG, LAMARCA A, et al. Cholangiocarcinoma 2020: The next horizon in mechanisms and management[J]. Nat Rev Gastroenterol Hepatol, 2020, 17( 9): 557- 588. DOI: 10.1038/s41575-020-0310-z.
    [3]
    VALLE JW, KELLEY RK, NERVI B, et al. Biliary tract cancer[J]. Lancet, 2021, 397( 10272): 428- 444. DOI: 10.1016/S0140-6736(21)00153-7.
    [4]
    NAGINO M, HIRANO S, YOSHITOMI H, et al. Clinical practice guidelines for the management of biliary tract cancers 2019: The 3rd English edition[J]. J Hepatobiliary Pancreat Sci, 2021, 28( 1): 26- 54. DOI: 10.1002/jhbp.870.
    [5]
    LI Y, LI DJ, CHEN J, et al. Application of joint detection of AFP, CA19-9, CA125 and CEA in identification and diagnosis of cholangiocarcinoma[J]. Asian Pac J Cancer Prev, 2015, 16( 8): 3451- 3455. DOI: 10.7314/apjcp.2015.16.8.3451.
    [6]
    RAZUMILAVA N, GORES GJ. Cholangiocarcinoma[J]. Lancet, 2014, 383( 9935): 2168- 2179. DOI: 10.1016/S0140-6736(13)61903-0.
    [7]
    ZHANG ZZ, WANG G, YIN SH, et al. Midkine: A multifaceted driver of atherosclerosis[J]. Clin Chim Acta, 2021, 521: 251- 257. DOI: 10.1016/j.cca.2021.07.024.
    [8]
    CAMPBELL VK, GATELY RP, KRISHNASAMY R, et al. Midkine and chronic kidney disease-associated multisystem organ dysfunctions[J]. Nephrol Dial Transplant, 2021, 36( 9): 1577- 1584. DOI: 10.1093/ndt/gfaa084.
    [9]
    FILIPPOU PS, KARAGIANNIS GS, CONSTANTINIDOU A. Midkine(MDK) growth factor: A key player in cancer progression and a promising therapeutic target[J]. Oncogene, 2020, 39( 10): 2040- 2054. DOI: 10.1038/s41388-019-1124-8.
    [10]
    CHOI YW, KIM YH, LEE J, et al. Strong immunoexpression of midkine is associated with multiple lymph node metastases in BRAFV600E papillary thyroid carcinoma[J]. Hum Pathol, 2015, 46( 10): 1557- 1565. DOI: 10.1016/j.humpath.2015.06.018.
    [11]
    GÜNGÖR C, ZANDER H, EFFENBERGER KE, et al. Notch signaling activated by replication stress-induced expression of midkine drives epithelial-mesenchymal transition and chemoresistance in pancreatic cancer[J]. Cancer Res, 2011, 71( 14): 5009- 5019. DOI: 10.1158/0008-5472.CAN-11-0036.
    [12]
    YAO X, WANG X, WANG ZS, et al. Clinicopathological and prognostic significance of epithelial mesenchymal transition-related protein expression in intrahepatic cholangiocarcinoma[J]. Onco Targets Ther, 2012, 5: 255- 261. DOI: 10.2147/OTT.S36213.
    [13]
    ZHANG YJ, ZUO CM, LIU LG, et al. Single-cell RNA-sequencing atlas reveals an MDK-dependent immunosuppressive environment in ErbB pathway-mutated gallbladder cancer[J]. J Hepatol, 2021, 75( 5): 1128- 1141. DOI: 10.1016/j.jhep.2021.06.023.
    [14]
    WANG D, BU F, ZHANG WW. The role of ubiquitination in regulating embryonic stem cell maintenance and cancer development[J]. Int J Mol Sci, 2019, 20( 11): 2667. DOI: 10.3390/ijms20112667.
    [15]
    CHEN Y, XU X, WANG YR, et al. Hypoxia-induced SKA3 promoted cholangiocarcinoma progression and chemoresistance by enhancing fatty acid synthesis via the regulation of PAR-dependent HIF-1a deubiquitylation[J]. J Exp Clin Cancer Res, 2023, 42( 1): 265. DOI: 10.1186/s13046-023-02842-7.
