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Critical pathways of oral squamous cell carcinoma: molecular biomarker and therapeutic intervention

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Abstract

The rapid growth of oral cancer is a significant concern, especially in developing countries due to the advanced lifestyle and 5-year survival despite advanced multimodality of cancer care. The poor modality might be due to the detection of disease in the advanced stage. Early detection and development of novel therapies can improve oral cancer patient survival. The PI3K/AKT/mTOR and RAS-RAF-MEK-ERK are very extensively exploited pathways in oral cancer. These pathways are very critical in the progression of tumorigenesis in oral cancer. This review focuses on the association of Ras/Raf/MEK/ERK and PI3K/AKT/mTOR pathways in terms of protein expression level, genetic mutation, and therapeutic intervention in oral cancer.

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References

  1. Gupta N, Gupta R, Acharya AK, Patthi B, Goud V, Reddy S, Garg A, Singla A. Changing trends in oral cancer—a global scenario. Nepal J Epidemiol. 2016;6(4):613–9. https://doi.org/10.3126/nje.v6i4.17255.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet. 2006;7(8):606–19. https://doi.org/10.1038/nrg1879.

    Article  PubMed  CAS  Google Scholar 

  3. Ferreira DM, Neves TJ, Lima LGCA, Alves FA, Begnami MD. Prognostic implications of the phosphatidylinositol 3-kinase/Akt signaling pathway in oral squamous cell carcinoma: overexpression of p-mTOR indicates an adverse prognosis. Appl Cancer Res. 2017;37(1):41–8. https://doi.org/10.1186/s41241-017-0046-4.

    Article  Google Scholar 

  4. Amornphimoltham P, Sriuranpong V, Patel V, Benavides F, Conti CJ, Sauk J, Sausville EA, Molinolo AA, Gutkind JS. Persistent activation of the Akt pathway in head and neck squamous cell carcinoma: a potential target for UCN-01. Clin Cancer Res. 2004;10(12 Pt 1):4029–37. https://doi.org/10.1158/1078-0432.CCR-03-0249.

    Article  PubMed  CAS  Google Scholar 

  5. Monteiro LS, Delgado ML, Ricardo S, Garcez F, do Amaral B, Warnakulasuriya S, Lopes C,. Phosphorylated mammalian target of rapamycin is associated with an adverse outcome in oral squamous cell carcinoma. Oral Surg, Oral Med, Oral Pathol Oral Radiol. 2013;115(5):638–45. https://doi.org/10.1016/j.oooo.2013.01.022.

    Article  Google Scholar 

  6. Stransky N, Egloff AM, Tward AD, Kostic AD, Cibulskis K, Sivachenko A, Kryukov GV, Lawrence MS, Sougnez C, McKenna A, Shefler E, Ramos AH, Stojanov P, Carter SL, Voet D, Cortes ML, Auclair D, Berger MF, Saksena G, Guiducci C, Onofrio RC, Parkin M, Romkes M, Weissfeld JL, Seethala RR, Wang L, Rangel-Escareno C, Fernandez-Lopez JC, Hidalgo-Miranda A, Melendez-Zajgla J, Winckler W, Ardlie K, Gabriel SB, Meyerson M, Lander ES, Getz G, Golub TR, Garraway LA, Grandis JR. The mutational landscape of head and neck squamous cell carcinoma. Science. 2011;333(6046):1157–60. https://doi.org/10.1126/science.1208130.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Patel V, Rosenfeldt HM, Lyons R, Servitja JM, Bustelo XR, Siroff M, Gutkind JS. Persistent activation of Rac1 in squamous carcinomas of the head and neck: evidence for an EGFR/Vav2 signaling axis involved in cell invasion. Carcinogenesis. 2007;28(6):1145–52. https://doi.org/10.1093/carcin/bgm008.

    Article  PubMed  CAS  Google Scholar 

  8. Maekawa M, Ishizaki T, Boku S, Watanabe N, Fujita A, Iwamatsu A, Obinata T, Ohashi K, Mizuno K, Narumiya S. Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase. Science. 1999;285(5429):895–8. https://doi.org/10.1126/science.285.5429.895.

    Article  PubMed  CAS  Google Scholar 

  9. Sharafinski ME, Ferris RL, Ferrone S, Grandis JR. Epidermal growth factor receptor targeted therapy of squamous cell carcinoma of the head and neck. Head Neck. 2010;32(10):1412–21. https://doi.org/10.1002/hed.21365.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Zhang H, Liu J, Fu X, Yang A. Identification of key genes and pathways in tongue squamous cell carcinoma using bioinformatics analysis. Med Sci Monit. 2017;23:5924–32. https://doi.org/10.12659/msm.905035.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Cuevas Gonzalez JC, Gaitan Cepeda LA, Borges Yanez SA, Cornejo AD, Mori Estevez AD, Huerta ER. p53 and p16 in oral epithelial dysplasia and oral squamous cell carcinoma: a study of 208 cases. Indian J Pathol Microbiol. 2016;59(2):153–8. https://doi.org/10.4103/0377-4929.182037.

