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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front Med    2014, Vol. 8 Issue (1) : 33-41     DOI: 10.1007/s11684-013-0301-3
The impact of hypoxia in hepatocellular carcinoma metastasis
Carmen Chak-Lui Wong, Alan Ka-Lun Kai, Irene Oi-Lin Ng()
The State Key Laboratory for Liver Research and Department of Pathology, The University of Hong Kong, Hong Kong, China
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Hypoxia is a common phenomenon in hepatocellular carcinoma (HCC). Hypoxia stabilizes transcription factor, hypoxia-inducible factor (HIF), to activate gene transcription. Expression of HIF is closely associated with metastasis and poor prognosis in HCC. HIF mediates expression of genes that are involved in every step of HCC metastasis including epithelial-mesenchymal transition, invasion of the extracellular matrix, intravasation, extravasation, and secondar y growth of the metastases. Because HIF is the central regulator of HCC metastasis, HIF inhibitors are attractive tools when used alone or as combined treatment to curb HCC metastasis. This review will summarize the current findings on the impact of hypoxia/HIF in HCC, with a particular focus on cancer metastasis.

Keywords hypoxia      hepatocellular carcinoma (HCC)      metastasis      hypoxia-inducible factor (HIF)     
Corresponding Authors: Ng Irene Oi-Lin,   
Issue Date: 26 April 2014
URL:     OR
Fig.1  Hypoxia is found in regions of HCC. Immunohistochemistry staining of pimonidazole shows hypoxic regions of HCC tumor derived from HCC cells, MHCC-97L, that were orthotopically implanted in nude mice. (A) O level reduces from peripheral to central region of the HCC tumors. Hypoxic regions are commonly found in (B) peri-necrotic regions and (C) central regions of HCC.
Fig.2  Molecular biology of hypoxia. In the presence of O (normoxia), PHDs hydroxylate HIF-1α at the proline residues that are recognized by VHL, targeting HIF-1α for ubiquitin-mediated proteosomal degradation. In the absence of O (hypoxia), HIF-1α dimerizes with HIF-1β to initiate gene transcription.
Fig.3  Hypoxia and HCC metastasis. Hypoxia regulates every step of HCC metastasis by inducing genes involved in cell motility and invasion, intravasation, extravasation, and colonization of the metastatic sites.
1 Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, Luo R, Feng J, Ye S, Yang TS, Xu J, Sun Y, Liang H, Liu J, Wang J, Tak WY, Pan H, Burock K, Zou J, Voliotis D, Guan Z. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 2009; 10(1): 25–34
doi: 10.1016/S1470-2045(08)70285-7 pmid:19095497
2 Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, H?ussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008; 359(4): 378–390
doi: 10.1056/NEJMoa0708857 pmid:18650514
3 Vaupel P, H?ckel M, Mayer A. Detection and characterization of tumor hypoxia using pO2 histography. Antioxid Redox Signal 2007; 9(8): 1221–1235
doi: 10.1089/ars.2007.1628 pmid:17536958
4 Loboda A, Jozkowicz A, Dulak J. HIF-1 and HIF-2 transcription factors—similar but not identical. Mol Cells 2010; 29(5): 435–442
