Digestive Diseases and Sciences

, Volume 61, Issue 8, pp 2303–2314 | Cite as

RETRACTED ARTICLE: CD109 Mediates Cell Survival in Hepatocellular Carcinoma Cells

  • Guijuan Zong
  • Zhiwei Xu
  • Shusen Zhang
  • Yifen Shen
  • Huiyuan Qiu
  • Guizhou Zhu
  • Song He
  • Tao TaoEmail author
  • Xudong ChenEmail author
Original Article



Hepatocellular carcinoma (HCC) accounts for 75–80 % of primary liver cancer, and usually arises after years of liver disease. Thus it is important to understand the molecular mechanisms which drive or mediate the development of HCC.


In this work, we examined whether CD109 was associated with a poor prognosis in HCC and explored possible underlying mechanisms.


We examined the CD109 and Ki67 expression levels in 97 patients with HCC using immunohistochemistry. CD109 levels in HCC cells were down-regulated by shRNA transfection. The cycle progression and cell proliferation status of HCC cells were evaluated by flow cytometry and CCK-8 assay. The effect of CD109 on proliferation and apoptosis was investigated by western blot and TUNEL activity assays.


The CD109 protein was up-regulated in HCC tissue compared with adjacent noncancerous tissue. CD109 expression levels in the 97 patients with HCC were positively correlated with histological grade. Univariate and multivariate survival analysis revealed that CD109 was a significant predictor of overall survival among HCC patients. CD109 shRNA knockdown delayed the G1–S phase transition, abrogated cell proliferation, and increased cell apoptosis. Furthermore, CD109 impaired TGF-β/Smad signaling through control of p-smad2.


CD109 promoted HCC proliferation and predicted poor prognosis. In addition, CD109 expression was associated with anti-apoptosis in HCC cells.


CD109 HCC Prognosis Proliferation Apoptosis 



This work was supported by the National Basic Research Program of China (973 Program, No. 2012CB822104), the National Natural Science Foundation of China (No. 81202368), Technology Innovation Program of Nantong University (YKC14055, YKC15052), Technology Innovation Program of Jiangsu Province (KYZZ15_0351), and a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

10620_2016_4149_MOESM1_ESM.tif (554 kb)
Supplementary material 1 (TIFF 554 kb)
10620_2016_4149_MOESM2_ESM.doc (16 kb)
Supplementary material 2 (DOC 16 kb)


