Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Clinical & Experimental Metastasis
Published in: Clinical & Experimental Metastasis 5/2015

01-06-2015 | Research Paper

Hepatoprotective and anti-tumor effects of targeting MMP-9 in hepatocellular carcinoma and its relation to vascular invasion markers

Authors: Mohammed A. F. Elewa, Mohammed M. Al-Gayyar, Mona F. Schaalan, Khaled H. Abd El Galil, Mohamed A. Ebrahim, Mamdouh M. El-Shishtawy

Published in: Clinical & Experimental Metastasis | Issue 5/2015

Login to get access

Abstract

The current study aims to evaluate the hepatoprotective and antitumor efficacy of doxycycline, as an matrix metalloproteases-9 (MMP-9) inhibitor, in an in vivo model of hepatocellular carcinoma (HCC). HCC was induced experimentally by thiocetamide (200 mg/kg) in rats that were treated with doxycycline (5 mg/kg for 16 weeks). Tumor severity was evaluated by measuring α-fetoprotein (AFP) levels, histopathologically by investigating liver sections stained with hematoxylin/eosin and assessing the survival rate. Liver homogenates were used for the measurements of MMP-9, fascin and hepatic heparan sulfate proteoglycan (HSPG) levels. Oxidative stress markers [malonaldehyde (MDA) and glutathione] as well as fibroblast growth factor-2 (FGF-2) gene expression were also among the assessed indicators. HCC in human and animal samples showed significant elevation in the levels of MMP-9 (231.7, 90 %), fascin (33.17, 140 %), as well as FGF-2 gene expression (342 % in animal samples; all respectively), associated with a significant decrease in hepatic HSPG level. Treatment of rats with doxycycline increased the animal survival rate (90 %) and decreased serum AFP level. Moreover, doxycycline ameliorated fibrosis and the induced massive hepatic tissue breakdown. It also restored the integrity of hepatic HSPGs and showed a magnificent inhibitory effect of tumor invasion cascade by significantly reducing the activities of MMP-9 (42 %) and fascin (50 %), as well as reducing the gene expression of FGF-2 (85.7 %). Furthermore, the antioxidant impact of doxycycline was evidenced by the significant elevation in glutathione level and depressing MDA level. To this end, doxycycline, proved promising hepatoprotective and antitumor activity and opens, thereby, a new horizon against vascular migration ability of the tumor cells.
Literature
1.
He S et al (2013) Study of RNA interference targeting NET-1 combination with sorafenib for hepatocellular carcinoma therapy in vitro and in vivo. Gastroenterol Res Pract 2013:685150PubMedCentralPubMedCrossRef
2.
Sun Q et al (2014) Notch1 is a potential therapeutic target for the treatment of human hepatitis B virus X protein-associated hepatocellular carcinoma. Oncol Rep 31(2):933–939PubMed
3.
Breuhahn K, Schirmacher P (2008) Reactivation of the insulin-like growth factor-II signaling pathway in human hepatocellular carcinoma. World J Gastroenterol 14(11):1690–1698PubMedCentralPubMedCrossRef
4.
Yao DF, Dong ZZ, Yao M (2007) Specific molecular markers in hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int 6(3):241–247PubMed
5.
Abdel-Rahman O (2013) Systemic therapy for hepatocellular carcinoma (HCC): from bench to bedside. J Egypt Natl Cancer Inst 25(4):165–171CrossRef
6.
Chen K et al (2014) Rationale of personalized immunosuppressive medication for hepatocellular carcinoma patients after liver transplantation. Liver Transplant Off Publ Am Assoc Study Liver Dis Int Liver Transplant Soc 20(3):261–269
