Immunohistochemical analysis of phospho-ERK1/2 in odontogenic cysts
DOI:
https://doi.org/10.1590/1678-7765-2026-0462Keywords:
p-ERK1/2, Immunohistochemistry, Odontogenic cysts, Odontogenic keratocyst, Calcifying odontogenic cystAbstract
Odontogenic cysts demonstrate variable biological behaviors and pathogenic mechanisms. The MAPK/ERK signaling pathway regulates cell proliferation and survival and may contribute to the pathogenesis of odontogenic cysts. Objective To evaluate the expression levels, cellular localization, and clinicopathological associations of p-ERK1/2 in dentigerous cysts (DCs), odontogenic keratocysts (OKCs), and calcifying odontogenic cysts (COCs). Methodology Immunohistochemistry was performed on 80 formalin-fixed paraffin-embedded tissue samples (16 DCs, 40 OKCs, and 24 COCs). The immunolocalization and expression levels of p-ERK1/2, a key downstream effector of the MAPK/ERK pathway, were semi-quantitatively evaluated and compared across cyst types. Associations between p-ERK1/2 expression and the clinicopathological characteristics of each lesion were also statistically analyzed. Results p-ERK1/2 was predominantly localized in the cytoplasm and/or nucleus of epithelial lining cells of OKCs. Most DCs (68.8%, p=0.006) and COCs (79.2%, p<0.001) showed significantly negative p-ERK1/2 immunostaining. In contrast, the majority of OKCs (75%) exhibited p-ERK1/2 expression. The median immunoreactive score of OKCs (5.49 (1.84-7.84)) was significantly higher than the scores for DCs (p=0.004) and COCs (p<0.001). No significant association was observed between p-ERK1/2 expression and any clinicopathological parameters in the DC and OKC groups. However, p-ERK1/2 expression in COCs was significantly associated with sex (p=0.047). Conclusions Elevated p-ERK1/2 expression in OKCs indicates that MAPK/ERK pathway activation may be specifically involved in OKC pathogenesis compared with DCs and COCs. However, the clinicopathological significance of p-ERK1/2 appears to be restricted to selected clinicopathological features in COCs.
Downloads
References
1- Soluk-Tekkesin M, Wright JM. The World Health Organization classification of odontogenic lesions: a summary of the changes of the 2022 (5th) edition. Turk Patoloji Derg. 2022;38(2):168-84. doi: 10.5146/tjpath.2022.01573
» https://doi.org/10.5146/tjpath.2022.01573
2- Dhanuthai K, Chantarangsu S, Klanrit P, Chamusri N, Aminishakib P, Kardouni Khoozestani N, et al. Cysts of the jaws: a multicentre study. Oral Dis. 2024;30(4):2347-54. doi: 10.1111/odi.14722
» https://doi.org/10.1111/odi.14722
3- Bilodeau EA, Hunter KD. Odontogenic and developmental oral lesions in pediatric patients. Head Neck Pathol. 2021;15(1):71-84. doi: 10.1007/s12105-020-01284-3
» https://doi.org/10.1007/s12105-020-01284-3
4- Gonçalves TO, Rangel RM, Marañón-Vásquez GA, Soares-Silva L, Agostini M, Abrahão AC, et al. Management and recurrence of the odontogenic keratocyst: an overview of systematic reviews. Oral Maxillofac Surg. 2024;28(4):1457-78. doi: 10.1007/s10006-024-01277-4
» https://doi.org/10.1007/s10006-024-01277-4
5- Yazdani J, Kahnamouii SS. Developmental odontogenic cysts of jaws: a clinical study of 245 cases. J Dent Res Dent Clin Dent Prospects. 2009;3(2):64-6. doi: 10.5681/joddd.2009.015
» https://doi.org/10.5681/joddd.2009.015
6- Ambele MA, Robinson L, van Heerden MB, Pepper MS, van Heerden WF. Comparative molecular genetics of odontogenic keratocysts in sporadic and syndromic patients. Mod Pathol. 2023;36(1):100002. doi: 10.1016/j.modpat.2022.100002
» https://doi.org/10.1016/j.modpat.2022.100002
7- Diniz MG, Gomes CC, Sousa SF, Xavier GM, Gomez RS. Oncogenic signalling pathways in benign odontogenic cysts and tumours. Oral Oncol. 2017;72:165-73. doi: 10.1016/j.oraloncology.2017.07.021
» https://doi.org/10.1016/j.oraloncology.2017.07.021
8- Ohata Y, Kayamori K, Yukimori A, Sumikura K, Ohsako T, Harada H, et al. A lesion categorized between ghost cell odontogenic carcinoma and dentinogenic ghost cell tumor with CTNNB1 mutation. Pathol Int. 2018;68(5):307-12. doi: 10.1111/pin.12659
» https://doi.org/10.1111/pin.12659
9- Garg K, Chandra S, Raj V, Fareed W, Zafar M. Molecular and genetic aspects of odontogenic tumors: a review. Iran J Basic Med Sci. 2015;18(6):529-36.