  1. 1.
    Tsao CM, et al. SOX1 functions as a tumor suppressor by antagonizing the WNT/beta-catenin signaling pathway in hepatocellular carcinoma. Hepatology. 2012;56:2277–2287.CrossRefGoogle Scholar
  2. 2.
    Cheng AS, et al. EZH2-mediated concordant repression of Wnt antagonists promotes beta-catenin-dependent hepatocarcinogenesis. Cancer Res. 2011;71:4028–4039.CrossRefGoogle Scholar
  3. 3.
    Zhang J, et al. Cancer specific long noncoding RNAs show differential expression patterns and competing endogenous RNA potential in hepatocellular carcinoma. PLoS One. 2015;10:e0141042.CrossRefGoogle Scholar
  4. 4.
    Hagikura M, et al. Correlation of pathological grade and tumor stage of urothelial carcinomas with CD109 expression. Pathol Int. 2010;60:735–743.CrossRefGoogle Scholar
  5. 5.
    Lin M, et al. Cell surface antigen CD109 is a novel member of the alpha(2) macroglobulin/C3, C4, C5 family of thioester-containing proteins. Blood. 2002;99:1683–1691.CrossRefGoogle Scholar
  6. 6.
    Hashimoto M, et al. Expression of CD109 in human cancer. Oncogene. 2004;23:3716–3720.CrossRefGoogle Scholar
  7. 7.
    Beije N, et al. Prognostic value and kinetics of circulating endothelial cells in patients with recurrent glioblastoma randomised to bevacizumab plus lomustine, bevacizumab single agent or lomustine single agent. A report from the Dutch Neuro-Oncology Group BELOB trial. Br J Cancer. 2015;113:226–231.CrossRefGoogle Scholar
  8. 8.
    Hwang SM, et al. Human platelet antigen genotyping and expression of CD109 (human platelet antigen 15) mRNA in various human cell types. Biomed Res Int. 2013;2013:946403.CrossRefGoogle Scholar
  9. 9.
    Hagiwara S, et al. Processing of CD109 by furin and its role in the regulation of TGF-beta signaling. Oncogene. 2010;29:2181–2191.CrossRefGoogle Scholar
  10. 10.
    Chan KS, et al. Identification, molecular characterization, clinical prognosis, and therapeutic targeting of human bladder tumor-initiating cells. Proc Natl Acad Sci USA. 2009;106:14016–14021.CrossRefGoogle Scholar
  11. 11.
    Ohshima Y, et al. CD109 expression levels in malignant melanoma. J Dermatol Sci. 2010;57:140–142.CrossRefGoogle Scholar
  12. 12.
    Cuppini L, et al. Prognostic value of CD109+ circulating endothelial cells in recurrent glioblastomas treated with bevacizumab and irinotecan. PLoS One. 2013;8:e74345.CrossRefGoogle Scholar
  13. 13.
    Xu Z, et al. USP11, deubiquitinating enzyme, associated with neuronal apoptosis following intracerebral hemorrhage. J Mol Neurosci. 2016;58:16–27.CrossRefGoogle Scholar
  14. 14.
    Xu Z, et al. Upregulated expression of karyopherin alpha2 is involved in neuronal apoptosis following intracerebral hemorrhage in adult rats. Cell Mol Neurobiol. 2015. [Epub ahead of print]. doi: 10.1007/s10571-015-0258-7.
  15. 15.
    Zhang S, et al. Overexpression of SYF2 correlates with enhanced cell growth and poor prognosis in human hepatocellular carcinoma. Mol Cell Biochem. 2015;410:1–9.Google Scholar
  16. 16.
    Sciarra A, et al. Morphophenotypic changes in human multistep hepatocarcinogenesis with translational implications. J Hepatol. 2016;64:87–93.CrossRefGoogle Scholar
  17. 17.
    Tan HY, et al. Autophagy-induced RelB/p52 activation mediates tumour-associated macrophage repolarisation and suppression of hepatocellular carcinoma by natural compound baicalin. Cell Death Dis. 2015;6:e1942.CrossRefGoogle Scholar
  18. 18.
    Zhang F, et al. SWATH- and iTRAQ-based quantitative proteomic analyses reveal an overexpression and biological relevance of CD109 in advanced NSCLC. J Proteomics. 2014;102:125–136.CrossRefGoogle Scholar
  19. 19.
    Dong F, et al. CD109 expression is increased in cutaneous squamous cell carcinoma. J Dermatol. 2014;41:947–949.CrossRefGoogle Scholar
  20. 20.
    Zhang JM, et al. CD109 attenuates TGF-beta1 signaling and enhances EGF signaling in SK-MG-1 human glioblastoma cells. Biochem Biophys Res Commun. 2015;459:252–258.CrossRefGoogle Scholar
  21. 21.
    Winocour S, et al. CD109, a novel TGF-beta antagonist, decreases fibrotic responses in a hypoxic wound model. Exp Dermatol. 2014;23:475–479.CrossRefGoogle Scholar
  22. 22.
    Bizet AA, et al. CD109-mediated degradation of TGF-beta receptors and inhibition of TGF-beta responses involve regulation of SMAD7 and Smurf2 localization and function. J Cell Biochem. 2012;113:238–246.CrossRefGoogle Scholar
  23. 23.
    Bizet AA, et al. The TGF-beta co-receptor, CD109, promotes internalization and degradation of TGF-beta receptors. Biochim Biophys Acta. 2011;1813:742–753.CrossRefGoogle Scholar
  24. 24.
    Yan HH, et al. CCL9 induced by TGF-beta signaling in myeloid cells enhances tumor cell survival in the premetastatic organ. Cancer Res. 2015;75:5283–5298.CrossRefGoogle Scholar
  25. 25.
    Wang XH, et al. TGF-beta1 pathway affects the protein expression of many signaling pathways, markers of liver cancer stem cells, cytokeratins, and TERT in liver cancer HepG cells. Tumour Biol. 2015. [Epub ahead of print].Google Scholar
  26. 26.
    Riemenschneider MJ, et al. TGF-ss isoforms in cancer: immunohistochemical expression and Smad-pathway-activity-analysis in thirteen major tumor types with a critical appraisal of antibody specificity and immunohistochemistry assay validity. Oncotarget. 2015;6:26770–26781.CrossRefGoogle Scholar
  27. 27.
    Dong F, et al. CD109 is a novel marker for squamous cell/adenosquamous carcinomas of the gallbladder. Diagn Pathol. 2015;10:137.CrossRefGoogle Scholar
  28. 28.
    Litvinov IV, et al. CD109 release from the cell surface in human keratinocytes regulates TGF-beta receptor expression, TGF-beta signalling and STAT3 activation: relevance to psoriasis. Exp Dermatol. 2011;20:627–632.CrossRefGoogle Scholar
  29. 29.
    van den Hoogen C, et al. High aldehyde dehydrogenase activity identifies tumor-initiating and metastasis-initiating cells in human prostate cancer. Cancer Res. 2010;70:5163–5173.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Guijuan Zong
    • 1
  • Zhiwei Xu
    • 2
    • 3
  • Shusen Zhang
    • 4
  • Yifen Shen
    • 2
  • Huiyuan Qiu
    • 2
  • Guizhou Zhu
    • 2
  • Song He
    • 1
  • Tao Tao
    • 2
    Email author
  • Xudong Chen
    • 1
    Email author
  1. 1.Department of PathologyAffiliated Cancer Hospital of Nantong UniversityNantongPeople’s Republic of China
  2. 2.Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Department of Immunology, Medical CollegeNantong UniversityNantongPeople’s Republic of China
  3. 3.Division of Regulatory Glycobiology, Institute of Molecular Biomembrane and GlycobiologyTohoku Pharmaceutical UniversitySendaiJapan
  4. 4.Department of GastroenterologyAffiliated Hospital of Nantong UniversityNantongPeople’s Republic of China

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