Role of hypoxia-inducible transcription factor 1alpha for progression and chemosensitivity of murine hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is a hypervascularized tumor entity with association of arterial vessel density with poor prognosis. The hypoxia-inducible transcription factor HIF-1alpha represents a pivotal regulator of angiogenesis and is thought to determine the angiogenic nature of HCC. However, the precise role of HIF-1alpha during the pathogenesis of HCC remains elusive. We established a functional inactivation of HIF-1alpha in vitro and in vivo via RNAi and Cre/loxP-mediated recombination, respectively, to determine HIF-1alpha's role for tumor growth and chemosensitivity in transgenic and orthotopic murine HCC models. HIF-1alpha-deficient HCC cells displayed significantly reduced anchorage-independent growth and enhanced sensitivity toward etoposide, while basic cellular proliferation was unaffected. Analysis of gross tumor growth failed to detect reduced growth of HIF-1alpha-deficient tumors in the orthotopic and the transgenic HCC model, respectively. In line with the in vitro data, treatment of HIF-1alpha-deficient tumors with etoposide resulted in greater antiproliferative efficacy when compared to wild-type mice. Taken together, our study does not support a pivotal role of HIF-1alpha for tumor growth and angiogenesis in two murine HCC models. However, our data point toward a significant function of HIF-1alpha in determining chemosensitivity of HCC and therefore warrant validation of HIF-1alpha-inhibitors as adjuvant therapeutic agents in clinical studies of human HCC.
Daskalow
Katjana
K
Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353, Berlin, Germany.
Rohwer
Nadine
N
Raskopf
Esther
E
Dupuy
Evelyne
E
Kühl
Anja
A
Loddenkemper
Christoph
C
Wiedenmann
Bertram
B
Schmitz
Volker
V
Cramer
Thorsten
T
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000473:pathology*; D002460:Cell Line; D049109:Cell Proliferation; D018450:Disease Progression; D015536:Down-Regulation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic
D051795:Hypoxia-Inducible Factor 1, alpha Subunit
Cell Death Differ. 2008 Apr;15(4):621-7
18259201
Proc Natl Acad Sci U S A. 1993 May 1;90(9):4304-8
8387214
Proc Natl Acad Sci U S A. 1995 Jun 6;92(12):5510-4
7539918
J Biol Chem. 1999 Jan 1;274(1):305-15
9867845
Oncogene. 2008 Sep 11;27(40):5354-8
18490920
Cancer Res. 2006 Dec 1;66(23):11263-70
17145871
Cancer Sci. 2008 Jan;99(1):121-8
17953712
J Hepatol. 1991 Sep;13(2):227-39
1660504
Hum Gene Ther. 2003 Apr 10;14(6):509-19
12718762
Cancer J. 2008 Mar-Apr;14(2):123-7
18391618
Cell Signal. 2008 Jan;20(1):60-72
17889508
J Hepatol. 2003 Jun;38(6):793-802
12763373
Br J Cancer. 2009 Mar 10;100(5):772-81
19223895
Curr Opin Cell Biol. 1997 Oct;9(5):701-6
9330874
Exp Cell Res. 2006 Sep 10;312(15):2908-20
16844113
Eur J Radiol. 2009 Dec;72(3):505-16
18835117
Nat Rev Cancer. 2003 Oct;3(10):721-32
13130303
J Hepatol. 2004 May;40(5):787-91
15094226
Cancer Res. 2000 Aug 1;60(15):4010-5
10945599
N Engl J Med. 2008 Jul 24;359(4):378-90
18650514
Curr Opin Genet Dev. 2004 Feb;14(1):81-5
15108809
Int J Cancer. 2007 Jan 15;120(2):268-77
17066447
Mol Cancer Ther. 2008 Jul;7(7):1961-73
18645006
J Hepatol. 2008 Dec;49(6):977-84
18845354
Nat Rev Cancer. 2002 Jan;2(1):38-47
11902584
Hepatology. 2008 Oct;48(4):1312-27
18821591
Sci STKE. 2007 Oct 09;2007(407):cm8
17925579
J Hepatol. 2004 Jan;40(1):117-23
14672622
Liver. 1999 Feb;19(1):12-8
9928760
Histochem Cell Biol. 2009 Jul;132(1):21-31
19350262
Cancer Sci. 2008 Oct;99(10):2055-61
19016766
Oncogene. 2003 May 22;22(21):3213-20
12761491
Hum Pathol. 1992 Jun;23(6):619-26
1317345
Int J Oncol. 2007 Nov;31(5):1103-10
17912436
J Hepatol. 2008;48 Suppl 1:S20-37
18304676
J Mol Med (Berl). 2002 Nov;80(11):703-14
12436347
Cancer Res. 2008 Dec 15;68(24):10113-20
19074877
Cancer Res. 2004 Aug 1;64(15):5496-503
15289360
Cancer Gene Ther. 2008 Jul;15(7):449-55
18421307
Cell. 2003 Mar 7;112(5):645-57
12628185
Virology. 1992 Apr;187(2):620-6
1312272
Cancer Cell. 2003 Aug;4(2):133-46
12957288
Adv Ther. 2008 Nov;25(11):1089-104
18972075
Mol Pharmacol. 2006 Feb;69(2):411-8
16254058
World J Gastroenterol. 2007 Jun 21;13(23):3176-82
17589895