Tumor Biology

, Volume 36, Issue 2, pp 737–745 | Cite as

CD105 promotes hepatocarcinoma cell invasion and metastasis through VEGF

  • Yan Li
  • Zhenhua Zhai
  • Dan Liu
  • Xinping Zhong
  • Xin Meng
  • Qingquan Yang
  • Jingang Liu
  • Hangyu Li
Research Article


Hepatocellular carcinoma (HCC) is a leading cause of cancer-related morbidity and mortality. Tumor neovascularization is necessarily required for tumor progression and metastasis. CD105 and vascular endothelial growth factor (VEGF) have separately been identified as important contributors to angiogenesis; however, it is unclear if these factors interact to promote the progression of HCC. The goal of this study was to determine the interaction between CD105 and VEGF in HCC, using HCC tissue samples and the human HCC cell line SMMC-7721. In a survey of 89 HCC tumor samples, we determined that CD105 and VEGF expressions were positively correlated with each other and expressed at a higher level in tumor cells. Furthermore, the expression of CD105 was closely related to the tumor-node-metastasis (TNM) staging of HCC, degree of tumor differentiation, portal vein invasion, and lymph node metastasis (P < 0.05). Next, we used a lentiviral system to stably overexpress CD105 in SMMC-7721 cells, which was confirmed at the messenger RNA (mRNA) and protein level. We observed that VEGF expression was increased in these cells, as was cell motility and migration, as assessed using a wound healing assay and Transwell chamber system, respectively. Using VEGF small interfering RNA (siRNA), we also demonstrated that elevated VEGF expression is required to promote increased cell motility and migration in CD105-overexpressing cells. In conclusion, we interpret our data to prove that CD105 promotes the invasion and metastases of liver cancer cells by increasing VEGF expression. These results provide a new theoretical and experimental basis for the treatment of liver cancer.


Hepatocellular carcinoma Angiogenesis Metastasis CD105 Vascular endothelial growth factor 



This work was supported by grants from the National Natural Science Foundation of China (No. 81071955) and the Scientific Research from Educational Department of Liaoning Province, China (No. 2011225019).

