Advertisement

Prognostic value of toll-like receptor 4 and nuclear factor-κBp65 in oral squamous cell carcinoma patients

Published:August 08, 2016DOI:https://doi.org/10.1016/j.oooo.2016.08.002

      Objective

      To investigate toll-like receptor 4 (TLR4) and nuclear factor-κBp65 (NF-κBp65) expression in oral squamous cell carcinoma (OSCC) tissues and the effects of their expression on the outcomes in patients with OSCC.

      Study Design

      TLR4 and NF-κBp65 expression was assessed in 110 patients with OSCC and in 32 normal oral mucosal samples using immunohistochemistry. Correlations between their expression and clinicopathologic parameters, including disease-free survival, disease-specific survival, and overall survival, were analyzed.

      Results

      High TLR4/NF-κBp65 expression was increased in OSCC tissues compared with normal oral mucosal tissues (all P < .05). High cytoplasmic TLR4 and NF-κBp65 expression was significantly correlated with the primary tumor stage, pN stage, differentiation, invasion depth, and pTNM stage (all P < .05). Cytoplasmic TLR4 expression was associated with NF-κBp65 expression in OSCC (all P < .05). Univariate analysis revealed that high cytoplasmic TLR4 and nuclear NF-κBp65 expression was significantly associated with lower disease-free survival, disease-specific survival, and overall survival rates (all P < .001). Further, multivariate analyses identified high cytoplasmic TLR4 and nuclear NF-κBp65 expression as independent prognostic factors (all P < .05).

      Conclusions

      The current findings suggest that the TLR4/NF-κBp65 signaling pathway is associated with survival of patients with OSCC and that it may serve as a potential therapeutic target.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      References