doi: 10.1007/s10059-010-0067-2 pmid:20396958
5 Huang GW, Yang LY, Lu WQ. Expression of hypoxia-inducible factor 1alpha and vascular endothelial growth factor in hepatocellular carcinoma: Impact on neovascularization and survival. World J Gastroenterol 2005; 11(11): 1705–1708
6 Zhang L, Huang G, Li X, Zhang Y, Jiang Y, Shen J, Liu J, Wang Q, Zhu J, Feng X, Dong J, Qian C. Hypoxia induces epithelial-mesenchymal transition via activation of SNAI1 by hypoxia-inducible factor- 1α in hepatocellular carcinoma. BMC Cancer 2013; 13(1): 108
doi: 10.1186/1471-2407-13-108 pmid:23496980
7 Xiang ZL, Zeng ZC, Fan J, Tang ZY, Zeng HY, Gao DM. Gene expression profiling of fixed tissues identified hypoxia-inducible factor-1alpha, VEGF, and matrix metalloproteinase-2 as biomarkers of lymph node metastasis in hepatocellular carcinoma. Clin Cancer Res 2011; 17(16): 5463–5472
doi: 10.1158/1078-0432.CCR-10-3096 pmid:21712445
8 Michaelson JS, Chen LL, Silverstein MJ, Cheongsiatmoy JA, Mihm MC Jr, Sober AJ, Tanabe KK, Smith BL, Younger J. Why cancer at the primary site and in the lymph nodes contributes to the risk of cancer death. Cancer 2009; 115(21): 5084–5094
doi: 10.1002/cncr.24542 pmid:19670457
9 Xiaohong S, Huikai L, Feng W, Ti Z, Yunlong C, Qiang L. Clinical significance of lymph node metastasis in patients undergoing partial hepatectomy for hepatocellular carcinoma. World J Surg 2010; 34(5): 1028–1033
doi: 10.1007/s00268-010-0400-0 pmid:20174806
10 Tanaka H, Yamamoto M, Hashimoto N, Miyakoshi M, Tamakawa S, Yoshie M, Tokusashi Y, Yokoyama K, Yaginuma Y, Ogawa K. Hypoxia-independent overexpression of hypoxia-inducible factor 1alpha as an early change in mouse hepatocarcinogenesis. Cancer Res 2006; 66(23): 11263–11270
doi: 10.1158/0008-5472.CAN-06-1699 pmid:17145871
11 Bangoura G, Liu ZS, Qian Q, Jiang CQ, Yang GF, Jing S. Prognostic significance of HIF-2alpha/EPAS1 expression in hepatocellular carcinoma. World J Gastroenterol 2007; 13(23): 3176–3182
12 Bangoura G, Yang LY, Huang GW, Wang W. Expression of HIF-2alpha/EPAS1 in hepatocellular carcinoma. World J Gastroenterol 2004; 10(4): 525–530
13 van Malenstein H, Gevaert O, Libbrecht L, Daemen A, Allemeersch J, Nevens F, Van Cutsem E, Cassiman D, De Moor B, Verslype C, van Pelt J. A seven-gene set associated with chronic hypoxia of prognostic importance in hepatocellular carcinoma. Clin Cancer Res 2010; 16(16): 4278–4288
doi: 10.1158/1078-0432.CCR-09-3274 pmid:20592013
14 Li H, Ge C, Zhao F, Yan M, Hu C, Jia D, Tian H, Zhu M, Chen T, Jiang G, Xie H, Cui Y, Gu J, Tu H, He X, Yao M, Liu Y, Li J. Hypoxia-inducible factor 1 alpha-activated angiopoietin-like protein 4 contributes to tumor metastasis via vascular cell adhesion molecule-1/integrin β1 signaling in human hepatocellular carcinoma. Hepatology 2011; 54(3): 910–919
doi: 10.1002/hep.24479 pmid:21674552
15 van der Slot AJ, Zuurmond AM, Bardoel AF, Wijmenga C, Pruijs HE, Sillence DO, Brinckmann J, Abraham DJ, Black CM, Verzijl N, DeGroot J, Hanemaaijer R, TeKoppele JM, Huizinga TW, Bank RA. Identification of PLOD2 as telopeptide lysyl hydroxylase, an important enzyme in fibrosis. J Biol Chem 2003; 278(42): 40967–40972