    Article  PubMed  Google Scholar 

  12. Karpathiou G, Stachowitz ML, Dumollard JM, Gavid M, Froudarakis M, Prades JM, Peoc’h M. Gene expression comparison between the primary tumor and its lymph node metastasis in head and neck squamous cell carcinoma: a pilot study. Cancer Genom Proteom. 2019;16(3):155–61. https://doi.org/10.21873/cgp.20121.

    Article  CAS  Google Scholar 

  13. Lin SC, Lin LH, Yu SY, Kao SY, Chang KW, Cheng HW, Liu CJ. FAT1 somatic mutations in head and neck carcinoma are associated with tumor progression and survival. Carcinogenesis. 2018;39(11):1320–30. https://doi.org/10.1093/carcin/bgy107.

    Article  PubMed  CAS  Google Scholar 

  14. Lee SH, Do SI, Lee HJ, Kang HJ, Koo BS, Lim YC. Notch1 signaling contributes to stemness in head and neck squamous cell carcinoma. Lab Invest. 2016;96(5):508–16. https://doi.org/10.1038/labinvest.2015.163.

    Article  PubMed  CAS  Google Scholar 

  15. Lui VW, Hedberg ML, Li H, Vangara BS, Pendleton K, Zeng Y, Lu Y, Zhang Q, Du Y, Gilbert BR, Freilino M, Sauerwein S, Peyser ND, Xiao D, Diergaarde B, Wang L, Chiosea S, Seethala R, Johnson JT, Kim S, Duvvuri U, Ferris RL, Romkes M, Nukui T, Kwok-Shing Ng P, Garraway LA, Hammerman PS, Mills GB, Grandis JR. Frequent mutation of the PI3K pathway in head and neck cancer defines predictive biomarkers. Cancer Discov. 2013;3(7):761–9. https://doi.org/10.1158/2159-8290.CD-13-0103.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Garg R, Kapoor V, Mittal M, Singh MK, Shukla NK, Das SN. Abnormal expression of PI3K isoforms in patients with tobacco-related oral squamous cell carcinoma. Clin Chim Acta. 2013;416:100–6. https://doi.org/10.1016/j.cca.2012.11.027.

    Article  PubMed  CAS  Google Scholar 

  17. Cheng H, Yang X, Si H, Saleh AD, Xiao W, Coupar J, Gollin SM, Ferris RL, Issaeva N, Yarbrough WG, Prince ME, Carey TE, Van Waes C, Chen Z. Genomic and transcriptomic characterization links cell lines with aggressive head and neck cancers. Cell Rep. 2018;25(5):1332-1345.e5. https://doi.org/10.1016/j.celrep.2018.10.007.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Radu A, Neubauer V, Akagi T, Hanafusa H, Georgescu MM. PTEN induces cell cycle arrest by decreasing the level and nuclear localization of cyclin D1. Mol Cell Biol. 2003;23(17):6139–49. https://doi.org/10.1128/MCB.23.17.6139-6149.2003.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Goel S, DeCristo MJ, McAllister SS, Zhao JJ. CDK4/6 inhibition in cancer: beyond cell cycle arrest. Trends Cell Biol. 2018;28(11):911–25. https://doi.org/10.1016/j.tcb.2018.07.002.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Shapiro GI. Cyclin-dependent kinase pathways as targets for cancer treatment. J Clin Oncol. 2006;24(11):1770–83. https://doi.org/10.1200/JCO.2005.03.7689.

    Article  PubMed  CAS  Google Scholar 

  21. Poomsawat S, Buajeeb W, Khovidhunkit SO, Punyasingh J. Alteration in the expression of cdk4 and cdk6 proteins in oral cancer and premalignant lesions. J Oral Pathol Med. 2010;39(10):793–9. https://doi.org/10.1111/j.1600-0714.2010.00909.x.

    Article  PubMed  Google Scholar 

  22. Goel S, Khurana N, Marwah A, Gupta S. Expression of cdk4 and p16 in oral lichen planus. J Oral Maxillofac Res. 2015;6(2):e4. https://doi.org/10.5037/jomr.2015.6204.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Shyam N, Rao NN, Narang RD, George J, Bommu SR, Kiran G. Immunohistochemical characterization of cyclin dependent kinase-4 in different histological grades of oral leukoplakia and oral squamous cell carcinoma. J Oral Maxillofac Pathol. 2014;18(1):36–41. https://doi.org/10.4103/0973-029X.131896.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Banerjee J, Pradhan R, Gupta A, Kumar R, Sahu V, Upadhyay AD, Chaterjee P, Dwivedi S, Dey S, Dey AB. CDK4 in lung, and head and neck cancers in old age: evaluation as a biomarker. Clin Transl Oncol. 2017;19(5):571–8. https://doi.org/10.1007/s12094-016-1565-2.

    Article  PubMed  CAS  Google Scholar 

  25. Poi MJ, Knobloch TJ, Sears MT, Warner BM, Uhrig LK, Weghorst CM, Li J. Alterations in RD(INK4/ARF) -mediated en bloc regulation of the INK4-ARF locus in human squamous cell carcinoma of the head and neck. Mol Carcinog. 2015;54(7):532–42. https://doi.org/10.1002/mc.22119.

