Study of Toll-like Receptor 3 Gene Polymorphism as a Novel Risk Factor for HCV-related Hepatocellular Carcinoma in Egypt

Author(s): Shimaa EL-Sharawy, Osama El- Sayed Negm, Sherief Abd-Elsalam*, Hesham Ahmed EL-Sorogy, Mona Ahmed Helmy Shehata

Journal Name: Current Cancer Drug Targets

Volume 20 , Issue 5 , 2020


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Abstract:

Background and Aims: Hepatocellular carcinoma (HCC) is a highly aggressive cancer with few treatment options. Toll-like receptor 3 (TLR3) plays a key role in innate immunity and may affect the development of cancers. This study aimed to investigate the association between TLR3 gene polymorphism and HCV-related hepatocellular carcinoma in Egypt.

Methods: This work was conducted on 70 individuals; fifty HCV cirrhotic patients were included in two groups; with HCC (30 patients) and without HCC (20 patients) compared with a group of 20 apparently healthy controls. All of the studied individuals underwent clinical-laboratory evaluation. TLR3 gene single-nucleotide polymorphism (SNP) (+1234C/T) was tested by polymerase chain reaction- restriction fragment length polymorphism.

Results: This study reported that the prevalence of TLR3 +1234TT genotype was significantly increased in cirrhotic patients with HCC than without HCC, while it was not detected at all among the controls. When analyzing the TLR3 SNP +1234C/T with different clinical parameters in HCC patients, there was a significant association between+1234C/T SNP; namely TT genotype and each of the hepatic focal lesions᾽ number, size and the patients᾽ higher Okuda and BCLC stages. No association could be detected between TLR3 SNP and the age, sex, Child-Pugh grades, MELD score or AFP of the studied HCC cases.

Conclusion: TLR3 gene SN P +1234C/T could be a novel risk factor for the HCV-related HCC among the Egyptian population.

Keywords: Toll-like receptor 3, hepatocellular carcinoma, HCV, Egypt, polymorphism, tumour markers.

