Toll-like receptors in hepatocellular carcinoma: potential novel targets for pharmacological intervention

References

• Kagan JC, Su T, Horng T, et al. TRAM couples endocytosis of toll-like receptor 4 to the induction of interferon-beta. Nat Immunol. 2008;9(4):361–368.
   PubMed Web of Science ®Google Scholar
• Goering J, Pope MR, Fleming SD. tlr2 regulates complement-mediated inflammation induced by blood loss during hemorrhage. Shock. 2016;45(1):33–39.
   PubMed Web of Science ®Google Scholar
• Singh V, Srivastava N, Kapoor R, et al. Single-nucleotide polymorphisms in genes encoding toll-like receptor −2, −3, −4, and −9 in a case-control study with bladder cancer susceptibility in a North Indian population. Arch Med Res. 2013;44(1):54–61.
   PubMed Web of Science ®Google Scholar
• de Oliveira JG, Silva AE. Polymorphisms of the TLR2 and TLR4 genes are associated with risk of gastric cancer in a Brazilian population. World J Gastroenterol. 2012;18(11):1235–1242.
   PubMed Web of Science ®Google Scholar
• Mandal RK, George GP, Mittal RD. Association of toll-like receptor (TLR) 2, 3 and 9 genes polymorphism with prostate cancer risk in North Indian population. Mol Biol Rep. 2012;39(7):7263–7269.
   PubMed Web of Science ®Google Scholar
• Pandey S, Mittal RD, Srivastava M, et al. Impact of toll-like receptors [TLR] 2 (−196 to −174 del) and TLR 4 (Asp299Gly, Thr399Ile) in cervical cancer susceptibility in North Indian women. Gynecol Oncol. 2009;114(3):501–505.
   PubMed Web of Science ®Google Scholar
• Yang ZH, Dai Q, Gu YJ, et al. Cytokine and chemokine modification by toll-like receptor polymorphisms is associated with nasopharyngeal carcinoma. Cancer Sci. 2012;103(4):653–658.
   PubMed Web of Science ®Google Scholar
• Boraska Jelavic T, Barisic M, Drmic Hofman I, et al. Microsatelite GT polymorphism in the toll-like receptor 2 is associated with colorectal cancer. Clin Genet. 2006;70(2):156–160.
   PubMed Web of Science ®Google Scholar
• Szabo G, Dolganiuc A, Mandrekar P. Pattern recognition receptors: a contemporary view on liver diseases. Hepatology. 2006;44(2):287–298.
   PubMed Web of Science ®Google Scholar
• Gao B, Jeong WI, Tian Z. Liver: an organ with predominant innate immunity. Hepatology. 2008;47(2):729–736.
   PubMed Web of Science ®Google Scholar
• Lin H, Hua F, Hu ZW. Autophagic flux, supported by toll-like receptor 2 activity, defends against the carcinogenesis of hepatocellular carcinoma. Autophagy. 2012;8(12):1859–1861.
   PubMed Web of Science ®Google Scholar
• Kennedy NJ, Cellurale C, Davis RJ. A radical role for p38 MAPK in tumor initiation. Cancer Cell. 2007;11(2):101–103.
   PubMed Web of Science ®Google Scholar
• Lin H, Liu XB, Yu JJ, et al. Antioxidant N-acetylcysteine attenuates hepatocarcinogenesis by inhibiting ROS/ER stress in TLR2 deficient mouse. PLoS One. 2013;8(10):e74130.
   Google Scholar
• Lin H, Yan J, Wang Z, et al. Loss of immunity-supported senescence enhances susceptibility to hepatocellular carcinogenesis and progression in toll-like receptor 2-deficient mice. Hepatology. 2013;57(1):171–182.
   PubMed Web of Science ®Google Scholar
• Li S, Sun R, Chen Y, et al. TLR2 limits development of hepatocellular carcinoma by reducing IL18-mediated immunosuppression. Cancer Res. 2015;75(6):986–995.