    Article  PubMed  CAS  Google Scholar 

  26. Khan R, Khan AQ, Lateef A, Rehman MU, Tahir M, Ali F, Hamiza OO, Sultana S. Glycyrrhizic acid suppresses the development of precancerous lesions via regulating the hyperproliferation, inflammation, angiogenesis and apoptosis in the colon of Wistar rats. PLoS One. 2013;8(2):e56020. https://doi.org/10.1371/journal.pone.0056020.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Mishra A, Bharti AC, Varghese P, Saluja D, Das BC. Differential expression and activation of NF-kappaB family proteins during oral carcinogenesis: role of high risk human papillomavirus infection. Int J Cancer. 2006;119(12):2840–50. https://doi.org/10.1002/ijc.22262.

    Article  PubMed  CAS  Google Scholar 

  28. Gupta A, Kumar R, Sahu V, Agnihotri V, Singh AP, Bhasker S, Dey S. NFkappaB-p50 as a blood based protein marker for early diagnosis and prognosis of head and neck squamous cell carcinoma. Biochem Biophys Res Commun. 2015;467(2):248–53. https://doi.org/10.1016/j.bbrc.2015.09.181.

    Article  PubMed  CAS  Google Scholar 

  29. Liu YC, Ho HC, Lee MR, Lai KC, Yeh CM, Lin YM, Ho TY, Hsiang CY, Chung JG. Early induction of cytokines/cytokine receptors and Cox2, and activation of NF-kappaB in 4-nitroquinoline 1-oxide-induced murine oral cancer model. Toxicol Appl Pharmacol. 2012;262(2):107–16. https://doi.org/10.1016/j.taap.2012.04.023.

    Article  PubMed  CAS  Google Scholar 

  30. Bano N, Yadav M, Mohania D, Das BC. The role of NF-kappaB and miRNA in oral cancer and cancer stem cells with or without HPV16 infection. PLoS One. 2018;13(10):e0205518. https://doi.org/10.1371/journal.pone.0205518.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Anbo N, Ogi K, Sogabe Y, Shimanishi M, Kaneko T, Dehari H, Miyazaki A, Hiratsuka H. Suppression of NF-κB/p65 inhibits the proliferation in oral squamous cancer cells. J Cancer Ther. 2013;04:891–7. https://doi.org/10.4236/jct.2013.44100.

    Article  CAS  Google Scholar 

  32. Beppu M, Ikebe T, Shirasuna K. The inhibitory effects of immunosuppressive factors, dexamethasone and interleukin-4, on NF-kappaB-mediated protease production by oral cancer. Biochim Biophys Acta. 2002;1586(1):11–22. https://doi.org/10.1016/s0925-4439(01)00080-1.

    Article  PubMed  CAS  Google Scholar 

  33. Rhodus NL, Ho V, Miller CS, Myers S, Ondrey F. NF-kappaB dependent cytokine levels in saliva of patients with oral preneoplastic lesions and oral squamous cell carcinoma. Cancer Detect Prev. 2005;29(1):42–5. https://doi.org/10.1016/j.cdp.2004.10.003.

    Article  PubMed  CAS  Google Scholar 

  34. Nakayama H, Ikebe T, Beppu M, Shirasuna K. High expression levels of nuclear factor kappaB, IkappaB kinase alpha and Akt kinase in squamous cell carcinoma of the oral cavity. Cancer. 2001;92(12):3037–44. https://doi.org/10.1002/1097-0142(20011215)92:12.

    Article  PubMed  CAS  Google Scholar 

  35. Sun J, Lu Z, Deng Y, Wang W, He Q, Yan W, Wang A. Up-regulation of INSR/IGF1R by C-myc promotes TSCC tumorigenesis and metastasis through the NF-kappaB pathway. Biochim Biophys Acta Mol Basis Dis. 2018;1864(5):1873–82. https://doi.org/10.1016/j.bbadis.2018.03.004.

    Article  PubMed  CAS  Google Scholar 

  36. Chen F, Liu F, Yan L, Lin L, Qiu Y, Wang J, Wu J, Bao X, Hu Z, Cai L, He B. A functional haplotype of NFKB1 influence susceptibility to oral cancer: a population-based and in vitro study. Cancer Med. 2018;7(5):2211–8. https://doi.org/10.1002/cam4.1453.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Gupta A, Agnihotri V, Kumar R, Upadhyay AD, Bhaskar S, Dwivedi S, Dey S. Effects of tobacco habits on the polymorphism of NFKB1 and NFKB1A gene of head and neck squamous cell carcinoma in Indian population. Asian Pac J Cancer Prev. 2017;27(7):1855–9.

    Google Scholar 

  38. Biswas NK, Das S, Maitra A, Sarin R, Majumder PP. Somatic mutations in arachidonic acid metabolism pathway genes enhance oral cancer post-treatment disease-free survival. Nat Commun. 2014;5:5835. https://doi.org/10.1038/ncomms6835.

    Article  PubMed  CAS  Google Scholar 

  39. El-Hakim IE, Langdon JD. Arachidonic acid cascade and oral squamous cell carcinoma. Clin Otolaryngol Allied Sci. 1991;16(6):563–73. https://doi.org/10.1111/j.1365-2273.1991.tb00975.x.

