title: Hyperthermia-induced NDRG2 upregulation inhibits the invasion of human hepatocellular carcinoma via suppressing ERK1/2 signaling pathway.
abstract: Hyperthermia (HT) has been proven to be able to alter the invasion capacity of cancer cells. However, the detailed mechanisms responsible for the anti-metastasis effects of HT have not been elucidated. N-myc downstream-regulated gene 2 (NDRG2), as a member of the NDRG family, has been suggested to be highly responsive to various stresses and is associated with tumor suppression. The present study aimed to investigate the biological role of NDRG2 in the invasion of human hepatocellular carcinoma (HCC) cells exposed to HT. We found that NDRG2 could be induced by HT at 45°C. In addition, NDRG2 overexpression inhibited the expression of matrix metallo proteinases-2 (MMP-2) and MMP-9 as well as the invasion of HCC cells, whereas knockingdown NDRG2 reversed the anti-invasion effect of HT in vivo. Further investigation revealed that the phosphorylation level of ERK1/2, but not that of JNK and p38MAPK, was reduced in NDRG2 overexpressing cells. Moreover, the knockdown of NDRG2 expression resulted in increased cell invasion, which was rescued by treating the HepG2 cells with the ERK1/2 inhibitor PD98059, but not with the p38MAPK inhibitor SB203580 or the JNK inhibitor SP600125. Finally, the synergistic cooperation of HT at 43°C and NDRG2 expression effectively reduced cytotoxicity and promoted the anti-invasion effect of HT at 45°C. Taken together, these data suggest that NDRG2 can be induced by HT and that it mediates the HT-caused inhibition of invasion in HCC cells by suppressing the ERK1/2 signaling pathway. The combined application of constitutive NDRG2 expression with HT may yield an optimized therapeutic benefit.
authors: Department of Oncology, State Key Discipline of Cell Biology, Xijing Hospital, the Fourth Military Medical University, Shaanxi, China.
authors: Yan
authors: Y
authors: Guo
authors: Ji
authors: J
authors: Ma
authors: Lin
authors: L
authors: Wu
authors: Qianrong
authors: Q
authors: Wang
authors: Xia
authors: X
authors: Li
authors: Xiaoming
authors: X
authors: Li
authors: Yuan
authors: Y
authors: Zhang
authors: Jian
authors: J
authors: Zhang
authors: Libo
authors: L
authors: Yao
authors: Jing
authors: J
authors: Zhang
authors: Wenchao
authors: W
authors: Liu
mesh_terms: D000818:Animals; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D055785:Gene Knockdown Techniques; D056945:Hep G2 Cells; D006358:Hot Temperature; D006801:Humans; D006979:Hyperthermia, Induced; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009336:Necrosis; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D034741:RNA, Small Interfering / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C466228:NDRG2 protein, human; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins
references: Int J Oral Maxillofac Surg. 2002 Feb;31(1):84-9
references: 11936406
references: BMC Cancer. 2011 Jun 16;11:251:1-9
references: 21676268
references: Proc Natl Acad Sci U S A. 2010 Nov 23;107(47):20477-82
references: 21059928
references: Nucleic Acids Res. 2008 Sep;36(16):5335-49
references: 18689861
references: J Physiol. 2009 Apr 1;587(Pt 7):1619-34
references: 19204049
references: Cancer Res. 2010 Jan 15;70(2):832-41
references: 20068172
references: Clin Chim Acta. 2000 Jun;296(1-2):17-33
references: 10807968
references: Eur J Cancer. 2006 May;42(7):981-7
references: 16564167
references: Int J Cancer. 2003 Sep 1;106(3):342-7
references: 12845671
references: Carcinogenesis. 2009 Apr;30(4):598-605
references: 19237607
references: Cancer Lett. 2007 Oct 28;256(2):207-17
references: 17640799
references: Biochim Biophys Acta. 2010 Feb;1801(2):106-13
references: 19815093
references: Curr Opin Mol Ther. 2010 Oct;12(5):561-9
references: 20886388
references: Clin Exp Metastasis. 2000;18(2):131-8
references: 11235988
references: J Cancer Res Clin Oncol. 2005 Mar;131(3):191-8
references: 15592684
references: Int J Radiat Biol. 1990 Nov;58(5):845-58
references: 1977828
references: Biochem Biophys Res Commun. 2007 Nov 16;363(2):361-7
references: 17888401
references: Cancer Lett. 2011 Nov 1;310(1):94-100
references: 21741166
references: Science. 2002 Mar 29;295(5564):2387-92
references: 11923519
references: World J Gastroenterol. 2004 Dec 1;10(23):3518-21
references: 15526377
references: Biochem Biophys Res Commun. 2009 Jul 24;385(2):198-203
references: 19450561
references: Clin Cancer Res. 2003 Mar;9(3):1155-60
references: 12631621
references: Crit Rev Oncol Hematol. 2002 Jul;43(1):33-56
references: 12098606
references: Cancer Sci. 2003 Sep;94(9):834-9
references: 12967484
references: PLoS One. 2010 Jul 14;5(7):e11584
references: 20644732
references: BMC Cancer. 2012 Aug 27;12:370
references: 22920753
references: Exp Cell Res. 2010 Jul 15;316(12):1985-93
references: 20206160
references: J Cancer Res Clin Oncol. 1995;121(7):423-8
references: 7635873
references: Cancer Invest. 2007 Oct;25(7):574-83
references: 18027151
references: Cancer Radiother. 2005 Nov;9(6-7):464-9
references: 16236541
references: Oncol Rep. 2011 Jun;25(6):1573-9
references: 21455587
references: Cancer Res. 2008 Jun 1;68(11):4210-20
references: 18519680
references: Cell Mol Life Sci. 2010 Apr;67(8):1371-81
references: 20127388
references: Eur J Cancer. 2011 Aug;47(12):1789-97
references: 21612914
references: Oral Oncol. 2010 Feb;46(2):111-5
references: 20036606
references: Gastroenterology. 2007 Jun;132(7):2557-76
references: 17570226
references: Gene. 2012 Jul 15;503(1):48-55
references: 22565195
references: Cell Physiol Biochem. 2008;21(1-3):239-50
references: 18209490
references: Biol Pharm Bull. 2008 Jul;31(7):1316-20
references: 18591767
references: PLoS One. 2012;7(2):e32368
references: 22393400
references: Cancer. 1990 Feb 15;65(4):901-7
references: 2297661
references: Carcinogenesis. 2009 Jun;30(6):927-36
references: 19336468
references: Exp Gerontol. 2009 Jun-Jul;44(6-7):406-12
references: 19298849