   PubMed Web of Science ®Google Scholar
• Huang Y, Cai B, Xu M, et al. Gene silencing of toll-like receptor 2 inhibits proliferation of human liver cancer cells and secretion of inflammatory cytokines. Plos One. 2012;7(7):e38890.
   Google Scholar
• Shi W, Su L, Li Q, et al. Suppression of toll-like receptor 2 expression inhibits the bioactivity of human hepatocellular carcinoma. Tumour Biol. 2014;35(10):9627–9637.
   PubMed Web of Science ®Google Scholar
• Nischalke HD, Coenen M, Berger C, et al. The toll-like receptor 2 (TLR2) −196 to −174 del/ins polymorphism affects viral loads and susceptibility to hepatocellular carcinoma in chronic hepatitis C. Int J Cancer. Journal international du cancer. 2012;130(6):1470–1475.
   PubMed Web of Science ®Google Scholar
• Salaun B, Coste I, Rissoan MC, et al. TLR3 can directly trigger apoptosis in human cancer cells. J Immunol. 2006;176(8):4894–4901.
   PubMed Web of Science ®Google Scholar
• Salaun B, Lebecque S, Matikainen S, et al. Toll-like receptor 3 expressed by melanoma cells as a target for therapy? Clin Cancer Res. 2007;13(15 Pt 1):4565–4574.
   PubMed Web of Science ®Google Scholar
• Testro AG, Visvanathan K. Toll-like receptors and their role in gastrointestinal disease. J Gastroenterol Hepatol. 2009;24(6):943–954.
   PubMed Web of Science ®Google Scholar
• Matijevic T, Marjanovic M, Pavelic J. Functionally active toll-like receptor 3 on human primary and metastatic cancer cells. Scand J Immunol. 2009;70(1):18–24.
   PubMed Web of Science ®Google Scholar
• Paone A, Starace D, Galli R, et al. Toll-like receptor 3 triggers apoptosis of human prostate cancer cells through a PKC-alpha-dependent mechanism. Carcinogenesis. 2008;29(7):1334–1342.
   PubMed Web of Science ®Google Scholar
• Xu YY, Chen L, Wang GL, et al. A synthetic dsRNA, as a TLR3 pathwaysynergist, combined with sorafenib suppresses HCC in vitro and in vivo. BMC Cancer. 2013;13:527.
   PubMed Web of Science ®Google Scholar
• Heylbroeck C, Balachandran S, Servant MJ, et al. The IRF-3 transcription factor mediates Sendai virus-induced apoptosis. J Virol. 2000;74(8):3781–3792.
   PubMed Web of Science ®Google Scholar
• Huang X, Li H, Wang J, et al. Genetic polymorphisms in toll-like receptor 3 gene are associated with the risk of hepatitis B virus-related liver diseases in a Chinese population. Gene. 2015;569(2):218–224.
   PubMed Web of Science ®Google Scholar
• Chew V, Abastado J-P. Immunomodulation of the tumor microenvironment by toll-like receptor-3 (TLR3) ligands. Oncoimmunology. 2013;2(4):e23493.
   Google Scholar
• Wu J, Lu M, Meng Z, et al. Toll-like receptor-mediated control of HBV replication by nonparenchymal liver cells in mice. Hepatology. 2007;46(6):1769–1778.
   PubMed Web of Science ®Google Scholar
• Shen P, Jiang T, Lu H, et al. Combination of poly I:C and arsenic trioxide triggers apoptosis synergistically via activation of TLR3 and mitochondrial pathways in hepatocellular carcinoma cells. Cell Biol Int. 2011;35(8):803–810.
   PubMed Web of Science ®Google Scholar
• Cheung PF, Yip CW, Ng LW, et al. Restoration of natural killer activity in hepatocellular carcinoma by treatment with antibody against granulin-epithelin precursor. Oncoimmunology. 2015;4(7):e1016706.
   Google Scholar
• Liu C. Guardian and selective killer: the versatile functions of TLR3 in hepatocellular carcinoma. J Natl Cancer Inst. 2012;104(23):1780–1782.
