This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yang, Z. F. Articles by Fan, S. T. Search for Related Content PubMed PubMed Citation Articles by Yang, Z. F. Articles by Fan, S. T.

The Potential Role of Hypoxia Inducible Factor 1 in Tumor Progression after Hypoxia and Chemotherapy in Hepatocellular Carcinoma

Centre for the Study of Liver Disease and Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong, China

This study investigates the possible molecular basis leading to failure in a treatment that is composed of hypoxia and chemotherapy in a rat orthotopic hepatoma model. Hypoxia was induced by hepatic artery ligation, whereas chemotherapeutic effect was achieved by intraportal injection of cisplatin. High-dose sodium salicylate was administered to achieve transcriptional blockade. Significant prolongation of animal survival was observed in the groups receiving hepatic artery ligation with cisplatin or sodium salicylate. Massive tumor cell necrosis and apoptosis were found in the ligation and all of the combined treatment groups. Up-regulation of hypoxia inducible factor 1 (HIF-1) and vascular endothelial growth factor (VEGF) at both mRNA and protein levels were detected in the groups receiving ligation and ligation with cisplatin, whereas a decreased level of von Hippel-Lindau tumor suppressor protein was identified in the group receiving ligation with cisplatin. Sodium salicylate enhanced expression of von Hippel-Lindau tumor suppressor protein but down-regulated HIF-1 and VEGF levels after ligation with or without cisplatin. An increased number of activated hepatic stellate cells in the tumors were observed in the ligation and ligation with cisplatin groups, whereas they were greatly reduced by sodium salicylate. In vitro study revealed that under hypoxic condition, both cisplatin and sodium salicylate could remarkably augment P53 and caspase 3 levels. Cisplatin stimulated HIF-1 up-regulation, whereas sodium salicylate suppressed HIF-1 expression. In conclusion, tumor progression after hypoxia and chemotherapy might be related to up-regulation of HIF-1 and subsequent VEGF production, and transcriptional blockade by sodium salicylate could enhance the therapeutic efficacy of hypoxia and chemotherapy.

This article has been cited by other articles:

				C. K. Lau, Z. F. Yang, D. W. Ho, M. N. Ng, G. C.T. Yeoh, R. T.P. Poon, and S. T. Fan An Akt/Hypoxia-Inducible Factor-1{alpha}/Platelet-Derived Growth Factor-BB Autocrine Loop Mediates Hypoxia-Induced Chemoresistance in Liver Cancer Cells and Tumorigenic Hepatic Progenitor Cells Clin. Cancer Res., May 15, 2009; 15(10): 3462 - 3471. [Abstract] [Full Text] [PDF]

				T. Amann, U. Maegdefrau, A. Hartmann, A. Agaimy, J. Marienhagen, T. S. Weiss, O. Stoeltzing, C. Warnecke, J. Scholmerich, P. J. Oefner, et al. GLUT1 Expression Is Increased in Hepatocellular Carcinoma and Promotes Tumorigenesis Am. J. Pathol., April 1, 2009; 174(4): 1544 - 1552. [Abstract] [Full Text] [PDF]

				R. J. Viola, J. M. Provenzale, F. Li, C.-Y. Li, H. Yuan, J. Tashjian, and M. W. Dewhirst In Vivo Bioluminescence Imaging Monitoring of Hypoxia-Inducible Factor 1{alpha}, a Promoter That Protects Cells, in Response to Chemotherapy Am. J. Roentgenol., December 1, 2008; 191(6): 1779 - 1784. [Abstract] [Full Text] [PDF]

				A. Weidemann, W. M. Bernhardt, B. Klanke, C. Daniel, B. Buchholz, V. Campean, K. Amann, C. Warnecke, M. S. Wiesener, K.-U. Eckardt, et al. HIF Activation Protects From Acute Kidney Injury J. Am. Soc. Nephrol., March 1, 2008; 19(3): 486 - 494. [Abstract] [Full Text] [PDF]

				T. W. Young, F. C. Mei, D. G. Rosen, G. Yang, N. Li, J. Liu, and X. Cheng Up-regulation of Tumor Susceptibility Gene 101 Protein in Ovarian Carcinomas Revealed by Proteomics Analyses Mol. Cell. Proteomics, February 1, 2007; 6(2): 294 - 304. [Abstract] [Full Text] [PDF]

				Z. F. Yang, R. T.P. Poon, Y. Liu, C. K. Lau, D. W. Ho, K. H. Tam, C. T. Lam, and S. T. Fan High doses of tyrosine kinase inhibitor PTK787 enhance the efficacy of ischemic hypoxia for the treatment of hepatocellular carcinoma: dual effects on cancer cell and angiogenesis. Mol. Cancer Ther., September 1, 2006; 5(9): 2261 - 2270. [Abstract] [Full Text] [PDF]

				N. O. Ibrahim, T. Hahn, C. Franke, D. P. Stiehl, R. Wirthner, R. H. Wenger, and D. M. Katschinski Induction of the Hypoxia-Inducible Factor System by Low Levels of Heat Shock Protein 90 Inhibitors Cancer Res., December 1, 2005; 65(23): 11094 - 11100. [Abstract] [Full Text] [PDF]

				T. Tanaka, I. Kojima, T. Ohse, R. Inagi, T. Miyata, J. R. Ingelfinger, T. Fujita, and M. Nangaku Hypoxia-inducible factor modulates tubular cell survival in cisplatin nephrotoxicity Am J Physiol Renal Physiol, November 1, 2005; 289(5): F1123 - F1133. [Abstract] [Full Text] [PDF]