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Molecular Cancer
Published in: Molecular Cancer 1/2013

Open Access 01-12-2013 | Research

Human tumor necrosis factor (TNF)-alpha-induced protein 8-like 2 suppresses hepatocellular carcinoma metastasis through inhibiting Rac1

Authors: Xuelei Cao, Li Zhang, Yongyu Shi, Yue Sun, Shen Dai, Chun Guo, Faliang Zhu, Qun wang, Jianing Wang, Xiaoyan Wang, Youhai H Chen, Lining Zhang

Published in: Molecular Cancer | Issue 1/2013

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Abstract

Background

Tumor invasion and metastasis are the major reasons for leading death of patients with hepatocellular carcinoma (HCC). Therefore, to identify molecules that can suppress invasion and metastasis of tumor will provide novel targets for HCC therapies. Tumor necrosis factor (TNF)-alpha-induced protein 8-like 2, TIPE2, is a novel immune negative molecule and an inhibitor of the oncogenic Ras in mice but its function in human is unclear. Our previous research has shown that TIPE2 is downregulated in human primary HCC compared with the paired adjacent non-tumor tissues.

Results

In present study, we provide evidence that TIPE2 inhibits effectively human hepatocellular carcinoma metastasis. The forced expression of TIPE2 in HCC-derived cell lines markedly inhibits tumor cell growth, migration and invasion in vitro and suppresses growth and metastasis of HCC in vivo. Clinical information from a cohort of 112 patients reveals that loss or reduced expression of TIPE2 in primary HCC tissues is significantly associated with tumor metastasis. Mechanically, TIPE2 inhibits the migration and invasion through targeting Rac1 and then reduces F-actin polymerization and expression of matrix metallopeptidase 9 (MMP9) and urokinase plasminogen activator (uPA).