   PubMedGoogle Scholar
• Abe R, Fujita Y, Yamagishi S. Angiogenesis and metastasis inhibitors for the treatment of malignant melanoma. Mini Rev Med Chem. 2007;7(6):649–661.
   PubMed Web of Science ®Google Scholar
• Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285(21):1182–1186.
   PubMed Web of Science ®Google Scholar
• Dudek A, Gupta K, Ramakrishnan S, et al. Tumor angiogenesis. J Oncol. 2010;2010:1–2.
   Google Scholar
• Guo Z, Chen L, Zhu Y, et al. Double-stranded RNA-induced TLR3 activation inhibits angiogenesis and triggers apoptosis of human hepatocellular carcinoma cells. Oncol Rep. 2012;27(2):396–402.
   PubMed Web of Science ®Google Scholar
• Xu YY, Chen L, Zhou JM, et al. Inhibitory effect of dsRNA TLR3 agonist in a rat hepatocellular carcinoma model. Mol Med Rep. 2013;8(4):1037–1042.
   PubMed Web of Science ®Google Scholar
• Liu T, Matsuguchi T, Tsuboi N, et al. Differences in expression of toll-like receptors and their reactivities in dendritic cells in BALB/c and C57BL/6 mice. Infect Immun. 2002;70(12):6638–6645.
   PubMed Web of Science ®Google Scholar
• Pimentel-Nunes P, Soares JB, Roncon-Albuquerque R Jr., et al. Toll-like receptors as therapeutic targets in gastrointestinal diseases. Expert Opin Ther Targets. 2010;14(4):347–368.
   PubMed Web of Science ®Google Scholar
• Rakoff-Nahoum S, Medzhitov R. Toll-like receptors and cancer. Nat Rev Cancer. 2009;9(1):57–63.
   PubMed Web of Science ®Google Scholar
• Chen R, Alvero AB, Silasi DA, et al. Cancers take their toll–the function and regulation of toll-like receptors in cancer cells. Oncogene. 2008;27(2):225–233.
   PubMed Web of Science ®Google Scholar
• Gu J, Sun R, Shen S, et al. The influence of TLR4 agonist lipopolysaccharides on hepatocellular carcinoma cells and the feasibility of its application in treating liver cancer. Onco Targets Ther. 2015;8:2215–2225.
   PubMed Web of Science ®Google Scholar
• Li H, Li Y, Liu D, et al. LPS promotes epithelial-mesenchymal transition and activation of TLR4/JNK signaling. Tumour Biol. 2014;35(10):10429–10435.
   PubMed Web of Science ®Google Scholar
• Wang Y, Cai J, Zeng X, et al. Downregulation of toll-like receptor 4 induces suppressive effects on hepatitis B virus-related hepatocellular carcinoma via ERK1/2 signaling. BMC Cancer. 2015;15:821.
   PubMed Web of Science ®Google Scholar
• Liu WT, Jing YY, Yu GF, et al. Toll like receptor 4 facilitates invasion and migration as a cancer stem cell marker in hepatocellular carcinoma. Cancer Letters. 2015;358(2):136–143.
   PubMed Web of Science ®Google Scholar
• Kubes P, Mehal WZ. Sterile inflammation in the liver. Gastroenterology. 2012;143(5):1158–1172.
   PubMed Web of Science ®Google Scholar
• Matijevic T, Pavelic J. Toll-like receptors: cost or benefit for cancer? Curr Pharm Des. 2010;16(9):1081–1090.
   PubMed Web of Science ®Google Scholar
• Wang Z, Lin H, Hua F, et al. Repairing DNA damage by XRCC6/KU70 reverses TLR4-deficiency-worsened HCC development via restoring senescence and autophagic flux. Autophagy. 2013;9(6):925–927.
   PubMed Web of Science ®Google Scholar
• Wang Y, Tu Q, Yan W, et al. CXC195 suppresses proliferation and inflammatory response in LPS-induced human hepatocellular carcinoma cells via regulating TLR4-MyD88-TAK1-mediated NF-kappaB and MAPK pathway. Biochem Biophys Res Commun. 2015;456(1):373–379.
