Hepatocellular carcinoma (HCC) is the fifth most common cancer in men and the seventh in women. HCC varies widely in incidence through the world, with rising incidence in Egypt. This study aimed to estimate the serum levels of matrix metalloproteinase-9 (MMP-9) and its substrate galectin-3 in order to evaluate their diagnostic accuracy and their relation to HCC-related clinical features.
Methods
For this purpose, serum levels of these biochemical markers were assessed in 50 HCC patients, 30 cirrhotic patients in addition to 10 healthy subjects as a control group using enzyme linked immune-sorbent assay (ELISA).
Results
In the present study, circulating level of galectin-3, MMP-9 increased significantly in HCC as compared to the control group (P = 0.044 and 0.04, respectively). However, no significant difference was observed between cirrhotic and HCC patients (P = 0.231 and 0.193, respectively). Our study found that HCC patients with metastatic spread had a significant elevation of both serum galectin-3 and MMP-9 levels (P = 0.028 and <0.0001, respectively). In addition, galectin-3 level significantly increased in HCC patients with poor prognosis suffering from portal vein invasion (P = 0.014). Moreover, MMP-9 increased significantly with increasing stage of Barcelona-Clinic Liver Cancer Group diagnostic and treatment strategy (P = 0.01).
Conclusion
MMP-9 and galectin-3 could be used as a guide for prognosis of HCC since they may play a role in HCC progression and metastasis. However, they are not useful markers for HCC diagnosis.
El-SeragHB. Hepatocellular carcinoma. N Engl J Med2011; 365: 1118–1127.
2.
ShirahaHYamamotoKNambaM. Human hepatocyte carcinogenesis (review). Int J Oncol2012; 42: 1133–1138.
3.
Abdel-GafarYSleemHTawfikM. Percutaneous ethanol injection in large size and multiple HCC: two years follow-up in 165 patients. Med J Cairo Univ2002; 70: 299–304.
4.
StefaniukPCianciaraJWiercinska-DrapaloA. Present and future possibilities for early diagnosis of hepatocellular carcinoma. World J Gastroenterol2010; 16: 418–424.
5.
El-TayehSFHusseinTDEl-HouseiniME. Serological biomarkers of hepatocellular carcinoma in Egyptian patients. Dis Markers2012; 32: 255–263.
6.
VerspagetHWKuyvenhovenJPSierCFMMatrix metalloproteinases in chronic liver disease and liver transplantation. In: LendeckelUHooperNM (eds). Proteases in gastrointestinal tissue2006; Vol. 5. Netherlands: Springer, pp. 209–234.
7.
YuQStamenkovicI. Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev2000; 14: 163–176.
8.
BergersGBrekkenRMcMahonG. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol2000; 2: 737–744.
9.
ChenRCuiJXuC. The significance of MMP-9 over MMP-2 in HCC invasiveness and recurrence of hepatocellular carcinoma after curative resection. Ann Surg Oncol2012; 19: S375–S384.
10.
TakenakaYFukumoriTRazA. Galectin-3 and metastasis. Glycoconj J2004; 19: 543–549.
11.
DumicJDabelicSFlögelM. Galectin-3: an open-ended story. Biochim Biophys Acta2006; 1760: 616–635.
12.
HsuDKDowlingCAJengKC. Galectin-3 expression is induced in cirrhotic liver and hepatocellular carcinoma. Int J Cancer1999; 81: 519–526.
13.
MatsudaYYamagiwaYFukushimaK. Expression of galectin-3 involved in prognosis of patients with hepatocellular carcinoma. Hepatol Res2008; 38: 1098–1111.
14.
PughRNMurray-LyonIMDawsonJL. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg1973; 60: 646–649.
15.
LlovetJMFusterJBruixJ. The Barcelona approach: diagnosis, staging, and treatment of hepatocellular carcinoma. Liver Transplant2004; 10: S115–S120.
16.
RessomHWXiaoJFTuliL. Utilization of metabolomics to identify serum biomarkers for hepatocellular carcinoma in patients with liver cirrhosis. Anal Chim Acta2012; 743: 90–100.
17.
MurashimaSTanakaMHaramakiM. A decrease in AFP level related to administration of interferon in patients with chronic hepatitis C and a high level of AFP. Dig Dis Sci2006; 51: 808–812.
18.
HayasakaASuzukiNFujimotoN. Elevated plasma levels of matrix metalloproteinase-9 (92-kd type IV collagenase/gelatinase B) in hepatocellular carcinoma. Hepatology1996; 24: 1058–1062.
19.
MurawakiYIkutaYOkamotoK. Plasma matrix metalloproteinase-9 (gelatinase B) in patients with hepatocellular carcinoma. Res Commun Mol Pathol Pharmacol2000; 108: 351–357.
20.
KamelLNessimIAbd-el-HadyA. Assessment of the clinical significance of serum vascular endothelial growth factor and matrix metalloproteinase-9 in patients with hepatocellular carcinoma. J Egypt Soc Parasitol2005; 35: 875–890.
21.
BadraGLotfyMEl-RefaieA. Significance of serum matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in chronic hepatitis C patients. Acta Microbiol Immunol Hung2010; 57: 29–42.
22.