    Article  PubMed  CAS  Google Scholar 

  40. Wang D, Chen S, Feng Y, Yang Q, Campbell BH, Tang X, Campbell WB. Reduced expression of 15-lipoxygenase 2 in human head and neck carcinomas. Tumour Biol. 2006;27(5):261–73. https://doi.org/10.1159/000094761.

    Article  PubMed  CAS  Google Scholar 

  41. Li N, Sood S, Wang S, Fang M, Wang P, Sun Z, Yang CS, Chen X. Overexpression of 5-lipoxygenase and cyclooxygenase 2 in hamster and human oral cancer and chemopreventive effects of zileuton and celecoxib. Clin Cancer Res. 2005;11(5):2089–96. https://doi.org/10.1158/1078-0432.

    Article  PubMed  CAS  Google Scholar 

  42. Metzger K, Angres G, Maier H, Lehmann WD. Lipoxygenase products in human saliva: patients with oral cancer compared to controls. Free Radic Biol Med. 1995;18(2):185–94. https://doi.org/10.1038/onc.2012.47.

    Article  PubMed  CAS  Google Scholar 

  43. Liu SY, Yen CY, Yang SC, Chiang WF, Chang KW. Overexpression of Rac-1 small GTPase binding protein in oral squamous cell carcinoma. J Oral Maxillofac Surg. 2004;62(6):702–7. https://doi.org/10.1016/j.joms.2004.02.002.

    Article  PubMed  Google Scholar 

  44. Su YF, Liang CY, Huang CY, Peng CY, Chen CC, Lin MC, Lin RK, Lin WW, Chou MY, Liao PH, Yang JJ. A putative novel protein, DEPDC1B, is overexpressed in oral cancer patients, and enhanced anchorage-independent growth in oral cancer cells that is mediated by Rac1 and ERK. J Biomed Sci. 2014;21:67. https://doi.org/10.1186/s12929-014-0067-1.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Skvortsov S, Dudas J, Eichberger P, Witsch-Baumgartner M, Loeffler-Ragg J, Pritz C, Schartinger VH, Maier H, Hall J, Debbage P, Riechelmann H, Lukas P, Skvortsova I. Rac1 as a potential therapeutic target for chemo-radioresistant head and neck squamous cell carcinomas (HNSCC). Br J Cancer. 2014;110(11):2677–87. https://doi.org/10.1038/bjc.2014.221.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Shi B, Ma C, Liu G, Guo Y. MiR-106a directly targets LIMK1 to inhibit proliferation and EMT of oral carcinoma cells. Cell Mol Biol Lett. 2019;24:1. https://doi.org/10.1186/s11658-018-0127-8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Hong KO, Lee JI, Hong SP, Hong SD. Thymosin beta4 induces proliferation, invasion, and epithelial-to-mesenchymal transition of oral squamous cell carcinoma. Amino Acids. 2016;48(1):117–27. https://doi.org/10.1007/s00726-015-2070-6.

    Article  PubMed  CAS  Google Scholar 

  48. Li D, Song H, Wu T, Xie D, Hu J, Zhao J, Shen Q, Fang L. MiR-519d-3p suppresses breast cancer cell growth and motility via targeting LIM domain kinase 1. Mol Cell Biochem. 2018;444(1–2):169–78. https://doi.org/10.1007/s11010-017-3241-4.

    Article  PubMed  CAS  Google Scholar 

  49. Su J, Zhou Y, Pan Z, Shi L, Yang J, Liao A, Liao Q, Su Q. Downregulation of LIMK1-ADF/cofilin by DADS inhibits the migration and invasion of colon cancer. Sci Rep. 2017;7:45624. https://doi.org/10.1038/srep45624.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Tan Y, Hu H, Tan W, Jin L, Liu J, Zhou H. MicroRNA-138 inhibits migration and invasion of non-small cell lung cancer cells by targeting LIMK1. Mol Med Rep. 2016;14(5):4422–8. https://doi.org/10.3892/mmr.2016.5769.

    Article  PubMed  CAS  Google Scholar 

  51. Bernard O. Lim kinases, regulators of actin dynamics. Int J Biochem Cell Biol. 2007;39(6):1071–6. https://doi.org/10.1016/j.biocel.2006.11.011.

    Article  PubMed  CAS  Google Scholar 

  52. Liotta LA, Kohn EC. The microenvironment of the tumour-host interface. Nature. 2001;411(6835):375–9. https://doi.org/10.1038/35077241.