doi: 10.1074/jbc.M307380200 pmid:12881513
16 Cox TR, Bird D, Baker AM, Barker HE, Ho MW, Lang G, Erler JT. LOX-mediated collagen crosslinking is responsible for fibrosis-enhanced metastasis. Cancer Res 2013; 73(6): 1721–1732
doi: 10.1158/0008-5472.CAN-12-2233 pmid:23345161
17 Condeelis J, Pollard JW. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 2006; 124(2): 263–266
doi: 10.1016/j.cell.2006.01.007 pmid:16439202
18 Noda T, Yamamoto H, Takemasa I, Yamada D, Uemura M, Wada H, Kobayashi S, Marubashi S, Eguchi H, Tanemura M, Umeshita K, Doki Y, Mori M, Nagano H. PLOD2 induced under hypoxia is a novel prognostic factor for hepatocellular carcinoma after curative resection. Liver Int 2012; 32(1): 110–118
doi: 10.1111/j.1478-3231.2011.02619.x pmid:22098155
19 Sternlicht MD, Werb Z. How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol 2001; 17(1): 463–516
doi: 10.1146/annurev.cellbio.17.1.463 pmid:11687497
20 Deryugina EI, Quigley JP. Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Rev 2006; 25(1): 9–34
doi: 10.1007/s10555-006-7886-9 pmid:16680569
21 Krishnamachary B, Berg-Dixon S, Kelly B, Agani F, Feldser D, Ferreira G, Iyer N, LaRusch J, Pak B, Taghavi P, Semenza GL. Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1. Cancer Res 2003; 63(5): 1138–1143
22 Yang S, Kim J, Ryu JH, Oh H, Chun CH, Kim BJ, Min BH, Chun JS. Hypoxia-inducible factor-2alpha is a catabolic regulator of osteoarthritic cartilage destruction. Nat Med 2010; 16(6): 687–693
doi: 10.1038/nm.2153 pmid:20495569
23 Fang JH, Zhou HC, Zeng C, Yang J, Liu Y, Huang X, Zhang JP, Guan XY, Zhuang SM. MicroRNA-29b suppresses tumor angiogenesis, invasion, and metastasis by regulating matrix metalloproteinase 2 expression. Hepatology 2011; 54(5): 1729–1740
doi: 10.1002/hep.24577 pmid:21793034
24 Arii S, Mise M, Harada T, Furutani M, Ishigami S, Niwano M, Mizumoto M, Fukumoto M, Imamura M. Overexpression of matrix metalloproteinase 9 gene in hepatocellular carcinoma with invasive potential. Hepatology 1996; 24(2): 316–322
doi: 10.1002/hep.510240206 pmid:8690399
25 Giannelli G, Bergamini C, Marinosci F, Fransvea E, Quaranta M, Lupo L, Schiraldi O, Antonaci S. Clinical role of MMP-2/TIMP-2 imbalance in hepatocellular carcinoma. Int J Cancer 2002; 97(4): 425–431
26 Padua D, Zhang XH, Wang Q, Nadal C, Gerald WL, Gomis RR, Massagué J. TGFbeta primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell 2008; 133(1): 66–77
doi: 10.1016/j.cell.2008.01.046 pmid:18394990
27 Zhang H, Wong CC, Wei H, Gilkes DM, Korangath P, Chaturvedi P, Schito L, Chen J, Krishnamachary B, Winnard PT Jr, Raman V, Zhen L, Mitzner WA, Sukumar S, Semenza GL. HIF-1-dependent expression of angiopoietin-like 4 and L1CAM mediates vascular metastasis of hypoxic breast cancer cells to the lungs. Oncogene 2012; 31(14): 1757–1770
doi: 10.1038/onc.2011.365 pmid:21860410