7.
Qin LX, Tang ZY (2002) The prognostic molecular markers in hepatocellular carcinoma. World J Gastroenterol 8(3):385–392PubMed
8.
9.
Yancopoulos GD et al (2000) Vascular-specific growth factors and blood vessel formation. Nature 407(6801):242–248PubMedCrossRef
10.
Lai JP et al (2008) Heparin-degrading sulfatases in hepatocellular carcinoma: roles in pathogenesis and therapy targets. Future Oncol (Lond Engl) 4(6):803–814CrossRef
11.
Segev A, Strauss BH (2004) Novel approaches for the treatment of chronic total coronary occlusions. J Interv Cardiol 17(6):411–416PubMedCrossRef
12.
13.
Tsunematsu H et al (2012) Fibroblast growth factor-2 enhances NK sensitivity of hepatocellular carcinoma cells. Int J Cancer 130(2):356–364PubMedCrossRef
14.
Ornitz DM et al (1996) Receptor specificity of the fibroblast growth factor family. J Biol Chem 271(25):15292–15297PubMedCrossRef
15.
Wang L et al (2012) A novel monoclonal antibody to fibroblast growth factor 2 effectively inhibits growth of hepatocellular carcinoma xenografts. Mol Cancer Ther 11(4):864–872PubMedCentralPubMedCrossRef
16.
Parks WC, Wilson CL, Lopez-Boado YS (2004) Matrix metalloproteinases as modulators of inflammation and innate immunity. Nat Rev Immunol 4(8):617–629PubMedCrossRef
17.
18.
Egeblad M, Werb Z (2002) New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2(3):161–174PubMedCrossRef
19.
20.
Kim KR et al (2011) The role of serum response factor in hepatocellular carcinoma: an association with matrix metalloproteinase. Oncol Rep 26(6):1567–1572PubMed
21.
Deryugina EI, Quigley JP (2006) Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Rev 25(1):9–34PubMedCrossRef
22.
Hidalgo M, Eckhardt SG (2001) Development of matrix metalloproteinase inhibitors in cancer therapy. J Natl Cancer Inst 93(3):178–193PubMedCrossRef
23.
Tae HJ et al (2012) Chronic treatment with a broad-spectrum metalloproteinase inhibitor, doxycycline, prevents the development of spontaneous aortic lesions in a mouse model of vascular Ehlers–Danlos syndrome. J Pharmacol Exp Ther 343(1):246–251PubMedCentralPubMedCrossRef
24.
Nowak E et al (2013) MMP-9 directed shRNAs as relevant inhibitors of matrix metalloproteinase 9 activity and signaling. Postepy Hig Med Dosw (Online) 67:742–749CrossRef
25.
Shuman Moss LA, Jensen-Taubman S, Stetler-Stevenson WG (2012) Matrix metalloproteinases: changing roles in tumor progression and metastasis. Am J Pathol 181(6):1895–1899PubMedCentralPubMedCrossRef
26.
Yamashiro S, et al. (1998) Fascin, an actin-bundling protein, induces membrane protrusions and increases cell motility of epithelial cells. Molecular biology of the cell 9 5): 993-1006
27.
Jayo A, Parsons M (2010) Fascin: a key regulator of cytoskeletal dynamics. Int J Biochem Cell Biol 42(10):1614–1617PubMedCrossRef
28.
Huang X et al (2012) Fascin and cortactin expression is correlated with a poor prognosis in hepatocellular carcinoma. Eur J Gastroenterol Hepatol 24(6):633–639PubMedCrossRef
29.
30.
Cross CE et al (1998) Oxidative stress and antioxidants at biosurfaces: plants, skin, and respiratory tract surfaces. Environ Health Perspect 106(Suppl 5):1241–1251PubMedCentralPubMedCrossRef
31.
Tayel A et al (2014) Suramin inhibits hepatic tissue damage in hepatocellular carcinoma through deactivation of heparanase enzyme. Eur J Pharmacol 728:151–160PubMedCrossRef