    Article  PubMed  CAS  Google Scholar 

  53. Yoshioka K, Foletta V, Bernard O, Itoh K. A role for LIM kinase in cancer invasion. Proc Natl Acad Sci USA. 2003;100(12):7247–52. https://doi.org/10.1073/pnas.1232344100.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Wang W, Eddy R, Condeelis J. The cofilin pathway in breast cancer invasion and metastasis. Nat Rev Cancer. 2007;7(6):429–40. https://doi.org/10.1038/nrc2148.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Polachini GM, Sobral LM, Mercante AM, Paes-Leme AF, Xavier FC, Henrique T, Guimaraes DM, Vidotto A, Fukuyama EE, Gois-Filho JF, Cury PM, Curioni OA, Michaluart P Jr, Silva AM, Wunsch-Filho V, Nunes FD, Leopoldino AM, Tajara EH. Proteomic approaches identify members of cofilin pathway involved in oral tumorigenesis. PLoS One. 2012;7(12):e50517. https://doi.org/10.1371/journal.pone.0050517.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Castro MA, Dal-Pizzol F, Zdanov S, Soares M, Muller CB, Lopes FM, Zanotto-Filho A, da Cruz Fernandes M, Moreira JC, Shacter E, Klamt F. CFL1 expression levels as a prognostic and drug resistance marker in nonsmall cell lung cancer. Cancer. 2010;116(15):3645–55. https://doi.org/10.1002/cncr.25125.

    Article  PubMed  CAS  Google Scholar 

  57. Coumans JVF, Davey RJ, Moens PDJ. Cofilin and profilin: partners in cancer aggressiveness. Biophys Rev. 2018;10(5):1323–35. https://doi.org/10.1007/s12551-018-0445-0.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Owusu Obeng E, Rusciano I, Marvi MV, Fazio A, Ratti S, Follo MY, Xian J, Manzoli L, Billi AM, Mongiorgi S, Ramazzotti G, Cocco L. Phosphoinositide-dependent signaling in cancer: a focus on phospholipase C isozymes. Int J Mol Sci. 2020;21(7):2581. https://doi.org/10.3390/ijms21072581.

    Article  PubMed Central  CAS  Google Scholar 

  59. Vitale-Cross L, Amornphimoltham P, Fisher G, Molinolo AA, Gutkind JS. Conditional expression of K-ras in an epithelial compartment that includes the stem cells is sufficient to promote squamous cell carcinogenesis. Cancer Res. 2004;64(24):8804–7. https://doi.org/10.1158/0008-5472.

    Article  PubMed  Google Scholar 

  60. Leelahavanichkul K, Amornphimoltham P, Molinolo AA, Basile JR, Koontongkaew S, Gutkind JS. A role for p38 MAPK in head and neck cancer cell growth and tumor-induced angiogenesis and lymphangiogenesis. Mol Oncol. 2014;8(1):105–18. https://doi.org/10.1016/j.molonc.2013.10.003.

    Article  PubMed  CAS  Google Scholar 

  61. Gill K, Mohanti BK, Ashraf MS, Singh AK, Dey S. Quantification of p38alphaMAP kinase: a prognostic marker in HNSCC with respect to radiation therapy. Clin Chim Acta. 2012;413(1–2):219–25. https://doi.org/10.1016/j.cca.2011.09.031.

    Article  PubMed  CAS  Google Scholar 

  62. Sahu V, Nigam L, Agnihotri V, Gupta A, Shekhar S, Subbarao N, Bhaskar S, Dey S. Diagnostic significance of p38 isoforms (p38alpha, p38beta, p38gamma, p38delta) in head and neck squamous cell carcinoma: comparative serum level evaluation and design of novel peptide inhibitor targeting the same. Cancer Res Treat. 2019;51(1):313–25. https://doi.org/10.4143/crt.2018.105.

    Article  PubMed  CAS  Google Scholar 

  63. Gill K, Kumar R, Mohanti BK, Dey S. Assessment of p38alpha in peripheral blood mononuclear cells (PBMC): a potential blood protein marker of head and neck squamous cell carcinoma. Clin Transl Oncol. 2013;15(11):969–73. https://doi.org/10.1007/s12094-013-1031-3.

    Article  PubMed  CAS  Google Scholar 

  64. Soni S, Saroch MK, Chander B, Tirpude NV, Padwad YS. MAPKAPK2 plays a crucial role in the progression of head and neck squamous cell carcinoma by regulating transcript stability. J Exp Clin Cancer Res. 2019;38(1):175. https://doi.org/10.1186/s13046-019-1167-2.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Banerjee J, Pradhan R, Gupta A, Kumar R, Sahu V, Upadhyay A, Chatterjee P, Dwivedi S, Dey S, Dey A. CDK4 in lung, and head and neck cancers in old age: evaluation as a biomarker. Clin Transl Oncol. 2016. https://doi.org/10.1007/s12094-016-1565-2.

    Article  PubMed  Google Scholar 

  66. Peyssonnaux C, Eychène A. The Raf/MEK/ERK pathway: new concepts of activation. Biol Cell. 2001;93(1–2):53–62. https://doi.org/10.1016/s0248-4900(01)01125-x.

    Article  PubMed  CAS  Google Scholar 

  67. Hoa M, Davis SL, Ames SJ, Spanjaard RA. Amplification of wild-type K-ras promotes growth of head and neck squamous cell carcinoma. Cancer Res. 2002;62(24):7154–6.

    PubMed  CAS  Google Scholar 

  68. Caulin C, Nguyen T, Longley MA, Zhou Z, Wang XJ, Roop DR. Inducible activation of oncogenic K-ras results in tumor formation in the oral cavity. Cancer Res. 2004;64(15):5054–8. https://doi.org/10.1158/0008-5472.

