Expression of hypoxia-inducible factor-1α in liver tumors after transcatheter arterial embolization in an animal model

  • Bin Liang (梁 斌)
  • Chuansheng Zheng (郑传胜)
  • Gansheng Feng (冯敢生)
  • Yong Wang (王 勇)
  • Hui Zhao (赵 辉)
  • Huimin Liang (梁惠民)
  • Enhua Xiao (肖恩华)


To examine the effect of transcatheter arterial embolization (TAE) of liver tumors on hypoxia-inducible factor-1α (HIF-1α) expression in the residual viable tumor, a total of 30 New Zealand White rabbits implanted with VX2 liver tumor were divided into 2 groups. TAE-treated group animals (n=15) were subjected to TAE with 150–250 μm polyvinyl alcohol particles. Control group animals (n=15) underwent sham embolization with distilled water. Six hours, 3 days or 7 days after TAE, the animals were sacrificed, and samples of tumor and adjacent normal liver tissue were harvested. Expression of HIF-1α protein was examined immunohistochemically. Real-time PCR was performed to examine the HIF-1α mRNA levels. Our results showed that HIF-1α protein was expressed in the VX2 tumors but not in the adjacent normal liver tissue. The HIF-1α-positive tumor cells were located predominantly at the periphery of necrotic tumor regions. The mean levels of HIF-1α protein were significantly higher in TAE-treated tumors than those in control tumors (P=0.002). Among the three sacrificing time points, the difference in increase in HIF-1α protein was significant between the two groups at the sacrificing time point of 6 h and 3 days after TAE (P=0.020, P=0.031, respectively), whereas no significant increase was noted 7 days after TAE (P=0.502). In contrast, although HIF-1α mRNA was expressed in TAE-treated and control VX2 tumors, there existed no significant difference in the HIF-1α mRNA level between the two groups (P=0.372). It is concluded that TAE of liver tumors increases the expression of HIF-1α at protein level in the residual viable tumor, which could be attributed to hypoxia generated by the procedure.