        • Mustafa R.
        • Rajaraman S.M.
        Study on translational medicine of RUNX3 expression in oral precancerous lesions and squamous cell carcinoma.
        J Int Transl Med. 2016; 4: 36-40
        • Yanping Z.
        • Rongchang L.
        Recent advances on salivary biomarkers in OSCC patients.
        J Oral Maxillofac Surg. 2014; 24: 237-240
        • Yakob M.
        • Fuentes L.
        • Wang M.B.
        • et al.
        Salivary biomarkers for detection of oral squamous cell carcinoma: current state and recent advances.
        Curr Oral Health Rep. 2014; 1: 133-141
        • Pratheepa L.
        • Ramani P.
        • Sherlin H.J.
        • et al.
        Expression of emerging novel tumor markers in oral squamous cell carcinoma and their clinical and pathological correlation to determine the prognosis and usefulness as a therapeutic target: a systematic review.
        J Nat Sci Res. 2012; 2: 57-66
        • Tingru S.
        • Meng Z.
        • Xiaozhi L.
        Investigation on the tumor markers of oral squamous cell carcinoma.
        J Mol Diagn. 2016; 02: 123-129
        • Bhattacharya D.
        • Yusuf N.
        Expression of toll-like receptors on breast tumors: taking a toll on tumor microenvironment.
        Int J Breast Cancer. 2012; 2012: 716564-716569
        • Hayden M.S.
        • Ghosh S.
        Signaling to NF-B.
        Genes Dev. 2004; 18: 2195-2224
        • Verstrepen L.
        • Bekaert T.
        • Chau T.L.
        • Tavernier J.
        • Chariot A.
        • Beyaert R.
        TLR-4, IL-1 R and TNF-R signaling to NF-kappaB: variations on a common theme.
        Cell Mol Life Sci. 2008; 65: 2964-2978
        • Tang H.
        • Wang F.
        • Zhou X.F.
        • et al.
        Relationship between TLR4 and NF-κB p65 protein expressions and clinical radiosensitivity of patients with esophageal squamous cell carcinoma.
        Pak J Med Sci. 2014; 30: 982-985
        • Shen B.
        • Dong P.
        • Ying X.J.
        • et al.
        Expression of ABCG2 and NF-κB p65 in nasopharyngeal cancer and its clinical significance.
        Chinese Clin Oncol. 2012; 17: 424-427
        • Alicandri-Ciufelli M.
        • Bonali M.
        • Piccinini A.
        • et al.
        Surgical margins in head and neck squamous cell carcinoma: what is “close”?.
        Eur Arch Otorhinolaryngol. 2013; 270: 2603-2609
        • Sutton D.N.
        • Brown J.S.
        • Rogers S.N.
        • Vaughan E.D.
        • Woolgar J.A.
        The prognostic implications of the surgical margin in oral squamous cell carcinoma.
        Int J Oral Maxillofac Surg. 2003; 32: 30-34
        • Barnes L.
        • Eveson J.W.
        • Reichart P.
        • Sidransky D.
        WHO Classification of Tumours, Pathology and Genetics of Head and Neck Tumours.
        IARC Press, Lyon, France2005
        • Huang S.H.
        • Hwang D.
        • Lockwood G.
        • Goldstein D.P.
        • O'Sullivan B.
        Predictive value of tumor thickness for cervical lymph-node involvement in squamous cell carcinoma of the oral cavity: a meta-analysis of reported studies.
        Cancer. 2009; 115: 1489-1497
        • Weng H.
        • Deng Y.
        • Xie Y.
        • Liu H.
        • Gong F.
        Expression and significance of HMGB1, TLR4 and NF-κB p65 in human epidermal tumors.
        BMC Cancer. 2013; 13: 311-320
        • Remmele W.
        • Stegner H.E.
        • Remmele W.
        • Stegner H.E.
        Vorschlag zur einheitlichen definition eines Immunreaktiven score (IRS) für den immunhistochemischen Östrogenrezeptor-Nachweis (ER-ICA) im Mammakarzinomgewebe.
        Pathologe. 1987; 8 ([in German]): 138-140
        • Landis J.R.
        • Koch G.G.
        The measurement of observer agreement for categorical data.
        Biometrics. 1977; 33: 159-174
        • Madsen C.V.
        • Dahl Steffensen K.
        • Waldstrøm M.
        • Jakobsen A.
        Immunohistochemical expression of platelet-derived growth factor receptors in ovarian cancer patients with long-term follow-up.
        Pathol Res Int. 2012; 2012: 851432-851439
        • Zlobec I.
        • Steele R.
        • Terracciano L.
        • Jass J.R.
        • Lugli A.
        Selecting immunohistochemical cut-off scores for novel biomarkers of progression and survival in colorectal cancer.
        J Clin Pathol. 2007; 60: 1112-1116
        • Ribeiro H.S.
        • Stevanato-Filho P.R.
        • Costa Jr., W.L.
        • Diniz A.L.
        • Herman P.
        • Coimbra F.J.
        Prognostic factors for survival in patients with colorectal liver metastases: experience of a single Brazilian cancer center.
        Arq Gastroenterol. 2012; 49: 266-272
        • Ripert T.
        • Azémar M.D.
        • Ménard J.
        • et al.
        Six years' experience with high-intensity focused ultrasonography for prostate cancer: oncological outcomes using the new “Stuttgart” definition for biochemical failure.
        BJU Int. 2011; 107: 1899-1905
        • Dirk R.
        • Stefan H.
        • Seibold N.D.
        • et al.
        Nuclear expression of p65 (RelA) in patients receiving post-operative radiotherapy for locally advanced squamous cell carcinoma of the head and neck.
        BMC Cancer. 2015; 15: 102-109
        • Cai M.Y.
        • Zhang B.
        • He W.P.
        • et al.
        Decreased expression of PinX1 protein is correlated with tumor development and is a new independent poor prognostic factor in ovarian carcinoma.
        Cancer Sci. 2010; 101: 1543-1549
        • Shi R.
        • Zhao Z.
        • Zhou H.
        • et al.
        Reduced expression of PinX1 correlates to progressive features in patients with prostate cancer.
        Cancer Cell Int. 2014; 14: 46-52
        • Zhang X.K.
        • Xu M.
        • Chen J.W.
        • et al.
        The prognostic significance of tyrosine-protein phosphatase nonreceptor type 12 expression in nasopharyngeal carcinoma.
        Tumour Biol. 2015; 36: 5201-5208
        • Rich A.M.
        • Hussaini H.M.
        • Parachuru V.P.
        • Seymour G.J.
        Toll-like receptors and cancer, particularly oral squamous cell carcinoma.
        Front Immunol. 2014; 5: 464-469