28 Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C, MacDonald DD, Jin DK, Shido K, Kerns SA, Zhu Z, Hicklin D, Wu Y, Port JL, Altorki N, Port ER, Ruggero D, Shmelkov SV, Jensen KK, Rafii S, Lyden D. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 2005; 438(7069): 820–827
doi: 10.1038/nature04186 pmid:16341007
29 von Marschall Z, Cramer T, H?cker M, Finkenzeller G, Wiedenmann B, Rosewicz S. Dual mechanism of vascular endothelial growth factor upregulation by hypoxia in human hepatocellular carcinoma. Gut 2001; 48(1): 87–96
doi: 10.1136/gut.48.1.87 pmid:11115828
30 Yoshiji H, Kuriyama S, Yoshii J, Ikenaka Y, Noguchi R, Hicklin DJ, Wu Y, Yanase K, Namisaki T, Kitade M, Yamazaki M, Tsujinoue H, Masaki T, Fukui H. Halting the interaction between vascular endothelial growth factor and its receptors attenuates liver carcinogenesis in mice. Hepatology 2004; 39(6): 1517–1524
doi: 10.1002/hep.20218 pmid:15185292
31 Coppola D, Szabo M, Boulware D, Muraca P, Alsarraj M, Chambers AF, Yeatman TJ. Correlation of osteopontin protein expression and pathological stage across a wide variety of tumor histologies. Clin Cancer Res 2004; 10(1 Pt 1): 184–190
32 Ye QH, Qin LX, Forgues M, He P, Kim JW, Peng AC, Simon R, Li Y, Robles AI, Chen Y, Ma ZC, Wu ZQ, Ye SL, Liu YK, Tang ZY, Wang XW. Predicting hepatitis B virus-positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning. Nat Med 2003; 9(4): 416–423
doi: 10.1038/nm843 pmid:12640447
33 Shevde LA, Das S, Clark DW, Samant RS. Osteopontin: an effector and an effect of tumor metastasis. Curr Mol Med 2010; 10(1): 71–81
doi: 10.2174/156652410791065381 pmid:20205680
34 Liu LP, Ho RL, Chen GG, Lai PB. Sorafenib inhibits hypoxia-inducible factor-1alpha synthesis: implications for antiangiogenic activity in hepatocellular carcinoma. Clin Cancer Res 2012; 18(20): 5662–5671
doi: 10.1158/1078-0432.CCR-12-0552 pmid:22929805.
35 Lee TK, Poon RT, Yuen AP, Ling MT, Wang XH, Wong YC, GuanXY, Man K, Tang ZY, Fan ST. Regulation of angiogenesis by Id-1 through hypoxia-inducible factor-1alpha-mediated vascular endothelial growth factor up-regulation in hepatocellular carcinoma. Clin Cancer Res 2006; 12(23): 6910–6919
36 Kadesch T (1993) Consequences of heteromeric interactions among helix-loop-helix proteins. Cell Growth Differ 1993; 4(1): 49–55
37 Sun BS, Dong QZ, Ye QH, Sun HJ, Jia HL, Zhu XQ, Liu DY, Chen J, Xue Q, Zhou HJ, Ren N, Qin LX. Lentiviral-mediated miRNA against osteopontin suppresses tumor growth and metastasis of human hepatocellular carcinoma. Hepatology 2008; 48(6): 1834–1842
doi: 10.1002/hep.22531 pmid:18972404
38 Zhu Y, Denhardt DT, Cao H, Sutphin PD, Koong AC, Giaccia AJ, Le QT. Hypoxia upregulates osteopontin expression in NIH-3T3 cells via a Ras-activated enhancer. Oncogene 2005; 24(43): 6555–6563
39 Fu XY, Wang HY, Tan L, Liu SQ, Cao HF, Wu MC. Overexpression of p28/gankyrin in human hepatocellular carcinoma and its clinical significance. World J Gastroenterol 2002; 8(4): 638–643
40 Higashitsuji H, Itoh K, Nagao T, Dawson S, Nonoguchi K, Kido T, Mayer RJ, Arii S, Fujita J. Reduced stability of retinoblastoma protein by gankyrin, an oncogenic ankyrin-repeat protein overexpressed in hepatomas. Nat Med 2000; 6(1): 96–99