Conclusion

Our results indicate that human TIPE2 is endogenous inhibitor of Rac1 in HCC by which it attenuates invasion and metastasis of HCC. The data suggest that TIPE2 will be a new target for HCC therapy.
Appendix
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Literature
1.
Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM: Estimates of worldwide burden of cancer in, 2008: GLOBOCAN 2008. Int J Cancer. 2008, 2010 (127): 2893-2917.
2.
Tung-Ping Poon R, Fan ST, Wong J: Risk factors, prevention, and management of postoperative recurrence after resection of hepatocellular carcinoma. Ann Surg. 2000, 232: 10-24. 10.1097/00000658-200007000-00003PubMedCentralCrossRefPubMed
3.
Sun H, Gong S, Carmody RJ, Hilliard A, Li L, Sun J, Kong L, Xu L, Hilliard B, Hu S, Shen H, Yang X, Chen YH: TIPE2, a negative regulator of innate and adaptive immunity that maintains immune homeostasis. Cell. 2008, 133: 415-426. 10.1016/j.cell.2008.03.026PubMedCentralCrossRefPubMed
4.
Zhang Y, Wei X, Liu L, Liu S, Wang Z, Zhang B, Fan B, Yang F, Huang S, Jiang F, Chen YH, Yi F: TIPE2, a novel regulator of immunity, protects against experimental stroke. J Biol Chem. 2012, 287: 32546-32555. 10.1074/jbc.M112.348755PubMedCentralCrossRefPubMed
5.
Li D, Song L, Fan Y, Li X, Li Y, Chen J, Zhu F, Guo C, Shi Y, Zhang L: Down-regulation of TIPE2 mRNA expression in peripheral blood mononuclear cells from patients with systemic lupus erythematosus. Clin Immunol. 2009, 133: 422-427. 10.1016/j.clim.2009.08.014CrossRefPubMed
6.
Xi W, Hu Y, Liu Y, Zhang J, Wang L, Lou Y, Qu Z, Cui J, Zhang G, Liang X, Ma C, Gao C, Chen Y, Liu S: Roles of TIPE2 in hepatitis B virus-induced hepatic inflammation in humans and mice. Mol Immunol. 2011, 48: 1203-1208. 10.1016/j.molimm.2011.03.002CrossRefPubMed
7.
Zhang X, Wang J, Fan C, Li H, Sun H, Gong S, Chen YH, Shi Y: Crystal structure of TIPE2 provides insights into immune homeostasis. Nat Struct Mol Biol. 2009, 16: 89-90. 10.1038/nsmb.1522CrossRefPubMed
8.
Wang Z, Fayngerts S, Wang P, Sun H, Johnson DS, Ruan Q, Guo W, Chen YH: TIPE2 protein serves as a negative regulator of phagocytosis and oxidative burst during infection. Proc Natl Acad Sci USA. 2012, 109: 15413-15418. 10.1073/pnas.1204525109PubMedCentralCrossRefPubMed
9.
Sun H, Zhuang G, Chai L, Wang Z, Johnson D, Ma Y, Chen YH: TIPE2 controls innate immunity to RNA by targeting the phosphatidylinositol 3-kinase-Rac pathway. J Immunol. 2012, 189: 2768-2773. 10.4049/jimmunol.1103477PubMedCentralCrossRefPubMed
10.
Gus-Brautbar Y, Johnson D, Zhang L, Sun H, Wang P, Zhang S, Chen YH: The anti-inflammatory TIPE2 is an inhibitor of the oncogenic Ras. Mol Cell. 2012, 45: 610-618. 10.1016/j.molcel.2012.01.006PubMedCentralCrossRefPubMed
11.
Zhang G, Hao C, Lou Y, Xi W, Wang X, Wang Y, Qu Z, Guo C, Chen Y, Zhang Y, Liu S: Tissue-specific expression of TIPE2 provides insights into its function. Mol Immunol. 2010, 47: 2435-2442. 10.1016/j.molimm.2010.06.016CrossRefPubMed
12.
Zhang L, Shi Y, Wang Y, Zhu F, Wang Q, Ma C, Chen YH: The unique expression profile of human TIPE2 suggests new functions beyond its role in immune regulation. Mol Immunol. 2011, 48: 1209-1215. 10.1016/j.molimm.2011.03.001CrossRefPubMed
13.
Lee TK, Man K, Ho JW, Wang XH, Poon RT, Sun CK, Ng KT, Ng IO, Xu R, Fan ST: Significance of the Rac signaling pathway in HCC cell motility: implications for a new therapeutic target. Carcinogenesis. 2005, 26: 681-687.CrossRefPubMed
14.
Jia YL, Shi L, Zhou JN, Fu CJ, Chen L, Yuan HF, Wang YF, Yan XL, Xu YC, Zeng Q, Yue W, Pei XT: Epimorphin promotes human hepatocellular carcinoma invasion and metastasis through activation of focal adhesion kinase/extracellular signal-regulated kinase/matrix metalloproteinase-9 axis. Hepatology. 2011, 54: 1808-1818. 10.1002/hep.24562CrossRefPubMed