32.
Darweish MM et al (2014) Chemopreventive and hepatoprotective effects of Epigallocatechin-gallate against hepatocellular carcinoma: role of heparan sulfate proteoglycans pathway. J Pharm Pharmacol 66(7):1032–1045PubMedCrossRef
33.
Zaghloul RA et al (2015) Evaluation of antiglypican-3 therapy as a promising target for amelioration of hepatic tissue damage in hepatocellular carcinoma. Eur J Pharmacol 746:353–362PubMedCrossRef
34.
Brookes ZL, Reilly CS, Brown NJ (2004) Differential effects of propofol, ketamine, and thiopental anaesthesia on the skeletal muscle microcirculation of normotensive and hypertensive rats in vivo. Br J Anaesth 93(2):249–256PubMedCrossRef
35.
Brookes ZL et al (2007) Proinflammatory and vasodilator effects of nociceptin/orphanin FQ in the rat mesenteric microcirculation are mediated by histamine. Am J Physiol Heart Circ Physiol 293(5):H2977–H2985PubMedCrossRef
36.
37.
Eyer P, Podhradsky D (1986) Evaluation of the micromethod for determination of glutathione using enzymatic cycling and Ellman’s reagent. Anal Biochem 153(1):57–66PubMedCrossRef
38.
Marklund S, Marklund G (1974) Involvement of the superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase. Eur J Biochem/FEBS 47(3):469–474CrossRef
39.
Cohen G, Dembiec D, Marcus J (1970) Measurement of catalase activity in tissue extracts. Anal Biochem 34:30–38PubMedCrossRef
40.
Hadler-Olsen E, Winberg JO, Uhlin-Hansen L (2013) Matrix metalloproteinases in cancer: their value as diagnostic and prognostic markers and therapeutic targets. Tumour Biol J Int Soc Oncodev Biol Med 34(4):2041–2051CrossRef
41.
Toyoshima M, Nakajima M (1999) Human heparanase. Purification, characterization, cloning, and expression. J Biol Chem 274(34):24153–24160PubMedCrossRef
42.
Ornitz DM (2000) FGFs, heparan sulfate and FGFRs: complex interactions essential for development. BioEssays News Reviews Mol Cell Dev Biol 22(2):108–112CrossRef
43.
Harmer NJ (2006) Insights into the role of heparan sulphate in fibroblast growth factor signalling. Biochem Soc Trans 34(Pt 3):442–445PubMed
44.
Powell WC, Matrisian LM (1996) Complex roles of matrix metalloproteinases in tumor progression. Curr Top Microbiol Immunol 213(Pt 1):1–21PubMed
45.
Goncalves JL et al (2012) Pro-inflammatory effects of the mushroom Agaricus blazei and its consequences on atherosclerosis development. Eur J Nutr 51(8):927–937PubMedCrossRef
46.
Ordonez R et al (2014) Inhibition of matrix metalloproteinase-9 and nuclear factor kappa B contribute to melatonin prevention of motility and invasiveness in HepG2 liver cancer cells. J Pineal Res 56(1):20–30PubMedCrossRef
47.
Lou L et al (2013) Enhancement of invasion of hepatocellular carcinoma cells through lysophosphatidic acid receptor. J Int Med Res 41(1):55–63PubMedCrossRef
48.
Roomi MW et al (2013) In vitro modulation of MMP-2 and MMP-9 in adult human sarcoma cell lines by cytokines, inducers and inhibitors. Int J Oncol 43(6):1787–1798PubMedCentralPubMed
49.
50.
Bernfield M et al (1999) Functions of cell surface heparan sulfate proteoglycans. Annu Rev Biochem 68:729–777PubMedCrossRef
51.
Purushothaman A et al (2008) Heparanase stimulation of protease expression implicates it as a master regulator of the aggressive tumor phenotype in myeloma. J Biol Chem 283(47):32628–32636PubMedCentralPubMedCrossRef
52.
53.
Yang Y et al (2002) Soluble syndecan-1 promotes growth of myeloma tumors in vivo. Blood 100(2):610–617PubMedCrossRef