KuyvenhovenJPvan HoekBBlomE. Assessment of the clinical significance of serum matrix metalloproteinases MMP-2 and MMP-9 in patients with various chronic liver diseases and hepatocellular carcinoma. Thromb Haemost2003; 89: 718–725.
23.
KwonOSLimDYKwonKA. Clinical usefulness of plasma activities of gelatinase (matrix metalloproteinase-2 and 9) in chronic liver disease. Taehan Kan Hakhoe Chi2003; 9: 222–230.
24.
MäättäMSoiniYLiakkaA. Differential expression of matrix metalloproteinase (MMP)-2, MMP-9, and membrane type 1-MMP in hepatocellular and pancreatic adenocarcinoma: implications for tumor progression and clinical prognosis. Clin Cancer Res2000; 6: 2726–2734.
25.
SakamotoYMafuneKMoriM. Overexpression of MMP-9 correlates with growth of small hepatocellular carcinoma. Int J Oncol2000; 17: 237–243.
26.
TangJCuiJChenR. A three-dimensional cell biology model of human hepatocellular carcinoma in vitro. Tumour Biol2011; 32: 469–479.
27.
LakkaSSGondiCSDinhDH. Specific interference of urokinase-type plasminogen activator receptor and matrix metalloproteinase-9 gene expression induced by double-stranded RNA results in decreased invasion, tumor growth, and angiogenesis in gliomas. J Biol Chem2005; 280: 21882–21892.
28.
SunMHHanXCJiaMK. Expressions of inducible nitric oxide synthase and matrix metalloproteinase-9 and their effects on angiogenesis and progression of hepatocellular carcinoma. World J Gastroenterol2005; 11: 5931–5937.
29.
ZhangQChenXZhouJ. CD147, MMP-2, MMP-9 and MVD-CD34 are significant predictors of recurrence after liver transplantation in hepatocellular carcinoma patients. Cancer Biol Ther2006; 5: 808–814.
30.
ZhongCGuoRPShiM. Expression and clinical significance of VEGF and MMP-9 in hepatocellular carcinoma. Ai Zheng2006; 25: 599–603.
31.
YangPYuanWHeJ. Overexpression of EphA2, MMP-9, and MVD-CD34 in hepatocellular carcinoma: Implications for tumor progression and prognosis. Hepatol Res2009; 39: 1169–1177.
32.
StamenkovicI. Matrix metalloproteinases in tumor invasion and metastasis. Semin Cancer Biol2000; 10: 415–433.
33.
ThieringerFRMaassTAnthonB. Liver-specific overexpression of matrix metalloproteinase 9 (MMP-9) in transgenic mice accelerates development of hepatocellular carcinoma. Mol Carcinog2012; 51: 439–448.
34.
NartDYamanBYilmazF. Expression of matrix metalloproteinase-9 in predicting prognosis of hepatocellular carcinoma after liver transplantation. Liver Transplant2010; 16: 621–630.
35.
ZuckerSCaoJChenWT. Critical appraisal of the use of matrix metalloproteinase inhibitors in cancer treatment. Oncogene2000; 19: 6642–6650.
36.
Nangia-MakkerPBalanVRazA. Regulation of tumor progression by extracellular galectin-3. Cancer Microenviron2008; 1: 43–51.
37.
OchiengJGreenBEvansS. Modulation of the biological functions of galectin-3 by matrix metalloproteinases. Biochim Biophys Acta1998; 1379: 97–106.
38.
ShekharMPNangia-MakkerPTaitL. Alterations in galectin-3 expression and distribution correlate with breast cancer progression: functional analysis of galectin-3 in breast epithelial-endothelial interactions. Am J Pathol2004; 165: 1931–1941.
39.
FangQQNiRZXiaoMB. Serum and tissue expressions of galectin-3 in hepatocellular carcinoma and the clinical significances. Zhonghua Gan Zang Bing Za Zhi2011; 19: 527–531.
40.
IurisciITinariNNatoliC. Concentrations of galectin-3 in the sera of normal controls and cancer patients. Clin Cancer Res2000; 6: 1389–1393.
41.
AkahaniSNangia-MakkerPInoharaH. Galectin-3: a novel antiapoptotic molecule with a functional BH1 (NWGR) domain of Bcl-2 family. Cancer Res1997; 57: 5272–5276.
42.
Nangia-MakkerPNakaharaSHoganV. Galectin-3 in apoptosis, a novel therapeutic target. J Bioenerg Biomembr2007; 39: 79–84.
43.
KrześlakALipińskaA. Galectin-3 as a multifunctional protein. Cell Mol Biol Lett2004; 9: 305–328.
44.
ZouJGlinskyVVLandonLA. Peptides specific to the galectin-3 carbohydrate recognition domain inhibit metastasis-associated cancer cell adhesion. Carcinogenesis2005; 26: 309–318.
45.
LiuFTRabinovichGA. Galectins as modulators of tumour progression. Nat Rev Cancer2005; 5: 29–41.
46.
MohafezOMMAbd EL-AzizMAAbd El-GhanyAA. The expression pattern of galectin-3 in the rat hepatocellular carcinoma. Bull Pharm Sci2011; 34: 181–187.
47.
LiuHYHuangZLYangGH. Inhibitory effect of modified citrus pectin on liver metastases in a mouse colon cancer model. World J Gastroenterol2008; 14: 7386–7391.
