Post-transcriptional regulation of heparanase gene expression by a 3' AU-rich element.
Heparanase up-regulation was documented in an increasing number of human carcinomas, associated with poor prognosis. The purpose of the current study was to identify mechanisms responsible for heparanase induction. We provide evidence that heparanase expression is regulated at the post-transcriptional level by sequences at the 3' untranslated region (3' UTR) of the gene. Constructing the 3' UTR immediately following the heparanase cDNA reduces heparanase enzymatic activity and protein levels, resulting in decreased cellular invasion capacity. We further identified a 185-bp sequence within the 3' UTR that mediates heparanase down-regulation, and characterized an adenine (A)/uracil (U)-rich consensus element (ARE) within this region. Deletion of the entire 185-bp region or the ARE eliminated the inhibitory effect of the 3' UTR, resulting in elevated heparanase levels and formation of larger tumor xenografts indistinguishable from those produced by heparanase-overexpressing cells in terms of size, vascularization, and Akt activation. These results suggest that loss of the ARE is an important regulatory mechanism contributing to heparanase induction in human cancer.
Arvatz
Gil
G
Cancer and Vascular Biology Research Center, Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.
Barash
Uri
U
Nativ
Ofer
O
Ilan
Neta
N
Vlodavsky
Israel
I
D020413:3' Untranslated Regions / Q000235:genetics*; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation / Q000235:genetics; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020871:RNA Stability / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D000099175:Heparanase
D020413:3' Untranslated Regions; D005966:Glucuronidase; D012333:RNA, Messenger; D000099175:Heparanase
Gene. 2000 Aug 8;253(2):171-8
10940554
Clin Cancer Res. 2005 Feb 1;11(3):1028-36
15709168
Biochem Biophys Res Commun. 2007 Mar 2;354(1):33-8
17208203
Cell Cycle. 2005 Jul;4(7):908-13
15917664
J Clin Invest. 2001 Aug;108(3):341-7
11489924
Cancer Res. 2003 Dec 15;63(24):8821-6
14695198
Cell. 2009 Aug 21;138(4):673-84
19703394
Br J Pharmacol. 2007 May;151(1):1-14
17339837
J Cell Mol Med. 2007 May-Jun;11(3):427-52
17635638
Oncogene. 2005 Oct 13;24(45):6765-72
16007175
Pathophysiol Haemost Thromb. 2008;36(3-4):195-203
19176992
Proc Natl Acad Sci U S A. 2004 Sep 14;101(37):13613-7
15342912
Nat Med. 1999 Jul;5(7):803-9
10395326
Cancer Res. 2009 Mar 1;69(5):1758-67
19244131
Cancer Res. 2008 Dec 15;68(24):10077-85
19074873
Oncogene. 2003 Oct 30;22(49):7737-49
14586400
J Cell Sci. 2007 Aug 1;120(Pt 15):2479-87
17646672
Blood. 2000 Oct 1;96(7):2528-36
11001907
Clin Cancer Res. 2007 Jul 15;13(14):4069-77
17634531
Cancer Res. 2003 Nov 15;63(22):7733-41
14633698
DNA Res. 2009 Feb;16(1):45-58
19001483
Int J Cancer. 2006 Apr 1;118(7):1609-17
16217746
Nat Rev Mol Cell Biol. 2001 Apr;2(4):237-46
11283721
Biochim Biophys Acta. 2001 Mar 21;1471(3):M99-108
11250066
Curr Pharm Des. 2007;13(20):2057-73
17627539
J Cell Sci. 2004 May 1;117(Pt 11):2249-58
15126626
Cancer Res. 2006 Feb 1;66(3):1455-63
16452201
Nucleic Acids Res. 2001 Jan 1;29(1):246-54
11125104
Int J Biochem Cell Biol. 2006;38(12):2018-39
16901744
Trends Biochem Sci. 1995 Nov;20(11):465-70
8578590
FASEB J. 2010 Apr;24(4):1239-48
20007507
J Biol Chem. 1999 Aug 20;274(34):24153-60
10446189
Pathophysiol Haemost Thromb. 2006;35(1-2):116-27
16855356
Nucleic Acids Res. 2006 Jan 03;33(22):7138-50
16391004
Pharmacol Ther. 2007 Apr;114(1):56-73
17320967
Cell Biochem Funct. 2008 Aug;26(6):676-83
18646256
Oncogene. 2006 Jun 29;25(28):3939-47
16474844
J Biol Chem. 2004 May 28;279(22):23536-41
15044433
Trends Biochem Sci. 2000 Aug;25(8):349-51
10916150
Curr Med Chem. 2006;13(18):2101-11
16918340