    Article  PubMed  Google Scholar 

  69. Shishkin S, Eremina L, Pashintseva N, Kovalev L, Kovaleva M. Cofilin-1 and other ADF/cofilin superfamily members in human malignant cells. Int J Mol Sci. 2016;18(1):10. https://doi.org/10.3390/ijms18010010.

    Article  PubMed Central  CAS  Google Scholar 

  70. Lee S, Helfman DM. Cytoplasmic p21Cip1 is involved in Ras-induced inhibition of the ROCK/LIMK/cofilin. J Biol Chem. 2004;279(3):1885–91. https://doi.org/10.1074/jbc.M306968200.

    Article  PubMed  CAS  Google Scholar 

  71. Aggarwal S, John S, Sapra L, Sharma SC, Das SN. Targeted disruption of PI3K/Akt/mTOR signaling pathway, via PI3K inhibitors, promotes growth inhibitory effects in oral cancer cells. Cancer Chemother Pharmacol. 2019;83(3):451–61. https://doi.org/10.1007/s00280-018-3746-x.

    Article  PubMed  CAS  Google Scholar 

  72. Yu CC, Hung SK, Lin HY, Chiou WY, Lee MS, Liao HF, Huang HB, Ho HC, Su YC. Targeting the PI3K/AKT/mTOR signaling pathway as an effectively radiosensitizing strategy for treating human oral squamous cell carcinoma in vitro and in vivo. Oncotarget. 2017;8(40):68641–53. https://doi.org/10.18632/oncotarget.19817.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Glorieux M, Dok R, Nuyts S. The influence of PI3K inhibition on the radiotherapy response of head and neck cancer cells. Sci Rep. 2020;10:16208. https://doi.org/10.1038/s41598-020-73249-z.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Dent P, Yacoub A, Fisher P, et al. MAPK pathways in radiation responses. Oncogene. 2003;22:5885–96.

    Article  CAS  Google Scholar 

  75. Hu K, Li K, Lv J, Feng J, Chen J, Wu H, Cheng F, et al. Suppression of the SLC7A11/glutathione axis causes synthetic lethality in KRAS-mutant lung adenocarcinoma. J Clin Invest. 2020;130(4):1752–66.

    Article  CAS  Google Scholar 

  76. Guba M, von Breitenbuch P, Steinbauer M, Koehl G, Flegel S, Hornung M, Bruns CJ, Zuelke C, Farkas S, Anthuber M, Jauch KW, Geissler EK. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med. 2002;8(2):128–35. https://doi.org/10.1038/nm0202-128.

    Article  PubMed  CAS  Google Scholar 

  77. Schedel F, Pries R, Thode B, Wollmann B, Wulff S, Jocham D, Wollenberg B, Kausch I. mTOR inhibitors show promising in vitro activity in bladder cancer and head and neck squamous cell carcinoma. Oncol Rep. 2011;25(3):763–8. https://doi.org/10.3892/or.2011.1146.

    Article  PubMed  CAS  Google Scholar 

  78. Sun Z, Sood S, Li N, Ramji D, Yang P, Newman RA, Yang CS, Chen X. Involvement of the 5-lipoxygenase/leukotriene A4 hydrolase pathway in 7,12-dimethylbenz[a]anthracene (DMBA)-induced oral carcinogenesis in hamster cheek pouch, and inhibition of carcinogenesis by its inhibitors. Carcinogenesis. 2006;27(9):1902–8. https://doi.org/10.1093/carcin/bgl039.

    Article  PubMed  CAS  Google Scholar 

  79. Koontongkaew S, Monthanapisut P, Saensuk T. Inhibition of arachidonic acid metabolism decreases tumor cell invasion and matrix metalloproteinase expression. Prostaglandins Other Lipid Mediat. 2010;93(3–4):100–8. https://doi.org/10.1016/j.prostaglandins.2010.07.002.

    Article  PubMed  CAS  Google Scholar 

  80. Hyde CA, Missailidis S. Inhibition of arachidonic acid metabolism and its implication on cell proliferation and tumour-angiogenesis. Int Immunopharmacol. 2009;9(6):701–15. https://doi.org/10.1016/j.intimp.2009.02.003.

    Article  PubMed  CAS  Google Scholar 

  81. Tanaka T, Nakayama H, Yoshitake Y, Irie A, Nagata M, Kawahara K, Takamune Y, Yoshida R, Nakagawa Y, Ogi H, Shinriki S, Ota K, Hiraki A, Ikebe T, Nishimura Y, Shinohara M. Selective inhibition of nuclear factor-kappaB by nuclear factor-kappaB essential modulator-binding domain peptide suppresses the metastasis of highly metastatic oral squamous cell carcinoma. Cancer Sci. 2012;103(3):455–63. https://doi.org/10.1111/j.1349-7006.2011.02174.x.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Tamatani T, Takamaru N, Hara K, Kinouchi M, Kuribayashi N, Ohe G, Uchida D, Fujisawa K, Nagai H, Miyamoto Y. Bortezomib-enhanced radiosensitization through the suppression of radiation-induced nuclear factor-kappaB activity in human oral cancer cells. Int J Oncol. 2013;42(3):935–44. https://doi.org/10.3892/ijo.2013.1786.