Key words

embolization hypoxia-inducible factor-1 liver neoplasms 


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  1. 1.
    Brown DB, Gould JE, Gervais DA, et al. Transcatheter therapy for hepatic malignancy: standardization of terminology and reporting criteria. J Vasc Interv Radiol, 2007,18(12):1469–1478CrossRefPubMedGoogle Scholar
  2. 2.
    Breedis C, Young G. The blood supply of neoplasms in the liver. Am J Pathol, 1954,30(5):969–977PubMedGoogle Scholar
  3. 3.
    Brown DB, Cardella JF, Sacks D, et al. Quality improvement guidelines for transhepatic arterial chemoembolization, embolization, and chemotherapeutic infusion for hepatic malignancy. J Vasc Interv Radiol, 2006,17(2 Pt 1):225–232PubMedCrossRefGoogle Scholar
  4. 4.
    Gupta S, Kobayashi S, Phongkitkarun S, et al. Effect of transcatheter hepatic arterial embolization on angiogenesis in an animal model. Invest Radiol, 2006,41(6):516–521CrossRefPubMedGoogle Scholar
  5. 5.
    Lee JK, Chung YH, Song BC, et al. Recurrences of hepatocellular carcinoma following initial remission by transcatheter arterial chemoembolization. J Gastroenterol Hepatol, 2002,17(1):52–58CrossRefPubMedGoogle Scholar
  6. 6.
    Liou TC, Shih SC, Kao CR, et al. Pulmonary metastasis of hepatocellular carcinoma associated with transarterial chemoembolization. J Hepatol, 1995,23(5):563–568CrossRefPubMedGoogle Scholar
  7. 7.
    Wang B, Xu H, Gao ZQ, et al. Increased expression of vascular endothelial growth factor in hepatocellular carcinoma after transcatheter arterial chemoembolization. Acta Radiol, 2008,49(5):523–529CrossRefPubMedGoogle Scholar
  8. 8.
    Song BC, Chung YH, Kim JA, et al. Association between insulin-like growth factor-2 and metastases after transcatheter arterial chemoembolization in patients with hepatocellular carcinoma: a prospective study. Cancer, 2001,91(12):2386–2393CrossRefPubMedGoogle Scholar
  9. 9.
    Huang J, He X, Lin X, et al. Effect of preoperative transcatheter arterial chemoembolization on tumor cell activity in hepatocellular carcinoma. Chin Med J (Engl), 2000,113(5):446–448Google Scholar
  10. 10.
    Kim YB, Park YN, Park C. Increased proliferation activities of vascular endothelial cells and tumour cells in residual hepatocellular carcinoma following transcatheter arterial embolization. Histopathology, 2001,38(2):160–166CrossRefPubMedGoogle Scholar
  11. 11.
    Kobayashi N, Ishii M, Ueno Y, et al. Co-expression of Bcl-2 protein and vascular endothelial growth factor in hepatocellular carcinomas treated by chemoembolization. Liver, 1999,19(1):25–31CrossRefPubMedGoogle Scholar
  12. 12.
    Semenza GL, Wang GL. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol, 1992,12(12): 5447–5454PubMedGoogle Scholar
  13. 13.
    Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer, 2003,3(10):721–732CrossRefPubMedGoogle Scholar
  14. 14.
    Ramsey DE, Kernagis LY, Soulen MC, et al. Chemoembolization of hepatocellular carcinoma. J Vasc Interv Radiol, 2002,13(9 Pt 2):S211–221CrossRefPubMedGoogle Scholar
  15. 15.
    Chen JH, Lin YC, Huang YS, et al. Induction of VX2 carcinoma in rabbit liver: comparison of two inoculation methods. Lab Anim, 2004,38(1):79–84CrossRefPubMedGoogle Scholar
  16. 16.
    Zhong H, De Marzo AM, Laughner E, et al. Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res, 1999,59(22):5830–5835PubMedGoogle Scholar
  17. 17.
    Schmittgen TD, Zakrajsek BA, Mills AG, et al. Quantitative reverse transcription-polymerase chain reaction to study mRNA decay: comparison of endpoint and real-time methods. Anal Biochem, 2000,285(2): 194–204CrossRefPubMedGoogle Scholar
  18. 18.
    Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer, 2003,3(10):721–732CrossRefPubMedGoogle Scholar
  19. 19.
    Yasuda S, Arii S, Mori A, et al. Hexokinase II and VEGF expression in liver tumors: correlation with hypoxia-inducible factor 1 alpha and its significance. J Hepatol, 2004,40(1):117–123CrossRefPubMedGoogle Scholar
  20. 20.
    Yang ZF, Poon RT, To J, et al. The potential role of hypoxia inducible factor 1alpha in tumor progression after hypoxia and chemotherapy in hepatocellular carcinoma. Cancer Res, 2004,64(15):5496–5503CrossRefPubMedGoogle Scholar
  21. 21.
    Wang Y, Feng GS, Qian J, et al. Effect of hepatic arterial blockage on HIF-1α and VEGF expression of transplanted hepatoma in rats. J Clin Radiol (Chinese), 2006,25(8): 775–777Google Scholar
  22. 22.
    Rhee TK, Young JY, Larson AC, et al. Effect of transcatheter arterial embolization on levels of hypoxia-inducible factor-1alpha in rabbit VX2 liver tumors. J Vasc Interv Radiol, 2007,18(5):639–645CrossRefPubMedGoogle Scholar
  23. 23.
    Virmani S, Rhee TK, Ryu RK, et al. Comparison of hypoxia-inducible factor-1alpha expression before and after transcatheter arterial embolization in rabbit VX2 liver tumors. J Vasc Interv Radiol, 2008,19(10):1483–1489CrossRefPubMedGoogle Scholar
  24. 24.
    Su C, Zhang HZ, Li WH, et al. Culture in vitro and related biological characteristics of rabbit VX2 carcinoma cells. J Fourth Mil Med Univ (Chinese), 2006,27(9):844–847Google Scholar
  25. 25.
    Serganova I, Doubrovin M, Vider J, et al. Molecular imaging of temporal dynamics and spatial heterogeneity of hypoxia-inducible factor-1 signal transduction activity in tumors in living mice. Cancer Res, 2004,64(17): 6101–6108CrossRefPubMedGoogle Scholar
  26. 26.
    Liu J, Qu R, Ogura M, et al. Real-time imaging of hypoxia-inducible factor-1 activity in tumor xenografts. J Radiat Res (Tokyo), 2005,46(1):93–102CrossRefGoogle Scholar
  27. 27.
    Kaur B, Khwaja FW, Severson EA, et al. Hypoxia and the hypoxia-inducible-factor pathway in glioma growth and angiogenesis. Neuro Oncol, 2005,7(2):134–153CrossRefPubMedGoogle Scholar
  28. 28.
    Helmlinger G, Yuan F, Dellian M, et al. Interstitial pH and pO2 gradients in solid tumors in vivo: high-resolution measurements reveal a lack of correlation. Nat Med, 1997,3(2):177–182CrossRefPubMedGoogle Scholar
  29. 29.
    Talks KL, Turley H, Gatter KC, et al. The expression and distribution of the hypoxia-inducible factors HIF-1αlpha and HIF-2alpha in normal human tissues, cancers, and tumor-associated macrophages. Am J Pathol, 2000,157(2): 411–421PubMedGoogle Scholar
  30. 30.
    Karth J, Ferrer FA, Perlman E, et al. Coexpression of hypoxia-inducible factor 1-alpha and vascular endothelial growth factor in Wilms’ tumor. J Pediatr Surg, 2000,35(12):1749–1753CrossRefPubMedGoogle Scholar
  31. 31.
    Gao W, Gao Y, Zhang G, et al. Hypoxia-induced expression of HIF-1αlpha and its target genes in umbilical venous endothelial cells of Tibetans and immigrant Han. Comp Biochem Physiol C Toxicol Pharmacol, 2005, 141(1):93–100CrossRefPubMedGoogle Scholar

Copyright information

© Huazhong University of Science and Technology and Springer Berlin Heidelberg 2009

Authors and Affiliations

  • Bin Liang (梁 斌)
    • 1
  • Chuansheng Zheng (郑传胜)
    • 1
  • Gansheng Feng (冯敢生)
    • 1
  • Yong Wang (王 勇)
    • 1
  • Hui Zhao (赵 辉)
    • 1
  • Huimin Liang (梁惠民)
    • 1
  • Enhua Xiao (肖恩华)
    • 2
  1. 1.Department of Radiology, Union Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
  2. 2.Department of Radiology, the Second Xiangya Hospital, Xiangya School of MedicineCentral South UniversityChangshaChina

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