        • DiDonato J.A.
        • Mercurio F.
        • Karin M.
        NF-κB and the link between inflammation and cancer.
        Immunol Rev. 2012; 246: 379-400
        • Inoue J.
        • Gohda J.
        • Akiyama T.
        • Semba K.
        NF-kappaB activation in development and progression of cancer.
        Cancer Sci. 2007; 98: 268-274
        • Xuchen Z.
        • Peiying S.
        • Salman Q.
        • et al.
        Cutting edge: TLR4 deficiency confers susceptibility to lethal oxidant lung injury.
        J Immunol. 2005; 175: 4834-4838
        • Garlanda C.
        • Riva F.
        • Bonavita E.
        • Gentile S.
        • Mantovani A.
        Decoys and regulatory “receptors” of the IL-1/toll-like receptor superfamily.
        Front Immunol. 2013; 4: 180-192
        • Conroy H.
        • Marshall N.A.
        • Mills K.H.
        TLR ligand suppression or enhancement of Treg cells? A double-edged sword in immunity to tumours.
        Oncogene. 2008; 27: 168-180
        • Sussman D.A.
        • Santaolalla R.
        • Bejarano P.A.
        • et al.
        In silico and ex vivo approaches identify a role for toll-like receptor 4 in colorectal cancer.
        J Exp Clin Cancer Res. 2014; 33: 45-57
        • Li Q.
        • Ayshamgul H.
        • Jiang Y.
        • et al.
        Expression of toll-like receptor 4 in cervical cell lines and cervical lesions and its relation to HPV16 infection.
        J Central South University. Med Sci. 2013; 38: 1110-1116
        • Djordjević G.
        • Matusan-Ilijas K.
        • Sinozić E.
        • et al.
        Relationship between vascular endothelial growth factor and nuclear factor-kappaB in renal cell tumors.
        Croat Med J. 2008; 49: 608-617
        • Weichert W.
        • Boehm M.
        • Gekeler V.
        • et al.
        High expression of RelA/p65 is associated with activation of nuclear factor-kappaB-dependent signaling in pancreatic cancer and marks a patient population with poor prognosis.
        Br J Cancer. 2007; 97: 523-530
        • Sun Z.
        • Luo Q.
        • Ye D.
        • Chen W.
        • Chen F.
        Role of toll-like receptor 4 on the immune escape of human oral squamous cell carcinoma and resistance of cisplatin-induced apoptosis.
        Mol Cancer. 2012; 11: 33-44
        • He Z.
        • Deng R.
        • Huang X.
        • et al.
        Lipopolysaccharide enhances OSCC migration by promoting epithelial-mesenchymal transition.
        J Oral Pathol Med. 2015; 44: 685-692
        • Huang B.
        • Zhao J.
        • Li H.
        • et al.
        Toll-like receptors on tumor cells facilitate evasion of immune surveillance.
        Cancer Res. 2005; 65: 5009-5014
        • Kelly M.G.
        • Alvero A.B.
        • Chen R.
        • et al.
        TLR-4 signaling promotes tumor growth and paclitaxel chemoresistance in ovarian cancer.
        Cancer Res. 2006; 66: 3859-3868
        • Zhang J.
        • Heshui W.U.
        • Wang L.
        • et al.
        Expression and significance of TLR2 and TLR4 in pancreatic carcinoma.
        Chin J Gen Surg. 2010; 19: 239-244
        • Kim K.H.
        • Jo M.S.
        • Suh D.S.
        • et al.
        Expression and significance of the TLR4/MyD88 signaling pathway in ovarian epithelial cancers.
        World J Surg Oncol. 2012; 10: 193-200
        • Andy W.
        • Bonnet M.C.
        • Manolis P.
        NF-κB in the regulation of epithelial homeostasis and inflammation.
        Cell Res. 2011; 21: 146-158
        • Yeh H.C.
        • Huang C.H.
        • Yang S.F.
        • et al.
        Nuclear factor-κB activation predicts an unfavourable outcome in human upper urinary tract urothelial carcinoma.
        BJU International. 2010; 106: 1223-1229
        • Ross J.S.
        • Kallakury B.V.
        • Sheehan C.E.
        • et al.
        Expression of nuclear factor-kappa B and I kappa B alpha proteins in prostatic adenocarcinomas: correlation of nuclear factor-kappa B immunoreactivity with disease recurrence.
        Clin Cancer Res. 2004; 10: 2466-2472
        • Murtas D.
        • Piras F.
        • Minerba L.
        • et al.
        Nuclear factor-κB expression is predictive of overall survival in patients with cutaneous melanoma.
        Oncol Lett. 2010; 1: 633-639
        • Abo El-Magd G.H.
        • Abd El-Fattah O.
        • Saied E.M.
        Immunohistochemical expression of nuclear factor kappa-B/p65 and cyclooxygenase-2 in non-small cell lung cancer patients: prognostic value and impact on survival.
        Egypt J Chest Dis Tuberc. 2014; 63: 193-200
        • Lee B.L.
        • Lee H.S.
        • Jung J.
        • et al.
        Nuclear factor-kappaB activation correlates with better prognosis and Akt activation in human gastric cancer.
        Clin Cancer Res. 2005; 11: 2518-2525
        • Gannon P.O.
        • Lessard L.
        • Stevens L.M.
        • et al.
        Large-scale independent validation of the nuclear factor-kappa B p65 prognostic biomarker in prostate cancer.
        Eur J Cancer. 2013; 49: 2441-2448
        • Sessions D.G.
        • Lenox J.
        • Spector G.J.
        • Chao C.
        • Chaudry O.A.
        Analysis of treatment results for base of tongue cancer.
        Laryngoscope. 2003; 113: 1252-1261
        • Sessions D.G.
        • Spector G.J.
        • Lenox J.
        • et al.
        Analysis of treatment results for floor-of-mouth cancer.
        Laryngoscope. 2000; 110: 1764-1772
        • Bloebaum M.
        • Poort L.
        • Böckmann R.
        • Kessler P.
        Survival after curative surgical treatment for primary oral squamous cell carcinoma.
        J Craniomaxillofac Surg. 2014; 42: 1572-1576
        • Kawamoto T.
        • Ii M.
        • Kitazaki T.
        • Iizawa Y.
        • Kimura H.
        TAK-242 selectively suppresses Toll-like receptor 4-signaling mediated by the intracellular domain.
        Eur J Pharmacol. 2008; 584: 40-48
        • Meyer C.
        • Pries R.
        • Wollenberg B.
        Established and novel NF-κB inhibitors lead to downregulation of TLR3 and the proliferation and cytokine secretion in HNSCC.
        Oral Oncol. 2011; 47: 818-826