    Article  PubMed  CAS  Google Scholar 

  83. LoTempio MM, Veena MS, Steele HL, Ramamurthy B, Ramalingam TS, Cohen AN, Chakrabarti R, Srivatsan ES, Wang MB. Curcumin suppresses growth of head and neck squamous cell carcinoma. Clin Cancer Res. 2005;11(19 Pt 1):6994–7002. https://doi.org/10.1158/1078-0432.CCR-05-0301.

    Article  PubMed  CAS  Google Scholar 

  84. Suzuki J, Ogawa M, Muto S, Itai A, Isobe M, Hirata Y, Nagai R. Novel IkB kinase inhibitors for treatment of nuclear factor-kB-related diseases. Expert Opin Investig Drugs. 2011;20(3):395–405. https://doi.org/10.1517/13543784.2011.559162.

    Article  PubMed  CAS  Google Scholar 

  85. Lin CW, Chin HK, Lee SL, Chiu CF, Chung JG, Lin ZY, Wu CY, Liu YC, Hsiao YT, Feng CH, Bai LY, Weng JR. Ursolic acid induces apoptosis and autophagy in oral cancer cells. Environ Toxicol. 2019;34(9):983–91. https://doi.org/10.1002/tox.22769.

    Article  PubMed  CAS  Google Scholar 

  86. Arora R, Bharti V, Gaur P, Aggarwal S, Mittal M, Das SN. Operculina turpethum extract inhibits growth and proliferation by inhibiting NF-kappaB, COX-2 and cyclin D1 and induces apoptosis by up regulating P53 in oral cancer cells. Arch Oral Biol. 2017;80:1–9. https://doi.org/10.1016/j.archoralbio.

    Article  PubMed  CAS  Google Scholar 

  87. Aggarwal S, Das SN. Garcinol inhibits tumour cell proliferation, angiogenesis, cell cycle progression and induces apoptosis via NF-kappaB inhibition in oral cancer. Tumour Biol. 2016;37(6):7175–84. https://doi.org/10.1007/s13277-015-4583-8.

    Article  PubMed  CAS  Google Scholar 

  88. Annamalai G, Suresh K. [6]-Shogaol attenuates inflammation, cell proliferation via modulate NF-kappaB and AP-1 oncogenic signaling in 7,12-dimethylbenz[a]anthracene induced oral carcinogenesis. Biomed Pharmacother. 2018;98:484–90. https://doi.org/10.1016/j.biopha.2017.12.009.

    Article  PubMed  CAS  Google Scholar 

  89. Kapoor V, Aggarwal S, Das SN. 6-Gingerol mediates its anti tumor activities in human oral and cervical cancer cell lines through apoptosis and cell cycle arrest. Phytother Res. 2016;30(4):588–95. https://doi.org/10.1002/ptr.5561.

    Article  PubMed  CAS  Google Scholar 

  90. Lin Y, Ukaji T, Koide N, Umezawa K. Inhibition of late and early phases of cancer metastasis by the NF-kappaB inhibitor DHMEQ derived from microbial bioactive metabolite epoxyquinomicin: a review. Int J Mol Sci. 2018;19(3):729. https://doi.org/10.3390/ijms19030729.

    Article  PubMed Central  CAS  Google Scholar 

  91. Scheurer MJJ, Brands RC, El-Mesery M, Hartmann S, Muller-Richter UDA, Kubler AC, Seher A. The selection of NFkappaB inhibitors to block inflammation and induce sensitisation to FasL-induced apoptosis in HNSCC cell lines is critical for their use as a prospective cancer therapy. Int J Mol Sci. 2019;20(6):1306. https://doi.org/10.3390/ijms20061306.

    Article  PubMed Central  CAS  Google Scholar 

  92. Ya-Hsuan L, et al. Promotion of ferroptosis in oral cancer cell lines by chrysophanol. Curr Topics Nutraceutical Res. 2020;18(3):273.

    Article  Google Scholar 

  93. Yi J, Zhu J, Wu J, Thompson CB, Jiang X. Oncogenic activation of PI3K-AKT-mTOR signaling suppresses ferroptosis via SREBP-mediated lipogenesis. PNAS. 2020;117(49):31189–97. https://doi.org/10.1073/pnas.2017152117.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Zainal NS, Lee BKB, Wong ZW, Chin IS, Yee PS, Gan CP, Mun KS, Rahman ZAA, Gutkind JS, Patel V, Cheong SC. Effects of palbociclib on oral squamous cell carcinoma and the role of PIK3CA in conferring resistance. Cancer Biol Med. 2019;16(2):264–75. https://doi.org/10.20892/j.issn.2095-3941.2018.0257.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Hsiao YT, Kuo CL, Chueh FS, Liu KC, Bau DT, Chung JG. Curcuminoids induce reactive oxygen species and autophagy to enhance apoptosis in human oral cancer cells. Am J Chin Med. 2018;46(5):1145–68. https://doi.org/10.1142/S0192415X1850060X.