   PubMed Web of Science ®Google Scholar
• Kew MC. Hepatitis B virus x protein in the pathogenesis of hepatitis B virus-induced hepatocellular carcinoma. J Gastroenterol Hepatol. 2011;26(Suppl 1):144–152.
   PubMed Web of Science ®Google Scholar
• Magee JA, Piskounova E, Morrison SJ. Cancer stem cells: impact, heterogeneity, and uncertainty. Cancer Cell. 2012;21(3):283–296.
   PubMed Web of Science ®Google Scholar
• Coffman RL, Sher A, Seder RA. Vaccine adjuvants: putting innate immunity to work. Immunity. 2010;33(4):492–503.
   PubMed Web of Science ®Google Scholar
• Steinhagen F, Kinjo T, Bode C, et al. TLR-based immune adjuvants. Vaccine. 2011;29(17): 3341–3355.
   PubMed Web of Science ®Google Scholar
• Hoebe CJ, Vermeiren AP, Dukers-Muijrers NH. Revaccination with Fendrix(R) or HBVaxPro(R) results in better response rates than does revaccination with three doses of Engerix-B(R) in previous non-responders. Vaccine. 2012;30(48):6734–6737.
   PubMed Web of Science ®Google Scholar
• Tanaka J, Sugimoto K, Shiraki K, et al. Functional cell surface expression of toll-like receptor 9 promotes cell proliferation and survival in human hepatocellular carcinomas. Int J Oncol. 2010;37(4):805–814.
   PubMed Web of Science ®Google Scholar
• Mohamed FE, Al-Jehani RM, Minogue SS, et al. Effect of toll-like receptor 7 and 9 targeted therapy to prevent the development of hepatocellular carcinoma. Liver Int. 2015;35(3):1063–1076.
   PubMed Web of Science ®Google Scholar
• Beutler B, Jiang Z, Georgel P, et al. Genetic analysis of host resistance: toll-like receptor signaling and immunity at large. Annu Rev Immunol. 2006;24:353–389.
   PubMed Web of Science ®Google Scholar
• Takeda K, Akira S. Toll-like receptors in innate immunity. Int Immunol. 2005;17(1):1–14.
   PubMed Web of Science ®Google Scholar
• Takeda K, Kaisho T, Akira S. Toll-like receptors. Annu Rev Immunol. 2003;21:335–376.
   PubMed Web of Science ®Google Scholar
• Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;124(4):783–801.
   PubMed Web of Science ®Google Scholar
• Nojiri K, Sugimoto K, Shiraki K, et al. The expression and function of toll-like receptors 3 and 9 in human colon carcinoma. Oncol Rep. 2013;29(5):1737–1743.
   PubMed Web of Science ®Google Scholar
• Eiro N, Altadill A, Juarez LM, et al. Toll-like receptors 3, 4 and 9 in hepatocellular carcinoma: relationship with clinicopathological characteristics and prognosis. Hepatol Res. 2014;44(7):769–778.
   PubMed Web of Science ®Google Scholar
• Peng S, Geng J, Sun R, et al. Polyinosinic-polycytidylic acid liposome induces human hepatoma cells apoptosis which correlates to the up-regulation of RIG-I like receptors. Cancer Sci. 2009;100(3):529–536.
   PubMed Web of Science ®Google Scholar
• Yu P, Cheng X, Guo J, et al. Toll-like receptors 2/4 agonists: a potential strategy for preventing invasion and metastasis of hepatocellular carcinoma. Gut. 2010;59(10):1447–1448; author reply 1448-1449
   PubMed Web of Science ®Google Scholar
• Liu Y, Yan W, Tohme S, et al. Hypoxia induced HMGB1 and mitochondrial DNA interactions mediate tumor growth in hepatocellular carcinoma through toll-like receptor 9. J Hepatol. 2015;63(1):114–121.