54.
Li Q et al (2002) Matrilysin shedding of syndecan-1 regulates chemokine mobilization and transepithelial efflux of neutrophils in acute lung injury. Cell 111(5):635–646PubMedCrossRef
55.
Yang X et al (2009) Signal transducers and activators of transcription mediate fibroblast growth factor-induced vascular endothelial morphogenesis. Cancer Res 69(4):1668–1677PubMedCentralPubMedCrossRef
56.
57.
Kanazawa S et al (2001) VEGF, basic-FGF, and TGF-beta in Crohn’s disease and ulcerative colitis: a novel mechanism of chronic intestinal inflammation. Am J Gastroenterol 96(3):822–828PubMed
58.
59.
Lin ZY, Chuang WL (2013) Hepatocellular carcinoma cells cause different responses in expressions of cancer-promoting genes in different cancer-associated fibroblasts. Kaohsiung J Med Sci 29(6):312–318PubMedCrossRef
60.
Pollard TD, Borisy GG (2003) Cellular motility driven by assembly and disassembly of actin filaments. Cell 112(4):453–465PubMedCrossRef
61.
Hashimoto Y et al (2006) Prognostic significance of fascin expression in advanced colorectal cancer: an immunohistochemical study of colorectal adenomas and adenocarcinomas. BMC Cancer 6:241PubMedCentralPubMedCrossRef
62.
Vignjevic D et al (2007) Fascin, a novel target of beta-catenin-TCF signaling, is expressed at the invasive front of human colon cancer. Cancer Res 67(14):6844–6853PubMedCrossRef
63.
Hayashi Y, Osanai M, Lee GH (2011) Fascin-1 expression correlates with repression of E-cadherin expression in hepatocellular carcinoma cells and augments their invasiveness in combination with matrix metalloproteinases. Cancer Sci 102(6):1228–1235PubMedCrossRef
64.
Lee TK et al (2007) Fascin over-expression is associated with aggressiveness of oral squamous cell carcinoma. Cancer Lett 254(2):308–315PubMedCrossRef
65.
Zhao Q et al (2010) Phosphorylation of fascin decreases the risk of poor survival in patients with esophageal squamous cell carcinoma. J Histochem Cytochem Off J Histochem Soc 58(11):979–988CrossRef
66.
Oh SY et al (2012) Prognostic impact of fascin-1 expression is more significant in advanced colorectal cancer. J Surg Res 172(1):102–108PubMedCrossRef
67.
Griffin MO et al (2010) Tetracyclines: a pleiotropic family of compounds with promising therapeutic properties. Review of the literature. Am J Physiol Cell Physiol 299(3):C539–C548PubMedCentralPubMedCrossRef
68.
Peterson JT (2004) Matrix metalloproteinase inhibitor development and the remodeling of drug discovery. Heart Fail Rev 9(1):63–79PubMedCrossRef
69.
Seftor RE et al (1998) Chemically modified tetracyclines inhibit human melanoma cell invasion and metastasis. Clin Exp Metastasis 16(3):217–225PubMedCrossRef
70.
Lokeshwar BL et al (2002) Inhibition of cell proliferation, invasion, tumor growth and metastasis by an oral non-antimicrobial tetracycline analog (COL-3) in a metastatic prostate cancer model. Int J Cancer 98(2):297–309PubMedCrossRef
71.
Ryan ME, et al. (2001) Excessive matrix metalloproteinase activity in diabetes: inhibition by tetracycline analogues with zinc reactivity. Current medicinal chemistry 8 3): 305-16
72.
Roomi MW et al (2014) In vitro modulation of MMP-2 and MMP-9 in pediatric human sarcoma cell lines by cytokines, inducers and inhibitors. Int J Oncol 44(1):27–34PubMedCentralPubMed
73.
Sun B et al (2007) Doxycycline influences microcirculation patterns in B16 melanoma. Exp Biol Med (Maywood, NJ) 232(10):1300–1307CrossRef