    [16]
    CEREZO-WALLIS D, CONTRERAS-ALCALDE M, TROULÉ K, et al. Midkine rewires the melanoma microenvironment toward a tolerogenic and immune-resistant state[J]. Nat Med, 2020, 26( 12): 1865- 1877. DOI: 10.1038/s41591-020-1073-3.
    [17]
    ZHAO SL, WANG HJ, NIE YZ, et al. Midkine upregulates MICA/B expression in human gastric cancer cells and decreases natural killer cell cytotoxicity[J]. Cancer Immunol Immunother, 2012, 61( 10): 1745- 1753. DOI: 10.1007/s00262-012-1235-3.
    [18]
    GUO XF, PAN Y, XIONG M, et al. Midkine activation of CD8+ T cells establishes a neuron-immune-cancer axis responsible for low-grade glioma growth[J]. Nat Commun, 2020, 11( 1): 2177. DOI: 10.1038/s41467-020-15770-3.
    [19]
    FLORES-BORJA F, BLAIR P. Mechanisms of induction of regulatory B cells in the tumour microenvironment and their contribution to immunosuppression and pro-tumour responses[J]. Clin Exp Immunol, 2022, 209( 1): 33- 45. DOI: 10.1093/cei/uxac029.
    [20]
    SHANG J, ZHA HR, SUN YF. Phenotypes, functions, and clinical relevance of regulatory B cells in cancer[J]. Front Immunol, 2020, 11: 582657. DOI: 10.3389/fimmu.2020.582657.
    [21]
    MICHAUD D, STEWARD CR, MIRLEKAR B, et al. Regulatory B cells in cancer[J]. Immunol Rev, 2021, 299( 1): 74- 92. DOI: 10.1111/imr.12939.
    [22]
    KATOPODI T, PETANIDIS S, CHARALAMPIDIS C, et al. Tumor-infiltrating dendritic cells: Decisive roles in cancer immunosurveillance, immunoediting, and tumor T cell tolerance[J]. Cells, 2022, 11( 20): 3183. DOI: 10.3390/cells11203183.
    [23]
    MOLLICA POETA V, MASSARA M, CAPUCETTI A, et al. Chemokines and chemokine receptors: New targets for cancer immunotherapy[J]. Front Immunol, 2019, 10: 379. DOI: 10.3389/fimmu.2019.00379.
    [24]
    KORBECKI J, BAJDAK-RUSINEK K, KUPNICKA P, et al. The role of CXCL16 in the pathogenesis of cancer and other diseases[J]. Int J Mol Sci, 2021, 22( 7): 3490. DOI: 10.3390/ijms22073490.
    [25]
    MEZZAPELLE R, LEO M, CAPRIOGLIO F, et al. CXCR4/CXCL12 activities in the tumor microenvironment and implications for tumor immunotherapy[J]. Cancers, 2022, 14( 9): 2314. DOI: 10.3390/cancers14092314.
    [26]
    SILIŅA K, SOLTERMANN A, ATTAR FM, et al. Germinal centers determine the prognostic relevance of tertiary lymphoid structures and are impaired by corticosteroids in lung squamous cell carcinoma[J]. Cancer Res, 2018, 78( 5): 1308- 1320. DOI: 10.1158/0008-5472.CAN-17-1987.
    [27]
    XIE N, CAI JB, ZHANG L, et al. Upregulation of B7-H4 promotes tumor progression of intrahepatic cholangiocarcinoma[J]. Cell Death Dis, 2017, 8( 12): 3205. DOI: 10.1038/s41419-017-0015-6.
    [28]
    KAMIYA T, OHTANI N. The role of immune cells in the liver tumor microenvironment: An involvement of gut microbiota-derived factors[J]. Int Immunol, 2022, 34( 9): 467- 474. DOI: 10.1093/intimm/dxac020.
    [29]
    QU P, HUANG XJ, ZHOU XC, et al. Loss of CD155 expression predicts poor prognosis in hepatocellular carcinoma[J]. Histopathology, 2015, 66( 5): 706- 714. DOI: 10.1111/his.12584.
    [30]
    DU XN, ALMEIDA PD, MANIERI N, et al. CD226 regulates natural killer cell antitumor responses via phosphorylation-mediated inactivation of transcription factor FOXO1[J]. Proc Natl Acad Sci U S A, 2018, 115( 50): E11731- E11740. DOI: 10.1073/pnas.1814052115.
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