   PubMed Web of Science ®Google Scholar
• Fukata M, Chen A, Vamadevan AS, et al. Toll-like receptor-4 promotes the development of colitis-associated colorectal tumors. Gastroenterology. 2007;133(6):1869–1881.
   PubMed Web of Science ®Google Scholar
• Zhang Y, Lin A, Sui Q, et al. Phosphorothioate modification of the TLR9 ligand CpG ODN inhibits poly(I:C)-induced apoptosis of hepatocellular carcinoma by entry blockade. Cancer Letters. 2014;355(1):76–84.
   PubMed Web of Science ®Google Scholar
• Schmidt C. Clinical setbacks for toll-like receptor 9 agonists in cancer. Nat Biotechnol. 2007;25(8):825–826.
   PubMed Web of Science ®Google Scholar
• Mantovani A, Allavena P, Sica A, et al. Cancer-related inflammation. Nature. 2008;454(7203):436–444.
   PubMed Web of Science ®Google Scholar
• Tsung A, Tohme S, Billiar TR. High-mobility group box-1 in sterile inflammation. J Intern Med. 2014;276(5):425–443.
   PubMed Web of Science ®Google Scholar
• Nishimura M, Naito S. Tissue-specific mRNA expression profiles of human toll-like receptors and related genes. Biol Pharm Bull. 2005;28(5):886–892.
   PubMed Web of Science ®Google Scholar
• Xia C, Lu M, Zhang Z, et al. TLRs antiviral effect on hepatitis B virus in HepG2 cells. J Appl Microbiol. 2008;105(5):1720–1727.
   PubMed Web of Science ®Google Scholar
• Liang Z, Wu S, Li Y, et al. Activation of toll-like receptor 3 impairs the dengue virus serotype 2 replication through induction of IFN-beta in cultured hepatoma cells. Plos One. 2011;6(8):e23346.
   Google Scholar
• Burdelya LG, Krivokrysenko VI, Tallant TC, et al. An agonist of toll-like receptor 5 has radioprotective activity in mouse and primate models. Science. 2008;320(5873):226–230.
   PubMed Web of Science ®Google Scholar
• Rhee SH, Im E, Pothoulakis C. Toll-like receptor 5 engagement modulates tumor development and growth in a mouse xenograft model of human colon cancer. Gastroenterology. 2008;135(2):518–528.
   PubMed Web of Science ®Google Scholar
• Cai Z, Sanchez A, Shi Z, et al. Activation of toll-like receptor 5 on breast cancer cells by flagellin suppresses cell proliferation and tumor growth. Cancer Res. 2011;71(7):2466–2475.
   PubMed Web of Science ®Google Scholar
• Yang C, Yun Q, Sun H, et al. Non-invasive imaging of toll-like receptor 5 expression using I-labeled mAb in the mice bearing H22 tumors. Oncol Lett. 2014;7(6):1919–1924.
   PubMed Web of Science ®Google Scholar
• Burdelya LG, Brackett CM, Kojouharov B, et al. Central role of liver in anticancer and radioprotective activities of toll-like receptor 5 agonist. Proc Natl Acad Sci U S A. 2013;110(20):E1857–E1866.
   PubMed Web of Science ®Google Scholar
• Cherfils-Vicini J, Platonova S, Gillard M, et al. Triggering of TLR7 and TLR8 expressed by human lung cancer cells induces cell survival and chemoresistance. J Clin Invest. 2010;120(4):1285–1297.
   PubMed Web of Science ®Google Scholar
• Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol. 2004;4(7):499–511.
   PubMed Web of Science ®Google Scholar
• Wolska A, Cebula-Obrzut B, Smolewski P, et al. Effects of toll-like receptor 7 and toll-like receptor 9 signaling stimulators and inhibitors on chronic lymphocytic leukemia cells ex vivo and their interactions with cladribine. Leuk Lymphoma. 2013;54(6):1268–1278.