[1]
Kremsdorf, D.; Soussan, P.; Paterlini-Brechot, P.; Brechot, C. Hepatitis B virus-related hepatocellular carcinoma: paradigms for viral-related human carcinogenesis. Oncogene, 2006, 25(27), 3823-3833.
[http://dx.doi.org/10.1038/sj.onc.1209559] [PMID: 16799624]
[2]
Velázquez, R.F.; Rodríguez, M.; Navascués, C.A.; Linares, A.; Pérez, R.; Sotorríos, N.G.; Martínez, I.; Rodrigo, L. Prospective analysis of risk factors for hepatocellular carcinoma in patients with liver cirrhosis. Hepatology, 2003, 37(3), 520-527.
[http://dx.doi.org/10.1053/jhep.2003.50093] [PMID: 12601348]
[3]
Abd-Elsalam, S.; Elwan, N.; Soliman, H.; Ziada, D.; Elkhalawany, W.; Salama, M.; Hawash, N.; Arafa, M.; Badawi, R.; Shehata, W.M.; Khalil, H.S.; Elmashad, N. Epidemiology of liver cancer in Nile delta over a decade: A single-center study. South Asian J. Cancer, 2018, 7(1), 24-26.
[http://dx.doi.org/10.4103/sajc.sajc_82_17] [PMID: 29600229]
[4]
Ziada, D.H.; El Sadany, S.; Soliman, H.; Abd-Elsalam, S.; Salama, M.; Hawash, N.; Selim, A.; Hamisa, M.; Elsabagh, H.M. Prevalence of hepatocellular carcinoma in chronic hepatitis C patients in Mid Delta, Egypt: A single center study. J. Egypt. Natl. Canc. Inst., 2016, 28(4), 257-262.
[http://dx.doi.org/10.1016/j.jnci.2016.06.001] [PMID: 27378258]
[5]
Abdelfattah, A.A.M.; Rizk, F.; Hawash, N.; Hanafy, A.; El-Kalla, F.; Abd-Elsalam, S. Randomized trial of preoperative administration of oral pregabalin for postoperative analgesia in patients scheduled for radiofrequency ablation of focal lesions in the liver. Int. J. Hyperthermia, 2018, 34(8), 1367-1371. Epub ahead of print
[http://dx.doi.org/10.1080/02656736.2018.1424946] [PMID: 29308685]
[6]
Negm, O.; Abou Saif, S.; El Gharib, M.; Yousef, M.; Abd-Elsalam, S. Role of low-molecular-weight heparins in prevention of thromboembolic complication after transarterial chemoembolization in hepatocellular carcinoma. Eur. J. Gastroenterol. Hepatol., 2017, 29(3), 317-321.
[http://dx.doi.org/10.1097/MEG.0000000000000790] [PMID: 27893491]
[7]
Sheta, E.; El-Kalla, F.; El-Gharib, M.; Kobtan, A.; Elhendawy, M.; Abd-Elsalam, S.; Mansour, L.; Amer, I. Comparison of single-session transarterial chemoembolization combined with microwave ablation or radiofrequency ablation in the treatment of hepatocellular carcinoma: a randomized-controlled study. Eur. J. Gastroenterol. Hepatol., 2016, 28(10), 1198-1203.
[http://dx.doi.org/10.1097/MEG.0000000000000688] [PMID: 27362551]
[8]
El-Gebaly, F.; Abou-Saif, S.; Elkadeem, M.; Helmy, A.; Abd-Elsalam, S.; Yousef, M.; Elkhouly, R.A.; Amer, I.F.; El-Demerdash, T. Study of Serum Soluble Programmed Death Ligand 1 as a Prognostic Factor in Hepatocellular Carcinoma in Egyptian Patients. Curr. Cancer Drug Targets, 2019, 19(11), 896-905. Epub ahead of print
[http://dx.doi.org/10.2174/1568009619666190718141647] [PMID: 31538897]
[9]
Hanafy, A.S.; Soliman, S.; Abd-Elsalam, S. Rescue therapy for chronic hepatitis C virus infection after repeated treatment failures: Impact on disease progression and risk of hepatocellular carcinoma. Hepatol. Res., 2018, 2018(Dec), 20.
[http://dx.doi.org/10.1111/hepr.13303] [PMID: 30570817]
[10]
Elwan, N.; Salem, ML.; Kobtan, A.; El-Kalla, F.; Mansour, L.; Yousef, M.; Al-Sabbagh, A.; Zidan, AA.; Abd-Elsalam, S. High numbers of myeloid derived suppressor cells in peripheral blood and ascitic fluid of cirrhotic and HCC patients. Immunol. Invest., 2017, 47(2), 169-180.
