MicroRNA-21 is involved in ionizing radiation-promoted liver carcinogenesis.
It has been known for decades that ionizing radiation (IR) promotes carcinogenesis and high-linear energy transfer (LET) IR has a higher risk than low-LET IR for carcinogenesis; however, the mechanism remains unclear. MicroRNAs (miRNAs) have a critical effect on carcinogenesis through post-transcriptional modification. In this study, our purpose is to explore whether miRNAs are involved in IR-(especially high-LET IR) promoted liver carcinogenesis. We showed here that among several hundred miRNAs, miR-21 was the only one that increased 6 folds in high-LET IR-promoted mouse liver tumors when compared with that in the non-irradiated liver tissues. We also showed that miR-21 was up-regulated in human or mouse hepatocytes after exposure to IR, as well as in liver tissues derived from whole body irradiated mice. The increased level of miR-21 was more significant in high-LET irradiated cells or liver tissues. After the non-irradiated, low-LET or high-LET irradiated human hepatocytes were over-expressed with miR-21, these cells became tumorigenesis in nude mice. The tumors derived from high-LET-irradiated-cells were largest, and accompanied by more significant changes in the miR-21-targets: PTEN and RECK. In addition, we showed that IR-induced up-regulation of miR-21 depended on the up-regulation/activation of AP-1 (at an earlier time, within 2 h) and the ErbB/Stat3 pathway (at a later time, more than 2 h), which was also IR dose dependent. Taken together, we conclude that IR-induced up-regulation of miR-21 plays an important role in IR (especially high-LET IR)-promoted liver carcinogenesis.
Zhu
Yun
Y
Yu
Xiaoyan
X
Fu
Hanjiang
H
Wang
Hongyan
H
Wang
Ping
P
Zheng
Xiaofei
X
Wang
Ya
Y
Nature. 2005 Feb 17;433(7027):769-73
15685193
Cell. 2009 Feb 20;136(4):586-91
19239879
Annu Rev Plant Biol. 2006;57:19-53
16669754
Carcinogenesis. 2000 Mar;21(3):397-404
10688860
J Hepatol. 2010 Jul;53(1):98-107
20447717
Gastroenterology. 2007 Aug;133(2):647-58
17681183
J Biol Chem. 1997 May 16;272(20):13452-7
9148971
Cancer Cell. 2005 Jun;7(6):575-89
15950906
J Biol Chem. 1996 Dec 13;271(50):31929-36
8943238
J Biol Chem. 2007 May 11;282(19):14328-36
17363372
Mol Biol Cell. 2008 Aug;19(8):3272-82
18508928
Cancer Res. 2008 Oct 1;68(19):8164-72
18829576
Adv Space Res. 1983;3(8):241-8
11542751
Cancer Res. 2009 Oct 15;69(20):8157-65
19826040
Genome Res. 2009 Jan;19(1):92-105
18955434
Hepatology. 2009 Aug;50(2):472-80
19585654
J Biol Chem. 1995 Dec 1;270(48):28790-6
7499402
Radiat Res Suppl. 1985;8:S188-95
3867083
BMC Cancer. 2009 May 28;9:163
19473551
Radiat Res. 2004 Jul;162(1):20-30
15222780
Proc Natl Acad Sci U S A. 2009 Jul 21;106(29):12085-90
19597153
Blood. 2007 Aug 15;110(4):1330-3
17496199
J Biol Chem. 2002 Oct 11;277(41):38486-93
11940572
J Clin Oncol. 2005 May 1;23(13):2892-9
15860847
Mol Cancer. 2007 Aug 23;6:54
17716371
Oncogene. 2008 Apr 3;27(15):2128-36
17968323
Radiat Res. 1998 May;149(5):517-20
9588363
Nat Rev Cancer. 2008 Jun;8(6):465-72
18451812
Oncogene. 2006 Jun 22;25(26):3638-48
16491125
Biol Pharm Bull. 2006 May;29(5):903-6
16651716
Cancer Res. 2009 Sep 15;69(18):7165-9
19738047
DNA Cell Biol. 2010 Sep;29(9):553-61
20380575
Nat Biotechnol. 2008 Apr;26(4):462-9
18362881
Oncogene. 2006 Apr 20;25(17):2537-45
16331254
Int J Clin Exp Med. 2009 Nov 22;2(4):348-53
20057978
J Biol Chem. 2008 Jan 11;283(2):1026-33
17991735
Oncogene. 2004 Aug 23;23(38):6404-28
15322514
Proc Natl Acad Sci U S A. 1990 Aug;87(15):5663-6
2116003
Hepatology. 2008 Jun;47(6):1955-63
18433021
Radiat Oncol. 2010 Mar 26;5:25
20346162
Cancer Res. 2008 Aug 1;68(15):6416-24
18676867
J Biol Chem. 2009 Jul 3;284(27):18515-24
19419954
J Mol Biol. 2008 May 2;378(3):492-504
18384814
Development. 2007 May;134(9):1635-41
17409118
Mol Cell Biol. 2008 Sep;28(17):5369-80
18591254
Nat Rev Cancer. 2006 Nov;6(11):857-66
17060945
Science. 2005 Dec 16;310(5755):1817-21
16308420