doi: 10.1038/71600 pmid:10613832
41 Fu J, Chen Y, Cao J, Luo T, Qian YW, Yang W, Ren YB, Su B, Cao GW, Yang Y, Yan YQ, Shen F, Wu MC, Feng GS, Wang HY. p28GANK overexpression accelerates hepatocellular carcinoma invasiveness and metastasis via phosphoinositol 3-kinase/AKT/hypoxia-inducible factor-1α pathways. Hepatology 2011; 53(1): 181–192
doi: 10.1002/hep.24015 pmid:21254169
42 Liu Y, Zhang JB, Qin Y, Wang W, Wei L, Teng Y, Guo L, Zhang B, Lin Z, Liu J, Ren ZG, Ye QH, Xie Y. PROX1 promotes hepatocellular carcinoma metastasis by way of up-regulating hypoxia-inducible factor 1α expression and protein stability. Hepatology 2013; 58(2): 692–705
doi: 10.1002/hep.26398 pmid:23505027
43 Artinyan A, Nelson R, Soriano P, Chung V, Retseck J, Reynolds J, Marx H, Kim J, Wagman L Treatment response to transcatheter arterial embolization and chemoembolization in primary and metastatic tumors of the liver. HPB (Oxford) 2008; 10(6): 396–404
doi: 10.1080/13651820802356564 pmid:19088924
44 Toyama T, Nitta N, Ohta S, Tanaka T, Nagatani Y, Takahashi M, Murata K, Shiomi H, Naka S, Kurumi Y, Tani T, Tabata Y. Clinical trial of cisplatin-conjugated gelatin microspheres for patients with hepatocellular carcinoma. Jpn J Radiol 2012; 30(1): 62–68
doi: 10.1007/s11604-011-0010-2 pmid:22194039
45 Llovet JM, Real MI, Monta?a X, Planas R, Coll S, Aponte J, Ayuso C, Sala M, Muchart J, Solà R, Rodés J, Bruix J; Barcelona Liver Cancer Group. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet 2002; 359(9319): 1734–1739
doi: 10.1016/S0140-6736(02)08649-X pmid:12049862
46 Lo CM, Ngan H, Tso WK, Liu CL, Lam CM, Poon RT, Fan ST, Wong J. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 2002; 35(5): 1164–1171
doi: 10.1053/jhep.2002.33156 pmid:11981766
47 Woo HY, Jang JW, Choi JY, Bae SH, You CR, Rha SE, Lee YJ, Yoon SK, Lee CD. Tumor doubling time after initial response to transarterial chemoembolization in patients with hepatocellular carcinoma. Scand J Gastroenterol 2010; 45(3): 332–339
doi: 10.3109/00365520903456573 pmid:20001605
48 Sun X, Jiang H, Jiang X, Tan H, Meng Q, Sun B, Xu R, Krissansen GW. Antisense hypoxia-inducible factor-1alpha augments transcatheter arterial embolization in the treatment of hepatocellular carcinomas in rats. Hum Gene Ther 2009; 20(4): 314–324
doi: 10.1089/hum.2008.164 pmid:19327024
49 Brahimi-Horn MC, Chiche J, Pouysségur J. Hypoxia and cancer. J Mol Med (Berl) 2007; 85(12): 1301–1307
doi: 10.1007/s00109-007-0281-3 pmid:18026916
50 Mazzone M, Dettori D, Leite de Oliveira R, Loges S, Schmidt T, Jonckx B, Tian YM, Lanahan AA, Pollard P, Ruiz de Almodovar C, De Smet F, Vinckier S, Aragonés J, Debackere K, Luttun A, Wyns S, Jordan B, Pisacane A, Gallez B, Lampugnani MG, Dejana E, Simons M, Ratcliffe P, Maxwell P, Carmeliet P. Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization. Cell 2009; 136(5): 839–851
doi: 10.1016/j.cell.2009.01.020 pmid:19217150
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