15.
Chen RX, Xia YH, Xue TC, Zhang H, Ye SL: Down-regulation of osteopontin inhibits metastasis of hepatocellular carcinoma cells via a mechanism involving MMP-2 and uPA. Oncol Rep. 2011, 25: 803-808.PubMed
16.
Kumar D, Gokhale P, Broustas C, Chakravarty D, Ahmad I, Kasid U: Expression of SCC-S2, an antiapoptotic molecule, correlates with enhanced proliferation and tumorigenicity of MDA-MB 435 cells. Oncogene. 2004, 23: 612-616. 10.1038/sj.onc.1207123CrossRefPubMed
17.
Dong QZ, Zhao Y, Liu Y, Wang Y, Zhang PX, Jiang GY, Dong XJ, Cui QZ, Wang EH: Overexpression of SCC-S2 correlates with lymph node metastasis and poor prognosis in patients with non-small-cell lung cancer. Cancer Sci. 2010, 101: 1562-1569. 10.1111/j.1349-7006.2010.01557.xCrossRefPubMed
18.
Cui J, Zhang G, Hao C, Wang Y, Lou Y, Zhang W, Wang J, Liu S: The expression of TIPE1 in murine tissues and human cell lines. Mol Immunol. 2011, 48: 1548-1555. 10.1016/j.molimm.2011.04.023CrossRefPubMed
19.
Liu S, Yu M, He Y, Xiao L, Wang F, Song C, Sun S, Ling C, Xu Z: Melittin prevents liver cancer cell metastasis through inhibition of the Rac1-dependent pathway. Hepatology. 2008, 47: 1964-1973. 10.1002/hep.22240CrossRefPubMed
20.
Santibanez JF, Kocic J, Fabra A, Cano A, Quintanilla M: Rac1 modulates TGF-beta1-mediated epithelial cell plasticity and MMP9 production in transformed keratinocytes. FEBS Lett. 2010, 584: 2305-2310. 10.1016/j.febslet.2010.03.042CrossRefPubMed
21.
Han Q, Leng J, Bian D, Mahanivong C, Carpenter KA, Pan ZK, Han J, Huang S: Rac1-MKK3-p38-MAPKAPK2 pathway promotes urokinase plasminogen activator mRNA stability in invasive breast cancer cells. J Biol Chem. 2002, 277: 48379-48385. 10.1074/jbc.M209542200CrossRefPubMed
22.
Dise RS, Frey MR, Whitehead RH, Polk DB: Epidermal growth factor stimulates Rac activation through Src and phosphatidylinositol 3-kinase to promote colonic epithelial cell migration. Am J Physiol Gastrointest Liver Physiol. 2008, 294: G276-285.CrossRefPubMed
23.
Cadamuro M, Nardo G, Indraccolo S, Dall’olmo L, Sambado L, Moserle L, Franceschet I, Colledan M, Massani M, Stecca T, Bassi N, Morton S, Spirli C, Fiorotto R, Fabris L, Strazzabosco M: Platelet-derived growth factor-D and Rho GTPases regulate recruitment of cancer-associated fibroblasts in cholangiocarcinoma. Hepatology. 2013, 58: 1042-1053.PubMedCentralCrossRefPubMed
24.
Tan TL, Fang N, Neo TL, Singh P, Zhang J, Zhou R, Koh CG, Chan V, Lim SG, Chen WN: Rac1 GTPase is activated by hepatitis B virus replication–involvement of HBX. Biochim Biophys Acta. 2008, 1783: 360-374. 10.1016/j.bbamcr.2007.10.024CrossRefPubMed
25.
Wu L, Cai C, Wang X, Liu M, Li X, Tang H: MicroRNA-142-3p, a new regulator of RAC1, suppresses the migration and invasion of hepatocellular carcinoma cells. FEBS Lett. 2011, 585: 1322-1330. 10.1016/j.febslet.2011.03.067CrossRefPubMed
26.
Roney KE, O’Connor BP, Wen H, Holl EK, Guthrie EH, Davis BK, Jones SW, Jha S, Sharek L, Garcia-Mata R, Bear JE, Ting JP: Plexin-B2 negatively regulates macrophage motility, Rac, and Cdc42 activation. PLoS One. 2011, 6: e24795- 10.1371/journal.pone.0024795PubMedCentralCrossRefPubMed
Metadata
Title
Human tumor necrosis factor (TNF)-alpha-induced protein 8-like 2 suppresses hepatocellular carcinoma metastasis through inhibiting Rac1
Authors
Xuelei Cao
Li Zhang
Yongyu Shi
Yue Sun
Shen Dai
Chun Guo
Faliang Zhu
Qun wang
Jianing Wang
Xiaoyan Wang
Youhai H Chen
Lining Zhang
Publication date
01-12-2013
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2013
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/1476-4598-12-149

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