   PubMed Web of Science ®Google Scholar
• Ochi A, Graffeo CS, Zambirinis CP, et al. Toll-like receptor 7 regulates pancreatic carcinogenesis in mice and humans. J Clin Invest. 2012;122(11):4118–4129.
   PubMed Web of Science ®Google Scholar
• Lin KJ, Lin TM, Wang CH, et al. Down-regulation of toll-like receptor 7 expression in hepatitis-virus-related human hepatocellular carcinoma. Hum Pathol. 2013;44(4):534–541.
   PubMed Web of Science ®Google Scholar
• Zhou Z, Yu X, Zhang J, et al. TLR7/8 agonists promote NK-DC cross-talk to enhance NK cell anti-tumor effects in hepatocellular carcinoma. Cancer Letters. 2015;369(2):298–306.
   PubMed Web of Science ®Google Scholar
• Smits EL, Ponsaerts P, Berneman ZN, et al. The use of TLR7 and TLR8 ligands for the enhancement of cancer immunotherapy. Oncologist. 2008;13(8):859–875.
   PubMed Web of Science ®Google Scholar
• Lee M, Park CS, Lee YR, et al. Resiquimod, a TLR7/8 agonist, promotes differentiation of myeloid-derived suppressor cells into macrophages and dendritic cells. Arch Pharm Res. 2014;37(9):1234–1240.
   PubMed Web of Science ®Google Scholar
• Kumar H, Kawai T, Akira S. Toll-like receptors and innate immunity. Biochem Biophys Res Commun. 2009;388(4):621–625.
   PubMed Web of Science ®Google Scholar
• Jing YY, Han ZP, Sun K, et al. Toll-like receptor 4 signaling promotes epithelial-mesenchymal transition in human hepatocellular carcinoma induced by lipopolysaccharide. BMC Med. 2012;10:98.
   PubMed Web of Science ®Google Scholar
• Seki E, Brenner DA. Toll-like receptors and adaptor molecules in liver disease: update. Hepatology. 2008;48(1):322–335.
   PubMed Web of Science ®Google Scholar
• Takeda K, Akira S. Microbial recognition by toll-like receptors. J Dermatol Sci. 2004;34(2):73–82.
   PubMed Web of Science ®Google Scholar
• Kawai T, Akira S. TLR signaling. Cell Death Differ. 2006;13(5):816–825.
   PubMed Web of Science ®Google Scholar
• Lobo NA, Shimono Y, Qian D, et al. The biology of cancer stem cells. Annu Rev Cell Dev Biol. 2007;23:675–699.
   PubMed Web of Science ®Google Scholar
• Sun YF, Xu Y, Yang XR, et al. Circulating stem cell-like epithelial cell adhesion molecule-positive tumor cells indicate poor prognosis of hepatocellular carcinoma after curative resection. Hepatology. 1458-1468;57(4):2013.
   Google Scholar
• Dapito DH, Mencin A, Gwak GY, et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell. 2012;21(4):504–516.
   PubMed Web of Science ®Google Scholar
• Darnaud M, Faivre J, Moniaux N. Targeting gut flora to prevent progression of hepatocellular carcinoma. J Hepatol. 2013;58(2):385–387.
   PubMed Web of Science ®Google Scholar
• French SW. Epigenetic events in liver cancer resulting from alcoholic liver disease. Alcohol Res. 2013;35(1):57–67.
   PubMed Web of Science ®Google Scholar
• Chen CL, Tsukamoto H, Liu JC, et al. Reciprocal regulation by TLR4 and TGF-beta in tumor-initiating stem-like cells. J Clin Invest. 2013;123(7):2832–2849.
   PubMed Web of Science ®Google Scholar
• Tsukamoto H, Mishra L, Machida K. Alcohol, TLR4-TGF-beta antagonism, and liver cancer. Hepatol Int. 2014;8(Suppl 2):408–412.
   PubMed Web of Science ®Google Scholar
• Naugler WE, Sakurai T, Kim S, et al. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science. 2007;317(5834):121–124.
   PubMed Web of Science ®Google Scholar