Document Type : Original Research


Department of Pathology, Faculty of Medicine, Fayoum University, Egypt


Background & Objective: Emerging evidence suggests that KRAS could play an important role in squamous cell carcinoma; however, its role in oral squamous cell carcinoma (OSCC) is largely unknown. The aim of the current study was to investigate the expression of KRAS, Ki-67, Cyclin D1, and Bcl2 in OSCC and their association with clinicopathological features.
Methods: Forty paraffin blocks of retrospective histologically diagnosed cases of OSCC and 20 blocks of oral leukoplakia with epithelial dysplasia were obtained from two hospitals between 2018 and 2021. The paraffin-embedded tissue was analyzed for the expression of KRAS for oral epithelial dysplasia and OSCC, and ki-67, Cyclin D1, and bcl2 were analyzed only for OSCC. The results were correlated with each other and with different clinicopathological features and were statistically analyzed.
Results: KRAS expression was significantly associated with histological tumor grade, tumor extent, presence of nodal and distant metastasis, pathological stage, and the presence of lymphovascular invasion (P=<0.001, 0.001, 0.001, 0.009, <0.001, and <0.001, respectively). The KRAS expression was positively correlated with the histological grade, tumor extent, nodal status, and the pathological stage (r=0.712, 0.649, 0.646, and 0.865, respectively). A positive correlation was also found with the expression of Bcl2, Cyclin D1, and Ki-67 (r=0.81, 0.723, and 0.698, respectively). The KRAS expression in oral epithelial dysplasia was significantly lower than that in OSCC (P=0.003).


Main Subjects

  1. Omura K. Current status of oral cancer treatment strategies: surgical treatments for oral squamous cell carcinoma. Int J Clin Oncol. 2014;19(3):423-30. [DOI:10.1007/s10147-014-0689-z] [PMID]
  2. Al-Jaber A, Al-Nasser L, El-Metwally A. Epidemiology of oral cancer in Arab countries. Saudi Med J. 2016;37(3):249-55. [PMCID] [DOI:10.15537/smj.2016.3.11388] [PMID]
  3. Vokes EE, Weichselbaum RR, Lippman SM, Hong WK. Head and neck cancer. N Engl J Med. 1993; 21;328(3):184-94. [DOI:10.1056/NEJM199301213280306] [PMID]
  4. Feller L, Lemmer J, Oral Squamous Cell Carcinoma: Epidemiology, Clinical Presentation and Treatment. Journal of Cancer Therapy. 2012;3(4):263-8. [DOI:10.4236/jct.2012.34037]
  5. Zaid KW, Chantiri M, Bassit G. Recombinant Human Bone Morphogenetic Protein-2 in Development and Progression of Oral Squamous Cell Carcinoma. Asian Pac J Cancer Prev. 2016; 17(3):927-32. [DOI:10.7314/APJCP.2016.17.3.927] [PMID]
  6. Sasaki T, Moles DR, Imai Y, Speight PM. Clinico-pathological features of squamous cell carcinoma of the oral cavity in patients <40 years of age. J Oral Pathol Med. 2005;34(3):129-33. [DOI:10.1111/j.1600-0714.2004.00291.x] [PMID]
  7. Khammissa RA, Meer S, Lemmer J, Feller L. Oral squamous cell carcinoma in a South African sample: Race/ethnicity, age, gender, and degree of histopathological differentiation. J Cancer Res Ther. 2014;10(4):908-14. [DOI:10.4103/0973-1482.138100] [PMID]
  8. Wang B, Zhang S, Yue K, Wang XD. The recurrence and survival of oral squamous cell carcinoma: a report of 275 cases. Chin J Cancer. 2013;32(11):614-8. [DOI:10.5732/cjc.012.10219] [PMID] [PMCID]
  9. Almangush A, Heikkinen I, Mäkitie AA, Coletta RD, Läärä E, Leivo I, et al. Prognostic biomarkers for oral tongue squamous cell carcinoma: a systematic review and meta-analysis. Br J Cancer. 2017; 5;117(6):856-66. [DOI:10.1038/bjc.2017.244] [PMID] [PMCID]
  10. Rivera C, Oliveira AK, Costa RAP, De Rossi T, Paes Leme AF. Prognostic biomarkers in oral squamous cell carcinoma: A systematic review. Oral Oncol. 2017;72:38-47. [PMID] [DOI:10.1016/j.oraloncology.2017.07.003]
  11. Wennerberg K, Rossman KL, Der CJ. The Ras superfamily at a glance. J Cell Sci. 2005;118(Pt 5):843-6. [DOI:10.1242/jcs.01660] [PMID]