Conflicts of interest



  1. 1.
    Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62:10–29.CrossRefPubMedGoogle Scholar
  2. 2.
    El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;132:2557–76.CrossRefPubMedGoogle Scholar
  3. 3.
    Han ZB, Chen HY, Fan JW, et al. Up-regulation of microRNA-155 promotes cancer cell invasion and predicts poor survival of hepatocellular carcinoma following liver transplantation. J Cancer Res Clin Oncol. 2012;138:153–61.CrossRefPubMedGoogle Scholar
  4. 4.
    Mittal K, Ebos J, Rini B. Angiogenesis and the tumor microenvironment: vascular endothelial growth factor and beyond. Semin Oncol. 2014;41:235–51.CrossRefPubMedGoogle Scholar
  5. 5.
    Quackenbush EJ, Letarte M. Identification of several cell surface proteins of non-T, non-B acute lymphoblastic leukemia by using monoclonal antibodies. J Immunol. 1985;34:1276–85.Google Scholar
  6. 6.
    Seon BK, Haba A, Matsuno F, et al. Endoglin-targeted cancer therapy. Curr Drug Deliv. 2011;8:135–43.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Henry-Berger J, Mouzat K, Baron S, et al. Endoglin (CD105) expression is regulated by the liver X receptor alpha (NR1H3) in human trophoblast cell line JAR. Biol Reprod. 2008;78:968–75.CrossRefPubMedGoogle Scholar
  8. 8.
    Hsueh C, Lin JD, Wu IC, et al. Vascular endothelial growth factors and angiopoietins in presentations and prognosis of papillary thyroid carcinoma. J Surg Oncol. 2011;103:395–99.CrossRefPubMedGoogle Scholar
  9. 9.
    Scartozzi M, Faloppi L, Svegliati Baroni G, et al. VEGF and VEGFR genotyping in the prediction of clinical outcome for HCC patients receiving Sorafenib: the ALICE-1 study. Int J Cancer. 2014;135:1247–56.CrossRefPubMedGoogle Scholar
  10. 10.
    Wood LM, Pan ZK, Guirnalda P, et al. Targeting tumor vasculature with novel Listeria-based vaccines directed against CD105. Cancer Immunol Immunother. 2011;60:931–42.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Li H, Sui C, Kong F, et al. Expression of HSP70 and JNK-related proteins in human liver cancer: potential effects on clinical outcome. Dig Liver Dis. 2007;39:663–70.CrossRefPubMedGoogle Scholar
  12. 12.
    Darakhshan S, Bidmeshkipour A, Mansouri K, et al. The effects of tamoxifen in combination with tranilast on CXCL12-CXCR4 axis and invasion in breast cancer cell lines. Iran J Pharm Res. 2014;13:683–93.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Biao W, Wei X, Yan Z, Xin D. Effects of chronic aluminum exposure on memory through multiple signal transduction pathways. Environ Toxicol Pharmacol. 2010;29:308–13.CrossRefGoogle Scholar
  14. 14.
    Jain RK. Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers. J Clin Oncol. 2013;31:2205–18.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Gacche RN, Meshram RJ. Targeting tumor micro-environment for design and development of novel anti-angiogenic agents arresting tumor growth. Prog Biophys Mol Biol. 2013;113:333–54.CrossRefPubMedGoogle Scholar
  16. 16.
    Hagberg CE, Mehlem A, Falkevall A, et al. Targeting VEGF-B as a novel treatment for insulin resistance and type 2 diabetes. Nature. 2012;490:426–30.CrossRefPubMedGoogle Scholar
  17. 17.
    Kumagai Y, Sobajima J, Higashi M, et al. Angiogenesis in superficial esophageal squamous cell carcinoma: assessment of microvessel density based on immunostaining for CD34 and CD105. Jpn J Clin Oncol. 2014;44:526–33.CrossRefPubMedGoogle Scholar
  18. 18.
    Nassiri F, Cusimano MD, Scheithauer BW, et al. Endoglin (CD105): a review of its role in angiogenesis and tumor diagnosis, progression and therapy. Anticancer Res. 2011;31:2283–90.PubMedGoogle Scholar
  19. 19.
    Saroufim A, Messai Y, Hasmim M, et al. Tumoral CD105 is a novel independent prognostic marker for prognosis in clear-cell renal cell carcinoma. Br J Cancer. 2014;110:1778–84.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Cwiklnska A, Sobstyl M, Kwasniewski W, Bednarek W. Microtissue density prognostic factor evaluation based on antigens CD34 and CD 105 in ovarian cancer patients. Ann Agric Environ Med. 2013;20:838–42.PubMedGoogle Scholar
  21. 21.
    Hsieh MC, Hsu HT, Hsiao PC, et al. Role of VEGF-C gene polymorphisms in susceptibility to hepatocellular carcinoma and its pathological development. J Clin Lab Anal. 2014;28:237–44.CrossRefPubMedGoogle Scholar
  22. 22.
    Benazzi C, Al-Dissi A, Chau CH, et al. Angiogenesis in spontaneous tumors and implications for comparative tumor biology. Scientific World Journal. 2014;2014:919570.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nature. 2011;473:298–307.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Benedito R, Rocha SF, Woeste M, et al. Notch-dependent VEGFR3 upregulation allows angiogenesis without VEGF-VEGFR2 signalling. Nature. 2012;484:110–4.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Yan Li
    • 1
  • Zhenhua Zhai
    • 2
  • Dan Liu
    • 1
  • Xinping Zhong
    • 3
  • Xin Meng
    • 4
  • Qingquan Yang
    • 5
  • Jingang Liu
    • 1
  • Hangyu Li
    • 1
    • 6
  1. 1.Department of General Surgery, Affiliated Shengjing HospitalChina Medical UniversityShenyangChina
  2. 2.Department of Oncology, Tumour Angiogenesis and Microenvironment Laboratory (TAML), First Affiliated HospitalLiaoning Medical CollegeJinzhouChina
  3. 3.Department of General Surgery, First Affiliated HospitalChina Medical UniversityShenyangChina
  4. 4.Department of Biochemistry and Molecular Biology, College of Basic Medical SciencesChina Medical UniversityShenyangChina
  5. 5.Department of General Surgery, Affiliated Shenzhou HospitalShenyang Medical CollegeShenyangChina
  6. 6.Affiliated Shengjing HospitalChina Medical UniversityShenyangChina

Personalised recommendations