    Article  PubMed  CAS  Google Scholar 

  96. Hoch MA, Cousins K, Nartey R, Riley K, Hartranft M. Two cases of combination therapy with cetuximab, paclitaxel, and cisplatin for advanced head and neck cancer. J Oncol Pharm Pract. 2018;24(7):553–4. https://doi.org/10.1177/1078155217722406.

    Article  PubMed  CAS  Google Scholar 

  97. Guigay J, Even C, Mayache-Badis L, Debbah M, Saada-Bouzid E, Tao Y, Deschamps F, Janot F, Lezghed N, Michel C. Long-term response in patient with recurrent oropharyngeal carcinoma treated with cetuximab, docetaxel and cisplatin (TPEx) as first-line treatment followed by cetuximab maintenance. Oral Oncol. 2017;68:114–8. https://doi.org/10.1016/j.oraloncology.2017.03.009.

    Article  PubMed  CAS  Google Scholar 

  98. Chih-Chia Yu, Shih-Kai H, Hon-Yi L, Wen-Yen C, Moon-Sing L, Hui-Fen L, Hsien-Bin H, Hsu-Chueh Ho, Yu-Chieh Su. Targeting the PI3K/AKT/mTOR signaling pathway as an effectively radiosensitizing strategy for treating human oral squamous cell carcinoma in vitro and in vivo. Oncotarget. 2017;8(40):68641–53. https://doi.org/10.18632/oncotarget.19817.

    Article  Google Scholar 

  99. Algazi AP, Grandis JR. Head and neck cancer in 2016: a watershed year for improvements in treatment? Nat Rev Clin Oncol. 2017;14(2):76–8. https://doi.org/10.1038/nrclinonc.2016.196.

    Article  PubMed  CAS  Google Scholar 

  100. Gill K, Nigam L, Singh R, Kumar S, Subbarao N, Chauhan SS, Dey S. The rational design of specific peptide inhibitor against p38alpha MAPK at allosteric-site: a therapeutic modality for HNSCC. PLoS One. 2014;9(7):1025. https://doi.org/10.1371/journal.pone.0101525.

    Article  Google Scholar 

  101. Lee JC, Chung LC, Chen YJ, Feng TH, Chen WT, Juang HH. Upregulation of B-cell translocation gene 2 by epigallocatechin-3-gallate via p38 and ERK signaling blocks cell proliferation in human oral squamous cell carcinoma cells. Cancer Lett. 2015;360(2):310–8. https://doi.org/10.1016/j.canlet.2015.02.034.

    Article  PubMed  CAS  Google Scholar 

  102. D’Ambrosio SM, Han C, Pan L, Kinghorn AD, Ding H. Aliphatic acetogenin constituents of avocado fruits inhibit human oral cancer cell proliferation by targeting the EGFR/RAS/RAF/MEK/ERK1/2 pathway. Biochem Biophys Res Commun. 2011;409(3):465–9. https://doi.org/10.1016/j.bbrc.2011.05.027.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Henson BS, Neubig RR, Jang I, Ogawa T, Zhang Z, Carey TE, D’Silva NJ. Galanin receptor 1 has anti-proliferative effects in oral squamous cell carcinoma. J Biol Chem. 2005;280(24):22564–71. https://doi.org/10.1074/jbc.M414589200.

    Article  PubMed  CAS  Google Scholar 

  104. Tang FY, Chiang EP, Chung JG, Lee HZ, Hsu CY. S-allylcysteine modulates the expression of E-cadherin and inhibits the malignant progression of human oral cancer. J Nutr Biochem. 2009;20(12):1013–20. https://doi.org/10.1016/j.jnutbio.2008.09.007.

    Article  PubMed  CAS  Google Scholar 

  105. Ko CP, Lin CW, Chen MK, Yang SF, Chiou HL, Hsieh MJ. Pterostilbene induce autophagy on human oral cancer cells through modulation of Akt and mitogen-activated protein kinase pathway. Oral Oncol. 2015;51(6):593–601. https://doi.org/10.1016/j.oraloncology.2015.03.007.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Biophysics, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India

    Sharmistha Dey, Abhinay Kumar Singh, Kartik Rawat, Vertica Agnihotri & Deepak Upadhaya

  2. Department of Radiation Oncology, Washington University in Saint Louis, St. Louis, USA

    Abhay Kumar Singh

  3. Department of Geriatric Medicine, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India

    Joyita Banerjee

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  1. Sharmistha Dey
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Contributions

SD: conception, interpretation, preparation of the manuscript, and supervision. AKS1: preparation of the manuscript and preparing figure and table. AKS2: searched LIMK, LOX part, and included in the manuscript, KR: searched about Coffilin and included in the manuscript, VA: searched about p38 and NF-kb and included in the manuscript. JB: searched CDK4 part and included in the manuscript. DU: preparation of references.

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Dey, S., Singh, A.K., Singh, A.K. et al. Critical pathways of oral squamous cell carcinoma: molecular biomarker and therapeutic intervention. Med Oncol 39, 30 (2022). https://doi.org/10.1007/s12032-021-01633-4

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