  12. Jancík S, Drábek J, Radzioch D, Hajdúch M. Clinical relevance of KRAS in human cancers. J Biomed Biotechnol. 2010;2010:150960. [DOI:10.1155/2010/150960] [PMID] [PMCID]
  13. Kranenburg O. The KRAS oncogene: past, present, and future. Biochim Biophys Acta. 2005; 25;1756(2):81-2. [DOI:10.1016/j.bbcan.2005.10.001] [PMID]
  14. Bos JL, Fearon ER, Hamilton SR, Verlaan-de Vries M, van Boom JH, van der Eb AJ, et al. Prevalence of ras gene mutations in human colorectal cancers. Nature. 1987 May 28-Jun 3;327(6120):293-7. Downward J. Role of receptor tyrosine kinases in G-protein-coupled receptor regulation of Ras: transactivation or parallel pathways? Biochem J. 2003; 15;376(Pt 3):e9-10. [DOI:10.1038/327293a0] [PMID]
  15. Schubbert S, Shannon K, Bollag G. Hyperactive Ras in developmental disorders and cancer. Nat Rev Cancer. 2007;7(4):295-308. [DOI:10.1038/nrc2109] [PMID]
  16. Smilek P, Neuwirthova J, Jarkovsky J, Dusek L, Rottenberg J, Kostrica R, et al. Epidermal growth factor receptor (EGFR) expression and mutations in the EGFR signaling pathway in correlation with anti-EGFR therapy in head and neck squamous cell carcinomas. Neoplasma. 2012;59 (5):508-15. [DOI:10.4149/neo_2012_065] [PMID]
  17. Almangush A, Mäkitie AA, Triantafyllou A, de Bree R, Strojan P, Rinaldo A, et al. staging and grading of oral squamous cell carcinoma: An update. Oral Oncol. 2020;107:104799. [DOI:10.1016/j.oraloncology.2020.104799] [PMID]
  18. Pollaers K, Hinton-Bayre A, Friedland PL, Farah CS. AJCC 8th Edition oral cavity squamous cell carcinoma staging - Is it an improvement on the AJCC 7th Edition? Oral Oncol. 2018 Jul;82:23-28. [DOI:10.1016/j.oraloncology.2018.04.018] [PMID]
  19. Lin X, Wen G, Wang S, Lu H, Li C, Wang X. Expression and role of EGFR, cyclin D1 and KRAS in laryngocarcinoma tissues. Exp Ther Med. 2019;17(1):782-790. [DOI:10.3892/etm.2018.7027]
  20. Xie X, Clausen OP, De Angelis P, Boysen M. The prognostic value of spontaneous apoptosis, Bax, Bcl-2, and p53 in oral squamous cell carcinoma of the tongue. Cancer. 1999;86(6):913-20. [DOI:10.1002/(SICI)1097-0142(19990915)86:63.0.CO;2-A]
  21. De Carvalho TG, De Carvalho AC, Maia DC, Ogawa JK, Carvalho AL, Vettore AL. Search for mutations in signaling pathways in head and neck squamous cell carcinoma. Oncol Rep. 2013; 30(1):334-40. [DOI:10.3892/or.2013.2455] [PMID]
  22. Cohen Y, Goldenberg-Cohen N, Shalmon B, Shani T, Oren S, Amariglio N, et al. Mutational analysis of PTEN/PIK3CA/AKT pathway in oral squamous cell carcinoma. Oral Oncol. 2011; 47(10):946-50. [PMID] [DOI:10.1016/j.oraloncology.2011.07.013]
  23. Christensen BC, Moyer BJ, Avissar M, Ouellet LG, Plaza SL, McClean MD, et al. A let-7 microRNA-binding site polymorphism in the KRAS 3' UTR is associated with reduced survival in oral cancers. Carcinogenesis. 2009;30(6): 1003-7. [DOI:10.1093/carcin/bgp099] [PMID] [PMCID]
  24. Wang WY, Chien YC, Wong YK, Lin YL, Lin JC. Effects of KRAS mutation and polymorphism on the risk and prognosis of oral squamous cell carcinoma. Head Neck. 2012;34(5):663-6. [DOI:10.1002/hed.21792] [PMID]
  25. Uberall I, Kolár Z, Trojanec R, Berkovcová J, Hajdúch M. The status and role of ErbB receptors in human cancer. Exp Mol Pathol. 2008;84(2):79-89. [DOI:10.1016/j.yexmp.2007.12.002] [PMID]
  26. Mustachio LM, Chelariu-Raicu A, Szekvolgyi L, Roszik J. Targeting KRAS in Cancer: Promising Therapeutic Strategies. Cancers (Basel). 2021; 10;13(6):1204. [DOI:10.3390/cancers13061204] [PMID] [PMCID]
  27. Tumuluri V, Thomas GA, Fraser IS. Analysis of the Ki-67 antigen at the invasive tumour front of human oral squamous cell carcinoma. J Oral Pathol Med. 2002;31(10):598-604. [PMID] [DOI:10.1034/j.1600-0714.2002.00042.x]
  28. Sapp JP, Eversole LR and Wysocki GP: Contemporary Oral and Maxillofacial Pathology. Chapter 6: Epithelial Disorders. 2nd edition. Mosby Year Book Inc, Maryland Heights, MO, 2004; pp184 193.