10- Guimarães LM, Coura BP, Gomez RS, Gomes CC. The molecular pathology of odontogenic tumors: expanding the spectrum of MAPK pathway driven tumors. Front Oral Health. 2021;2:740788. doi: 10.3389/froh.2021.740788
» https://doi.org/10.3389/froh.2021.740788
11- Seto M, Ohta M, Asaoka Y, Ikenoue T, Tada M, Miyabayashi K, et al. Regulation of the hedgehog signaling by the mitogen-activated protein kinase cascade in gastric cancer. Mol Carcinog. 2009;48(8):703-12. doi: 10.1002/mc.20516
» https://doi.org/10.1002/mc.20516
12- Anastas JN, Moon RT. WNT signalling pathways as therapeutic targets in cancer. Nat Rev Cancer. 2013;13(1):11-26. doi: 10.1038/nrc3419
» https://doi.org/10.1038/nrc3419
13- Zhan T, Rindtorff N, Boutros M. Wnt signaling in cancer. Oncogene. 2017;36(11):1461-73. doi: 10.1038/onc.2016.304
» https://doi.org/10.1038/onc.2016.304
14- Anastas JN. Functional crosstalk between WNT signaling and tyrosine kinase signaling in cancer. Semin Oncol. 2015;42(6):820-31. doi: 10.1053/j.seminoncol.2015.09.020
» https://doi.org/10.1053/j.seminoncol.2015.09.020
15- Song L, Li ZY, Liu WP, Zhao MR. Crosstalk between Wnt/ß-catenin and Hedgehog/Gli signaling pathways in colon cancer and implications for therapy. Cancer Biol Ther. 2015;16(1):1-7. doi: 10.4161/15384047.2014.972215
» https://doi.org/10.4161/15384047.2014.972215
16- Sanchez-Vega F, Mina M, Armenia J, Chatila WK, Luna A, La KC, et al. Oncogenic signaling pathways in The Cancer Genome Atlas. Cell. 2018;173(2):321-37.e10. doi: 10.1016/j.cell.2018.03.035
» https://doi.org/10.1016/j.cell.2018.03.035
17- Ramos JW. The regulation of extracellular signal-regulated kinase (ERK) in mammalian cells. Int J Biochem Cell Biol. 2008;40(12):2707-19. doi: 10.1016/j.biocel.2008.04.009
» https://doi.org/10.1016/j.biocel.2008.04.009
18- Ormanns S, Siveke JT, Heinemann V, Haas M, Sipos B, Schlitter AM, et al. pERK, pAKT and p53 as tissue biomarkers in erlotinib-treated patients with advanced pancreatic cancer: a translational subgroup analysis from AIO-PK0104. BMC Cancer. 2014;14:624. doi: 10.1186/1471-2407-14-624
» https://doi.org/10.1186/1471-2407-14-624
19- Theiss AP, Chafin D, Bauer DR, Grogan TM, Baird GS. Immunohistochemistry of colorectal cancer biomarker phosphorylation requires controlled tissue fixation. PLoS One. 2014;9(11):e113608. doi: 10.1371/journal.pone.0113608
» https://doi.org/10.1371/journal.pone.0113608
20- Tsujino I, Nakanishi Y, Hiranuma H, Shimizu T, Hirotani Y, Ohni S, et al. Increased phosphorylation of ERK1/2 is associated with worse chemotherapeutic outcome and a poor prognosis in advanced lung adenocarcinoma. Med Mol Morphol. 2016;49(2):98-109. doi: 10.1007/s00795-015-0130-3
» https://doi.org/10.1007/s00795-015-0130-3
21- Marín C, Niklander SE, Martínez-Flores R. Genetic profile of adenomatoid odontogenic tumor and ameloblastoma. A systematic review. Front Oral Health. 2021;2:767474. doi: 10.3389/froh.2021.767474
» https://doi.org/10.3389/froh.2021.767474
22- Coura BP, Bernardes VF, Sousa SF, França JA, Pereira NB, Pontes HA, et al. KRAS mutations drive adenomatoid odontogenic tumor and are independent of clinicopathological features. Mod Pathol. 2019;32(6):799-806. doi: 10.1038/s41379-018-0194-4
» https://doi.org/10.1038/s41379-018-0194-4
23- Pereira NB, Bastos VC, Souza JC, Diniz MG, Vitório JG, Kitten GT, et al. First insights for targeted therapies in odontogenic myxoma. Clin Oral Investig. 2020;24(7):2451-8. doi: 10.1007/s00784-019-03107-4
» https://doi.org/10.1007/s00784-019-03107-4
24- Pankam J, Kitkumthorn N, Khovidhunkit SP, Bumalee D, Lapthanasupkul P. Analysis of oncogene mutations in odontogenic myxoma. Mod Pathol. 2025;38(12):100856. doi: 10.1016/j.modpat.2025.100856
» https://doi.org/10.1016/j.modpat.2025.100856