[11]
Watany, M; Badawi, R; Elkhalawany, W Abd-Elsalam, S Study of Dickkopf-1 (DKK-1) Gene Expression in Hepatocellular Carcinoma Patients. Journal of Clinical and Diagnostic Research 02/2017, 2017, 11(2)
[12]
Freedman, L.S.; Edwards, B.K.; Ries, L.A.G.; Young, J.L. Cancer incidence in four member countries (Cyprus, Egypt, Israel and Jordan) of middle east cancer consortium (MECC)compared with US SEER; National cancer Institute . Bethesda, MD: NIH Pub, 2006, pp. 06-5873.
[13]
el-Zayadi, A.R.; Badran, H.M.; Barakat, E.M.F.; Attia, Mel-D.; Shawky, S.; Mohamed, M.K.; Selim, O.; Saeid, A. Hepatocellular carcinoma in Egypt: a single center study over a decade. World J. Gastroenterol., 2005, 11(33), 5193-5198.
[PMID: 16127751]
[14]
Naugler, W.E.; Sakurai, T.; Kim, S.; Maeda, S.; Kim, K.; Elsharkawy, A.M.; Karin, M. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science, 2007, 317(5834), 121-124.
[http://dx.doi.org/10.1126/science.1140485] [PMID: 17615358]
[15]
Beutler, B.; Jiang, Z.; Georgel, P.; Crozat, K.; Croker, B.; Rutschmann, S.; Du, X.; Hoebe, K. Genetic analysis of host resistance: Toll-like receptor signaling and immunity at large. Annu. Rev. Immunol., 2006, 24, 353-389.
[http://dx.doi.org/10.1146/annurev.immunol.24.021605.090552] [PMID: 16551253]
[16]
Faure, E.; Thomas, L.; Xu, H.; Medvedev, A.; Equils, O.; Arditi, M. Bacterial lipopolysaccharide and IFN-gamma induce Toll-like receptor 2 and Toll-like receptor 4 expression in human endothelial cells: role of NF-kappa B activation. J. Immunol., 2001, 166(3), 2018-2024.
[http://dx.doi.org/10.4049/jimmunol.166.3.2018] [PMID: 11160251]
[17]
Barton, G.M.; Kagan, J.C.; Medzhitov, R. Intracellular localization of Toll-like receptor 9 prevents recognition of self DNA but facilitates access to viral DNA. Nat. Immunol., 2006, 7(1), 49-56.
[http://dx.doi.org/10.1038/ni1280] [PMID: 16341217]
[18]
Matsumura, T.; Degawa, T.; Takii, T.; Hayashi, H.; Okamoto, T.; Inoue, J.; Onozaki, K. TRAF6-NF-kappaB pathway is essential for interleukin-1-induced TLR2 expression and its functional response to TLR2 ligand in murine hepatocytes. Immunology, 2003, 109(1), 127-136.
[http://dx.doi.org/10.1046/j.1365-2567.2003.01627.x] [PMID: 12709026]
[19]
Horscroft, N.J.; Pryde, D.C.; Bright, H. Antiviral applications of Toll-like receptor agonists. J. Antimicrob. Chemother., 2012, 67(4), 789-801.
[http://dx.doi.org/10.1093/jac/dkr588] [PMID: 22258929]
[20]
Harmey, J.H.; Bucana, C.D.; Lu, W.; Byrne, A.M.; McDonnell, S.; Lynch, C.; Bouchier-Hayes, D.; Dong, Z. Lipopolysaccharide-induced metastatic growth is associated with increased angiogenesis, vascular permeability and tumor cell invasion. Int. J. Cancer, 2002, 101(5), 415-422.
[http://dx.doi.org/10.1002/ijc.10632] [PMID: 12216068]
[21]
Guo, Z.; Chen, L.; Zhu, Y.; Zhang, Y.; He, S.; Qin, J.; Tang, X.; Zhou, J.; Wei, Y. Double-stranded RNA-induced TLR3 activation inhibits angiogenesis and triggers apoptosis of human hepatocellular carcinoma cells. Oncol. Rep., 2012, 27(2), 396-402.
[PMID: 22075935]
[22]
Tanja, MG.; Rue, B. The polymorphisms in Toll-like receptor genes and cancer risk. Period biol., 2012, 114(4), 461-469.
[23]
Miller, S.A.; Dykes, D.D.; Polesky, H.F.A. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res., 1988, 16(3), 1215.