  29. Wang HC, Chiang CJ, Liu TC, Wu CC, Chen YT, Chang JG, et al. Immunohistochemical Expression of Five Protein Combinations Revealed as Prognostic Markers in Asian Oral Cancer. Front Genet. 2021;15;12:643461. [DOI:10.3389/fgene.2021.643461] [PMID] [PMCID]
  30. da Silva SD, Ferlito A, Takes RP, Brakenhoff RH, Valentin MD, Woolgar JA, et al. Advances and applications of oral cancer basic research. Oral Oncol. 2011;47(9):783-91. [PMID] [DOI:10.1016/j.oraloncology.2011.07.004]
  31. Jing Y, Zhou Q, Zhu H, Zhang Y, Song Y, Zhang X, Huang X, Yang Y, Ni Y, Hu Q. Ki-67 is an independent prognostic marker for the recurrence and relapse of oral squamous cell carcinoma. Oncol Lett. 2019;17(1):974-980. [DOI:10.3892/ol.2018.9647]
  32. Gadbail AR, Sarode SC, Chaudhary MS, Gondivkar SM, Tekade SA, Yuwanati M, et al. Ki67 Labelling Index predicts clinical outcome and survival in oral squamous cell carcinoma. J Appl Oral Sci. 2021; 1;29:e20200751. [DOI:10.1590/1678-7757-2020-0751] [PMID] [PMCID]
  33. Saikrishana P, Sivapathasundharam B, Rafiuddeen IS, Krishnan B. Expression of bcl-2 oncoprotien in oral squamous cell carcinoma--an immunohistochemical study. Indian J Pathol Microbiol. 2002;45(3):283-7.
  34. Abdel Aziz MM, Zaki MM, Farg DA, El Kourdy Immunohistochemical expression of Bcl-2 in oral squamous cell carcinoma: a clinicopathological correlation. Egypt J Pathol. 2019; 39:257-62. [DOI:10.4103/EGJP.EGJP_33_19]
  35. Popović B, Jekić B, Novaković I, Luković LJ, Tepavcević Z, Jurisić V, et al. Bcl-2 expression in oral squamous cell carcinoma. Ann N Y Acad Sci. 2007;1095:19-25.
  36. Leemans CR, Braakhuis BJ, Brakenhoff RH. The molecular biology of head and neck cancer. Nat Rev Cancer. 2011;11(1):9-22. [DOI:10.1038/nrc2982] [PMID]
  37. Pestell RG, Albanese C, Reutens AT, Segall JE, Lee RJ, Arnold A. The cyclins and cyclin-dependent kinase inhibitors in hormonal regulation of proliferation and differentiation. Endocr Rev. 1999;20(4):501-34. [DOI:10.1210/edrv.20.4.0373] [PMID]
  38. Tashiro E, Tsuchiya A, Imoto M. Functions of cyclin D1 as an oncogene and regulation of cyclin D1 expression. Cancer Sci. 2007;98(5):629-35. [DOI:10.1111/j.1349-7006.2007.00449.x] [PMID]
  39. Huang SF, Cheng SD, Chuang WY, Chen IH, Liao CT, Wang HM, et al. Cyclin D1 overexpression and poor clinical outcomes in Taiwanese oral cavity squamous cell carcinoma. World J Surg Oncol.2012; 10: 40. [PMCID] [DOI:10.1186/1477-7819-10-40] [PMID]
  40. Ramos-García P, González-Moles MÁ, Ayén Á, González-Ruiz L, Ruiz-Ávila I, Lenouvel D, Gil-Montoya JA, et al. Asymmetrical proliferative pattern loss linked to cyclin D1 overexpression in adjacent non-tumour epithelium in oral squamous cell carcinoma. Arch Oral Biol. 2019; 97:12-17. [DOI:10.1016/j.archoralbio.2018.10.007] [PMID]
  41. Hanken H, Gröbe A, Cachovan G, Smeets R, Simon R, Sauter G, et al. CCND1 amplification and cyclin D1 immunohistochemical expression in head and neck squamous cell carcinomas. Clin Oral Investig. 2014; 18(1):269-76. [DOI:10.1007/s00784-013-0967-6] [PMID]
  42. Ramos-García P, González-Moles MÁ, González-Ruiz L, Ruiz-Ávila I, Ayén Á, Gil-Montoya JA. Prognostic and clinicopathological significance of cyclin D1 expression in oral squamous cell carcinoma: A systematic review and meta-analysis. Oral Oncol. 2018;83:96-106. [DOI:10.1016/j.oraloncology.2018.06.007] [PMID]
  43. Zhao Y, Yu D, Li H, Nie P, Zhu Y, Liu S, et al. Cyclin D1 overexpression is associated with poor clinicopathological outcome and survival in oral squamous cell carcinoma in Asian populations: insights from a meta-analysis. PLoS One. 2014; 27;9(3):e93210. [PMID] [PMCID] [DOI:10.1371/journal.pone.0093210]