25- Gomes IP, Bastos VC, Guimarães LM, Gomes CC. The molecular basis of odontogenic cysts and tumours. J Oral Pathol Med. 2023;52(4):351-6. doi: 10.1111/jop.13401
» https://doi.org/10.1111/jop.13401
26- Nickolaychuk B, McNicol A, Gilchrist J, Birek C. Evidence for a role of mitogen-activated protein kinases in proliferating and differentiating odontogenic epithelia of inflammatory and developmental cysts. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2002;93(6):720-9. doi: 10.1067/moe.2002.123496
» https://doi.org/10.1067/moe.2002.123496
27- Torres OK, Silva LA, Freitas RA, Silveira ÉJ, Miguel MC. Immunoexpression of HSP27 does not seem to influence the prognosis of oral tongue squamous cell carcinoma. Braz Dent J. 2023;34(5):125-33. doi: 10.1590/0103-6440202305036
» https://doi.org/10.1590/0103-6440202305036
28- Pankam J, Lapthanasupkul P, Kitkumthorn N, Khovidhunkit SP. Molecular alterations in MAPK/ERK, ß-Catenin/Wnt, and PI3K/mTOR pathways in adenomatoid odontogenic tumor. J Appl Oral Sci. 2026;34:e20260073. doi: 10.1590/1678-7765-2026-0073
» https://doi.org/10.1590/1678-7765-2026-0073
29- Lapthanasupkul P, Pankam J, Khovidhunkit SP, Seneetuntigul P, Kitkumthorn N. Investigation of oncogenic gene mutation and associated protein expression in ameloblastic carcinoma. Oral Dis. 2026. doi: 10.1111/odi.70420
» https://doi.org/10.1111/odi.70420
30- Srinagesh S, Sahana NS, Suganya G, Renuga S, Natarajan S, Kulkarni M. Expression of PTCH gene in ameloblastoma and odontogenic keratocyst: a comparative study. J Oral Maxillofac Pathol. 2023;27(2):427. doi: 10.4103/jomfp.jomfp_198_22
» https://doi.org/10.4103/jomfp.jomfp_198_22
31- Liu J, Xiao Q, Xiao J, Niu C, Li Y, Zhang X, et al. Wnt/ß-catenin signalling: function, biological mechanisms, and therapeutic opportunities. Signal Transduct Target Ther. 2022;7(1):3. doi: 10.1038/s41392-021-00762-6
» https://doi.org/10.1038/s41392-021-00762-6
32- Kalyanasundaram S, Kandasamy S, John RR. Evaluation of expression of WNT1 and PTCH genes in peripheral blood of patients with odontogenic cysts and tumours of the jaws by quantitative RT-PCR: a pilot study. J Maxillofac Oral Surg. 2023;22(4):1123-9. doi: 10.1007/s12663-023-02014-2
» https://doi.org/10.1007/s12663-023-02014-2
33- Yamasaki S, Shintani T, Ando T, Miyauchi M, Yanamoto S. Transformation of an odontogenic keratocyst into a solid variant of odontogenic keratocyst/keratoameloblastoma during long-term follow-up: a case report. Mol Med Rep. 2024;29(3):44. doi: 10.3892/mmr.2024.13168
» https://doi.org/10.3892/mmr.2024.13168
34- Welsch T, Kleeff J, Friess H. Molecular pathogenesis of pancreatic cancer: advances and challenges. Curr Mol Med. 2007;7(5):504-21. doi: 10.2174/156652407781387082
» https://doi.org/10.2174/156652407781387082
35- Hoyos Cadavid AM, Kaminagakura E, Rodrigues MF, Pinto CA, Teshima TH, Alves FA. Immunohistochemical evaluation of Sonic Hedgehog signaling pathway proteins (Shh, Ptch1, Ptch2, Smo, Gli1, Gli2, and Gli3) in sporadic and syndromic odontogenic keratocysts. Clin Oral Investig. 2019;23(1):153-9. doi: 10.1007/s00784-018-2421-2
» https://doi.org/10.1007/s00784-018-2421-2
36- Baddireddy SM, Manyam R, Thomas DC. Expression of EGFR and survivin in ameloblastoma, odontogenic keratocyst and calcifying odontogenic cyst - an immunohistochemical study. J Oral Maxillofac Pathol. 2023;27(2):424. doi: 10.4103/jomfp.jomfp_187_22
Downloads
Published
Issue
Section
License
Copyright (c) 2026 Nakarin Kitkumthorn, Jintana Pankam, Siribang-on Piboonniyom Khovidhunkit, Athittaya Phaephayom, Puangwan Lapthanasupkul
This work is licensed under a Creative Commons Attribution 4.0 International License.
Todo o conteúdo do periódico, exceto onde está identificado, está licenciado sob uma Licença Creative Commons do tipo atribuição CC-BY.