[http://dx.doi.org/10.1093/nar/16.3.1215] [PMID: 3344216]
[24]
Kirkpatrick, L.A.; Feeney, B.C. A simple guide to IBM SPSS statistics for version 20.0. Student ed. Belmont; Calif.: Wadsworth, Cengage Learning, 2013.
[25]
Hajarizadeh, B.; Grebely, J.; Dore, G.J. Epidemiology and natural history of HCV infection. Nat. Rev. Gastroenterol. Hepatol., 2013, 10(9), 553-562.
[http://dx.doi.org/10.1038/nrgastro.2013.107] [PMID: 23817321]
[26]
Ahmed, O.A.; Kaisar, H.H.; Hawash, N.; Samir, H.; Shabana, S.S.T.; Hassan A Fouad, M.; Rizk, F.; Abd-Elsalam, S. Efficacy of sofosbuvir plus ribavirin with or without peginterferon-alfa in treatment of a cohort of Egyptian patients with hepatitis C virus infection. Infect. Disord. Drug Targets, 2017, 17(2), 95-100.
[http://dx.doi.org/10.2174/1871526517666170417143216] [PMID: 28413993]
[27]
Abd-Elsalam, S.; Sharaf-Eldin, M.; Soliman, S.; Elfert, A.; Badawi, R.; Ahmad, Y.K. Efficacy and safety of sofosbuvir plus ribavirin for treatment of cirrhotic patients with genotype 4 hepatitis C virus in real-life clinical practice. Arch. Virol., 2018, 163(1), 51-56.
[http://dx.doi.org/10.1007/s00705-017-3573-0] [PMID: 28983675]
[28]
Ahmed, O.A.; Kaisar, H.H.; Badawi, R.; Hawash, N.; Samir, H.; Shabana, S.S.; Fouad, M.H.A.; Rizk, F.H.; Khodeir, S.A.; Abd-Elsalam, S. Efficacy and safety of sofosbuvir-ledipasvir for treatment of a cohort of Egyptian patients with chronic hepatitis C genotype 4 infection. Infect. Drug Resist., 2018, 11(11), 295-298.
[http://dx.doi.org/10.2147/IDR.S153060] [PMID: 29535545]
[29]
Ahmed, O.A.; Elsebaey, M.A.; Fouad, M.H.A.; Elashry, H.; Elshafie, A.I.; Elhadidy, A.A.; Esheba, N.E.; Elnaggar, M.H.; Soliman, S.; Abd-Elsalam, S. Outcomes and predictors of treatment response with sofosbuvir plus daclatasvir with or without ribavirin in Egyptian patients with genotype 4 hepatitis C virus infection. Infect. Drug Resist., 2018, 11(11), 441-445.
[http://dx.doi.org/10.2147/IDR.S160593] [PMID: 29628768]
[30]
Ahmed, O.A.; Safwat, E.; Khalifa, M.O.; Elshafie, A.I.; Fouad, M.H.A.; Salama, M.M.; Naguib, G.G.; Eltabbakh, M.M.; Sherief, A.F.; Abd-Elsalam, S. Sofosbuvir Plus Daclatasvir in Treatment of Chronic Hepatitis C Genotype 4 Infection in a Cohort of Egyptian Patients: An Experiment the Size of Egyptian Village. Int. J. Hepatol., 2018, 20189616234
[http://dx.doi.org/10.1155/2018/9616234] [PMID: 29755792]
[31]
Abd-Elsalam, S.; Badawi, R.; Elnawasany, S. Sofosbuvir, pegylated interferon and ribavirin in treatment of an Egyptian cohort with hepatitis C virus infection in real life clinical practice. Infect. Disord. Drug Targets, 2018, 2018 Epub ahead of print
[http://dx.doi.org/10.2174/1871526518666180912121835] [PMID: 30207250]
[32]
Abdelmoemen, G.; Khodeir, S.A.; Abou-Saif, S.; Kobtan, A.; Abd-Elsalam, S. Prevalence of occult hepatitis C virus among hemodialysis patients in Tanta university hospitals: a single-center study. Environ. Sci. Pollut. Res. Int., 2018, 25(6), 5459-5464.
[http://dx.doi.org/10.1007/s11356-017-0897-y] [PMID: 29214477]
[33]
World Health Organization (WHO) Europe. Hepatitis: data and statistics., 2016.http://www.euro.who.int/en/health-topics/communicable-diseases/ hepatitis /data-and-statistics
[34]
Boyle, P.; Levin, B. World cancer report; Lyon: IARC Press, 2008. ISBN 978 92 832 0423 7.
[35]
Kim, S.H.; Lim, H.K.; Lee, W.J.; Cho, J.M.; Jang, H.J. Needle-tract implantation in hepatocellular carcinoma: frequency and CT findings after biopsy with a 19.5-gauge automated biopsy gun. Abdom. Imaging, 2000, 25(3), 246-250.
[http://dx.doi.org/10.1007/s002610000025] [PMID: 10823443]
[36]
Baghdady, I.; Fouad, F.; Sayed, M. Serum markers for the early detection of hepatocellular carcinoma in patients with chronic viral hepatitis C infection. Menoufia Med. J., 2014, 27, 744-750.
[37]
Mokhtar, N.; Gouda, I.; Adel, I. Cancer pathology registry 2003-2004 and time trend analysis.malignant digestive system tumors; Mokhtar, N.; Gouda, I; Adel, I., Ed.; Elsheraa Press: Cairo, 2007, pp. 55-67.
[38]
Shehata, M.A.; Abou El-Enein, A.; El-Sharnouby, G.A. Significance of toll-like receptors 2 and 4 mRNA expression in chronic hepatitis C virus infection. Egypt. J. Immunol., 2006, 13(1), 141-152.
[PMID: 17974158]
[39]
Lee, S.O.; Brown, R.A.; Razonable, R.R. Association between a functional polymorphism in Toll-like receptor 3 and chronic hepatitis C in liver transplant recipients. Transpl. Infect. Dis., 2013, 15(2), 111-119.
[http://dx.doi.org/10.1111/tid.12033] [PMID: 23240626]
[40]
Lopes, JAG.; Canha, MB.; Unes, PP. Innate immunity and hepatocarcinoma: Can toll-like receptors open the door to oncogenesis? World J. Hepatol., 2016, 28(3), 162-182.
[41]
Kurt, M.; Onal, K.; Sayilir, A. The Role of Mean Platelet volume in the diagnosis of hepatocellular carcinoma in patients with chronic liver disease. Hepatogastroenterology, 2012, 59
[42]
Metwaly, H.A.; Al-Gayyar, M.M.; Eletreby, S.; Ebrahim, M.A.; El-Shishtawy, M.M. Relevance of serum levels of interleukin-6 and syndecan-1 in patients with hepatocellular carcinoma. Sci. Pharm., 2012, 80(1), 179-188.
[http://dx.doi.org/10.3797/scipharm.1110-07] [PMID: 22396913]
[43]
Elshayeb, E.I.; Mohamed, A.R.K.; Nada, F.E. Serum Serotonin as a Novel Marker for Hepatocellular Carcinoma. Adv Res Gastroentero Hepatol, 2016, 1(5)555571
[http://dx.doi.org/10.19080/ARGH.2016.01.555571]
[44]
Soyemi, O.M.; Otegbayo, J.A.; Ola, S.O.; Akere, A.; Soyemi, T. Comparative diagnostic efficacy of serum squamous cell carcinoma antigen in hepatocellular carcinoma. BMC Res. Notes, 2012, 5, 403.
[http://dx.doi.org/10.1186/1756-0500-5-403] [PMID: 22856336]
[45]
Zhou, Y.; Yin, X.; Ying, J. Golgi protein 73 versus alpha-fetoprotein as a biomarker for hepatocellular carcinoma: A diagnostic meta-analysis. BMC Cancer, 2012, 12, 12-17.
[http://dx.doi.org/10.1186/1471-2407-12-17]
[46]
Tung, E.K.; Ng, I.O. Biomarker for HCC diagnosis. Linchuang Zhongliuxue Zazhi, 2012, 1, 5.
[47]
Colombo, M. Screening for cancer in viral hepatitis. Clin. Liver Dis., 2001, 5(1), 109-122.
[http://dx.doi.org/10.1016/S1089-3261(05)70156-2] [PMID: 11218910]
[48]
Johnson, P.J. The role of serum alpha-fetoprotein estimation in the diagnosis and management of hepatocellular carcinoma. Clin. Liver Dis., 2001, 5(1), 145-159.
[http://dx.doi.org/10.1016/S1089-3261(05)70158-6] [PMID: 11218912]
[49]
Sironi, M.; Biasin, M.; Cagliani, R.; Forni, D.; De Luca, M.; Saulle, I.; Lo Caputo, S.; Mazzotta, F.; Macías, J.; Pineda, J.A.; Caruz, A.; Clerici, M. A common polymorphism in TLR3 confers natural resistance to HIV-1 infection. J. Immunol., 2012, 188(2), 818-823.
[http://dx.doi.org/10.4049/jimmunol.1102179] [PMID: 22174453]
[50]
Dai, J.; Hu, Z.; Dong, J.; Xu, L.; Pan, S.; Jiang, Y.; Jin, G.; Chen, Y.; Shen, H. Host immune gene polymorphisms were associated with the prognosis of non-small-cell lung cancer in Chinese. Int. J. Cancer, 2012, 130(3), 671-676.
[http://dx.doi.org/10.1002/ijc.26067] [PMID: 21412764]
[51]
Kawai, T.; Akira, S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat. Immunol., 2010, 11(5), 373-384.
[http://dx.doi.org/10.1038/ni.1863] [PMID: 20404851]
[52]
Castro, F.A.; Försti, A.; Buch, S.; Kalthoff, H.; Krauss, C.; Bauer, M.; Egberts, J.; Schniewind, B.; Broering, D.C.; Schreiber, S.; Schmitt, M.; Hampe, J.; Hemminki, K.; Schafmayer, C. TLR-3 polymorphism is an independent prognostic marker for stage II colorectal cancer. Eur. J. Cancer, 2011, 47(8), 1203-1210.
[http://dx.doi.org/10.1016/j.ejca.2010.12.011] [PMID: 21239167]
[53]
Li, G.; Zheng, Z. Toll-like receptor 3 genetic variants and susceptibility to hepatocellular carcinoma and HBV-related hepatocellular carcinoma. Tumour Biol., 2013, 34(3), 1589-1594.
[http://dx.doi.org/10.1007/s13277-013-0689-z] [PMID: 23404408]
[54]
Bergé, M.; Bonnin, P.; Sulpice, E.; Vilar, J.; Allanic, D.; Silvestre, J.S.; Lévy, B.I.; Tucker, G.C.; Tobelem, G.; Merkulova-Rainon, T. Small interfering RNAs induce target-independent inhibition of tumor growth and vasculature remodeling in a mouse model of hepatocellular carcinoma. Am. J. Pathol., 2010, 177(6), 3192-3201.
[http://dx.doi.org/10.2353/ajpath.2010.100157] [PMID: 20971743]
[55]
Chew, V.; Tow, C.; Huang, C.; Bard-Chapeau, E.; Copeland, N.G.; Jenkins, N.A.; Weber, A.; Lim, K.H.; Toh, H.C.; Heikenwalder, M.; Ng, I.O.; Nardin, A.; Abastado, J.P. Toll-like receptor 3 expressing tumor parenchyma and infiltrating natural killer cells in hepatocellular carcinoma patients. J. Natl. Cancer Inst., 2012, 104(23), 1796-1807.
[http://dx.doi.org/10.1093/jnci/djs436] [PMID: 23197495]
[56]
Al-Qahtani, A.; Al-Ahdal, M.; Abdo, A.; Sanai, F.; Al-Anazi, M.; Khalaf, N.; Viswan, N.A.; Al-Ashgar, H.; Al-Humaidan, H.; Al-Suwayeh, R.; Hussain, Z.; Alarifi, S.; Al-Okail, M.; Almajhdi, F.N. Toll-like receptor 3 polymorphism and its association with hepatitis B virus infection in Saudi Arabian patients. J. Med. Virol., 2012, 84(9), 1353-1359.
[http://dx.doi.org/10.1002/jmv.23271] [PMID: 22825813]
[57]
Xu, Y.Y.; Chen, L.; Wang, G.L.; Zhou, J.M.; Zhang, Y.X.; Wei, Y.Z.; Zhu, Y.Y.; Qin, J. A synthetic dsRNA, as a TLR3 pathwaysynergist, combined with sorafenib suppresses HCC in vitro and in vivo. BMC Cancer, 2013, 13, 527.
[http://dx.doi.org/10.1186/1471-2407-13-527] [PMID: 24195809]
[58]
Zou, H.; Wang, W.K.; Liu, Y.L.; Braddock, M.; Zheng, M.H.; Huang, D.S. Toll-like receptors in hepatocellular carcinoma: potential novel targets for pharmacological intervention. Expert Opin. Ther. Targets, 2016, 20(9), 1127-1135.
[http://dx.doi.org/10.1517/14728222.2016.1168809] [PMID: 26998881]
[59]
Shimaa, M.M. 2017.
[60]
Watany, M.; Badawi, R.; Elkhalawany, W.; Abd-Elsalam, S. Study of Dickkopf-1 (DKK-1) Gene Expression in Hepatocellular Carcinoma Patients. J. Clin. Diagn. Res., 2017, 11(2), OC32-OC34.
[http://dx.doi.org/10.7860/JCDR/2017/23095.9450] [PMID: 28384913]


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VOLUME: 20
ISSUE: 5
Year: 2020
Published on: 04 June, 2020
Page: [382 - 389]
Pages: 8
DOI: 10.2174/1568009620666200319102929
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