74.
Krylova IV, Shalaev VA, Isakov SV (1991) Individual prognosis of chronic B-lymphoid leukemia course. Gematol transfuziol 36(10):19–21PubMed
75.
Wang CY et al (2013) Activation of PPARgamma is required for hydroxysafflor yellow A of Carthamus tinctorius to attenuate hepatic fibrosis induced by oxidative stress. Phytomed Int J Phytother Phytopharmacol 20(7):592–599CrossRef
76.
Calvisi DF et al (2005) Activation of the canonical Wnt/beta-catenin pathway confers growth advantages in c-Myc/E2F1 transgenic mouse model of liver cancer. J Hepatol 42(6):842–849PubMedCrossRef
77.
78.
Weiss SJ et al (1985) Oxidative autoactivation of latent collagenase by human neutrophils. Science (New York, NY) 227(4688):747–749CrossRef
79.
Senturker S et al (1997) Oxidative DNA base damage and antioxidant enzyme levels in childhood acute lymphoblastic leukemia. FEBS Lett 416(3):286–290PubMedCrossRef
80.
Liu DY et al (2003) Expression of telomerase activity and oxidative stress in human hepatocellular carcinoma with cirrhosis. World J Gastroenterol 9(8):1859–1862PubMed
81.
Yagan A, Kesim S, Liman N (2014) Effect of low-dose doxycycline on serum oxidative status, gingival antioxidant levels, and alveolar bone loss in experimental periodontitis in rats. J Periodontol 85(3):478–489PubMedCrossRef
82.
Creemers EE et al (2001) Matrix metalloproteinase inhibition after myocardial infarction: a new approach to prevent heart failure? Circ Res 89(3):201–210PubMedCrossRef
83.
Park JL, Lucchesi BR (1999) Mechanisms of myocardial reperfusion injury. Ann Thorac Surg 68(5):1905–1912PubMedCrossRef
84.
Kraus RL et al (2005) Antioxidant properties of minocycline: neuroprotection in an oxidative stress assay and direct radical-scavenging activity. J Neurochem 94(3):819–827PubMedCrossRef
85.
Hashimoto Y, Parsons M, Adams JC (2007) Dual actin-bundling and protein kinase C-binding activities of fascin regulate carcinoma cell migration downstream of Rac and contribute to metastasis. Mol Biol Cell 18(11):4591–4602PubMedCentralPubMedCrossRef
Metadata
Title
Hepatoprotective and anti-tumor effects of targeting MMP-9 in hepatocellular carcinoma and its relation to vascular invasion markers
Authors
Mohammed A. F. Elewa
Mohammed M. Al-Gayyar
Mona F. Schaalan
Khaled H. Abd El Galil
Mohamed A. Ebrahim
Mamdouh M. El-Shishtawy
Publication date
01-06-2015
Publisher
Springer Netherlands
Published in
Clinical & Experimental Metastasis / Issue 5/2015
Print ISSN: 0262-0898
Electronic ISSN: 1573-7276
DOI
https://doi.org/10.1007/s10585-015-9721-6

Other articles of this Issue 5/2015

Clinical & Experimental Metastasis 5/2015 Go to the issue

Erratum

Erratum to: Kurt Hellmann D.M., D.Phil. Oxon. A happy 90th birthday!

Research Paper

Loss of PCDH9 is associated with the differentiation of tumor cells and metastasis and predicts poor survival in gastric cancer

OriginalPaper

Transketolase is upregulated in metastatic peritoneal implants and promotes ovarian cancer cell proliferation

Research Paper

Amino-terminal fragments of laminin γ2 chain stimulate migration of metastatic breast cancer cells by interacting with CD44

Research Paper

Nationwide trends in incidence, treatment and survival of colorectal cancer patients with synchronous metastases

OriginalPaper

NANOG signaling promotes metastatic capability of immunoedited tumor cells
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits