Carcinogenesis, Vol. 22, No. 9, 1363-1371,
September 2001
© 2001 Oxford University Press
CANCER BIOLOGY |
Hepatocyte growth factor signalling stimulates hypoxia inducible factor-1 (HIF-1) activity in HepG2 hepatoma cells
Institute of General Pathology and CNR Center for Research on Cell Pathology, University of Milan, via L.Mangiagalli, 31-20133 Milan, Italy
Hepatocyte growth factor (HGF), a multifunctional cytokine of mesenchymal origin, activates the DNA binding of hypoxia inducible factor-1 (HIF-1) in the HepG2 cell line: the activated complex contained the inducible 
subunit. An increased expression of HIF-1 (mRNA and nuclear protein levels) was observed. To investigate the molecular basis of the HIF-1 response under this non-hypoxic condition, we evaluated first the expression of putative target genes. We found a time-dependent increase in steady-state mRNA levels of heme oxygenase and urokinase plasminogen activator at 4 h, followed by that of urokinase receptor at 10 h. The enhanced expression of these genes might confer the invasive phenotype, since HGF is a proliferative and scatter factor. Second, we examined some aspects of HIF-1 activity regulation in HGF-treated cells with the following findings: (i) the activation of HIF-1 DNA binding was prevented by proteasome blockade, probably because stabilization of the cytosolic -subunit protein level is not sufficient to generate a functional form: also under these conditions nuclear protein level of HIF-1 did not increase; (ii) N-acetylcysteine, a free radical scavenger, strongly decreased HIF-1 activation suggesting a role of reactive oxygen species in this process; (iii) the thiol reducing agent dithiothreitol was ineffective. Third, consistent with these data, N-acetylcysteine reduced the stimulatory effect of HGF on stress kinase activities, while p42/44 mitogen activated kinase (MAPK) was unmodified, suggesting an involvement of c-Jun-N-terminal kinase (JNK) and p38 MAPK in HIF-1 activation. Finally, LY 294002 induced the blockade of phosphatidylinositol 3-kinase (PI3K), one of the principal transducers of HGF/Met receptor signalling, prevented the enhancement of HIF-1 DNA binding and JNK activity, but the inhibition of p42/44 MAPK phosphorylation with PD 98059 was ineffective. In conclusion, we suggest that HGF triggers a signal transduction cascade involving PI3K and ultimately activates HIF-1.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  E. Matteucci, P. Bendinelli, and M. A. Desiderio Nuclear localization of active HGF receptor Met in aggressive MDA-MB231 breast carcinoma cells Carcinogenesis, June 1, 2009; 30(6): 937 - 945. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. KOGA, K. KIHARA, and L. NECKERS Inhibition of Cancer Invasion and Metastasis by Targeting the Molecular Chaperone Heat-shock Protein 90 Anticancer Res, March 1, 2009; 29(3): 797 - 807. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. J. P. Deudero, C. Caramelo, M. C. Castellanos, F. Neria, R. Fernandez-Sanchez, O. Calabia, S. Penate, and F. R. Gonzalez-Pacheco Induction of Hypoxia-inducible Factor 1{alpha} Gene Expression by Vascular Endothelial Growth Factor J. Biol. Chem., April 25, 2008; 283(17): 11435 - 11444. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Dulak, J. Deshane, A. Jozkowicz, and A. Agarwal Heme Oxygenase-1 and Carbon Monoxide in Vascular Pathobiology: Focus on Angiogenesis Circulation, January 15, 2008; 117(2): 231 - 241. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Ide, Y. Kitajima, A. Miyoshi, T. Ohtsuka, M. Mitsuno, K. Ohtaka, and K. Miyazaki The Hypoxic Environment in Tumor-Stromal Cells Accelerates Pancreatic Cancer Progression via the Activation of Paracrine Hepatocyte Growth Factor/c-Met Signaling Ann. Surg. Oncol., September 1, 2007; 14(9): 2600 - 2607. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Matteucci, E. Ridolfi, P. Maroni, P. Bendinelli, and M. A. Desiderio c-Src/Histone Deacetylase 3 Interaction Is Crucial for Hepatocyte Growth Factor Dependent Decrease of CXCR4 Expression in Highly Invasive Breast Tumor Cells Mol. Cancer Res., August 1, 2007; 5(8): 833 - 845. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. De Ponti, R. Carini, E. Alchera, M. P. Nitti, M. Locati, E. Albano, G. Cairo, and L. Tacchini Adenosine A2a receptor-mediated, normoxic induction of HIF-1 through PKC and PI-3K-dependent pathways in macrophages J. Leukoc. Biol., August 1, 2007; 82(2): 392 - 402. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Maroni, P. Bendinelli, E. Matteucci, and M. A. Desiderio HGF induces CXCR4 and CXCL12-mediated tumor invasion through Ets1 and NF-{kappa}B Carcinogenesis, February 1, 2007; 28(2): 267 - 279. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Ramanathan, G. Pinhal-Enfield, I. Hao, and S. J. Leibovich Synergistic Up-Regulation of Vascular Endothelial Growth Factor (VEGF) Expression in Macrophages by Adenosine A2A Receptor Agonists and Endotoxin Involves Transcriptional Regulation via the Hypoxia Response Element in the VEGF Promoter Mol. Biol. Cell, January 1, 2007; 18(1): 14 - 23. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Tanaka, M. Yamamoto, N. Hashimoto, M. Miyakoshi, S. Tamakawa, M. Yoshie, Y. Tokusashi, K. Yokoyama, Y. Yaginuma, and K. Ogawa Hypoxia-Independent Overexpression of Hypoxia-Inducible Factor 1{alpha} as an Early Change in Mouse Hepatocarcinogenesis Cancer Res., December 1, 2006; 66(23): 11263 - 11270. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Lee, S. Y. Park, E. K. Lee, C. G. Park, H. C. Chung, S. Y. Rha, Y. K. Kim, G.-U. Bae, B. K. Kim, J.-W. Han, et al. Activation of Hypoxia-Inducible Factor-1{alpha} Is Necessary for Lysophosphatidic Acid-Induced Vascular Endothelial Growth Factor Expression. Clin. Cancer Res., November 1, 2006; 12(21): 6351 - 6358. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Tammali, K. V. Ramana, S. S. Singhal, S. Awasthi, and S. K. Srivastava Aldose Reductase Regulates Growth Factor-Induced Cyclooxygenase-2 Expression and Prostaglandin E2 Production in Human Colon Cancer Cells Cancer Res., October 1, 2006; 66(19): 9705 - 9713. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Basireddy, J. T. Lindsay, A. Agarwal, and D. F. Balkovetz Epithelial cell polarity and hypoxia influence heme oxygenase-1 expression by heme in renal epithelial cells Am J Physiol Renal Physiol, October 1, 2006; 291(4): F790 - F795. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Wu and R. Wang Carbon Monoxide: Endogenous Production, Physiological Functions, and Pharmacological Applications Pharmacol. Rev., December 1, 2005; 57(4): 585 - 630. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. H. Wenger, D. P. Stiehl, and G. Camenisch Integration of Oxygen Signaling at the Consensus HRE Sci. Signal., October 18, 2005; 2005(306): re12 - re12. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. M. Emerling, L. C. Platanias, E. Black, A. R. Nebreda, R. J. Davis, and N. S. Chandel Mitochondrial Reactive Oxygen Species Activation of p38 Mitogen-Activated Protein Kinase Is Required for Hypoxia Signaling Mol. Cell. Biol., June 15, 2005; 25(12): 4853 - 4862. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. K. Lee, K. Man, J. W. Ho, X. H. Wang, R. T. Poon, C. K. Sun, K. T. Ng, I. O. Ng, R. Xu, and S. T. Fan Significance of the Rac signaling pathway in HCC cell motility: implications for a new therapeutic target Carcinogenesis, March 1, 2005; 26(3): 681 - 687. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. McMahon, F. Grondin, P. P. McDonald, D. E. Richard, and C. M. Dubois Hypoxia-enhanced Expression of the Proprotein Convertase Furin Is Mediated by Hypoxia-inducible Factor-1: IMPACT ON THE BIOACTIVATION OF PROPROTEINS J. Biol. Chem., February 25, 2005; 280(8): 6561 - 6569. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. M. Comerford, E. P. Cummins, and C. T. Taylor c-Jun NH2-Terminal Kinase Activation Contributes to Hypoxia-Inducible Factor 1{alpha}-Dependent P-Glycoprotein Expression in Hypoxia Cancer Res., December 15, 2004; 64(24): 9057 - 9061. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. F. Higgins, M. P. Biju, Y. Akai, A. Wutz, R. S. Johnson, and V. H. Haase Hypoxic induction of Ctgf is directly mediated by Hif-1 Am J Physiol Renal Physiol, December 1, 2004; 287(6): F1223 - F1232. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Tacchini, C. De Ponti, E. Matteucci, R. Follis, and M.A. Desiderio Hepatocyte growth factor-activated NF-{kappa}B regulates HIF-1 activity and ODC expression, implicated in survival, differently in different carcinoma cell lines Carcinogenesis, November 1, 2004; 25(11): 2089 - 2100. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Ma, P. Freitag, J. Zhou, B. Brune, S. Frede, and J. Fandrey Thyroid hormone induces erythropoietin gene expression through augmented accumulation of hypoxia-inducible factor-1 Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2004; 287(3): R600 - R607. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. M. Sikorski, T. Hock, N. Hill-Kapturczak, and A. Agarwal The story so far: molecular regulation of the heme oxygenase-1 gene in renal injury Am J Physiol Renal Physiol, March 1, 2004; 286(3): F425 - F441. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. H. WENGER Cellular adaptation to hypoxia: O2-sensing protein hydroxylases, hypoxia-inducible transcription factors, and O2-regulated gene expression FASEB J, August 1, 2002; 16(10): 1151 - 1162. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Arsham, D. R. Plas, C. B. Thompson, and M. C. Simon Phosphatidylinositol 3-Kinase/Akt Signaling Is Neither Required for Hypoxic Stabilization of HIF-1alpha nor Sufficient for HIF-1-dependent Target Gene Transcription J. Biol. Chem., April 19, 2002; 277(17): 15162 - 15170. [Abstract] [Full Text] [PDF]
|
|