Abstract
Purpose
Adenoid cystic carcinoma (ACC) is an intriguing lesion because it shows a slow growth in the beginning, but a late poor prognosis due to perineural invasion, metastasis and recurrence. This study aimed to investigate whether Akt signaling would be deregulated in adenoid cystic carcinoma and its consequence in the expression of associated proteins.
Methods
The expression of the Akt, p-Akt, NFκB, β-catenin, cyclin D1 and COX-2 was assessed by immunohistochemistry in 10 cases of ACC, 17 cases of pleomorphic adenoma (PA), and 7 cases of normal salivary gland (NSG).
Results
p-Akt was overexpressed in ACC when compared to NSG. NFκB, β-catenin, and COX-2 were overexpressed in ACC and PA when compared to NSG. Most proteins were slightly higher expressed in ACC than in PA, but they never reached significance. p-Akt expression positively correlated with NFκB, β-catenin, cyclin D1 and COX-2 in ACC and PA, while this correlation trended to be negative in for these proteins (except for NFκB) in NSG using Person’s correlation analysis, but without reaching significance.
Conclusions
Our results indicate an abnormal activation of Akt signaling pathway, which can be an important regulator of tumor biology in ACC. Activated Akt correlated with the expression of NFκB, β-catenin and COX-2, which can potentially influence cell survival in ACC.
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References
El-Nagar AK, Chan JKC, Grandis JR et al (2017) WHO classification of head and neck tumours, 4th edn. IARC Press, Lyon
Safoura S, Mohamad E, Nosrat-Allah E, Fereshte E (2011) Immunohistochemical expression of progesterone receptors in pleomorphic adenoma and adenoid cystic carcinoma. J Cancer Res Ther 7:23. https://doi.org/10.4103/0973-1482.80440
Deangelis AF, Tsui A, Wiesenfeld D, Chandu A (2011) Outcomes of patients with adenoid cystic carcinoma of the minor salivary glands. Int J Oral Maxillofac Surg 40:710–714. https://doi.org/10.1016/j.ijom.2011.02.010
Brazão-Silva MT, Cardoso SV, de Faria PR et al (2013) Adenoid cystic carcinoma of the salivary gland: a clinicopathological study of 49 cases and of metallothionein expression with regard to tumour behaviour. Histopathology 63:802–809. https://doi.org/10.1111/his.12227
Khan a J, DiGiovanna MP, Ross D et al (2001) Adenoid cystic carcinoma: a retrospective clinical review. Int J Cancer 96:149–158. https://doi.org/10.1002/ijc.1013
Giancotti FG (2014) Deregulation of cell signaling in cancer. FEBS Lett 588:2558–2570. https://doi.org/10.1016/j.febslet.2014.02.005
Ito FA, Ito K, Vargas PA et al (2005) Salivary gland tumors in a Brazilian population: a retrospective study of 496 cases. Int J Oral Maxillofac Surg 34:533–536. https://doi.org/10.1016/j.ijom.2005.02.005
Chummun S, McLean NR, Kelly CG et al (2001) Adenoid cystic carcinoma of the head and neck. Br J Plast Surg 54:476–480. https://doi.org/10.1054/bjps.2001.3636
Gupta AK, Wilke WW, Taylor EN et al (2009) Signaling pathways in adenoid cystic cancers: implications for treatment. Cancer Biol Ther 8:1947–1951. https://doi.org/10.4161/cbt.8.20.9596
Dodd RL, Slevin NJ (2006) Salivary gland adenoid cystic carcinoma: a review of chemotherapy and molecular therapies. Oral Oncol 42:759–769. https://doi.org/10.1016/j.oraloncology.2006.01.001
Ellington CL, Goodman M, Kono SA et al (2012) Adenoid cystic carcinoma of the head and neck: incidence and survival trends based on 1973–2007 surveillance, epidemiology, and end results data. Cancer 118:4444–4451. https://doi.org/10.1002/cncr.27408
Altomare DA, Testa JR (2005) Perturbations of the AKT signaling pathway in human cancer. Oncogene 24:7455–7464. https://doi.org/10.1038/sj.onc.1209085
Martini M, De Santis MC, Braccini L et al (2014) PI3K/AKT signaling pathway and cancer: an updated review. Ann Med 46:372–383. https://doi.org/10.3109/07853890.2014.912836
de Lima MDDM, Marques YMFS, de Melo Alves S et al (2009) MDM2, P53, P21WAF1and pAKT protein levels in genesis and behaviour of adenoid cystic carcinoma. Cancer Epidemiol 33:142–146. https://doi.org/10.1016/j.canep.2009.04.016
Younes MN, Park YW, Yazici YD et al (2006) Concomitant inhibition of epidermal growth factor and vascular endothelial growth factor receptor tyrosine kinases reduces growth and metastasis of human salivary adenoid cystic carcinoma in an orthotopic nude mouse model. Mol Cancer Ther 5:2696–2705. https://doi.org/10.1158/1535-7163.MCT-05-0228
Bellacosa A, Chan TO, Ahmed NN et al (1998) Akt activation by growth factors is a multiple-step process: the role of the PH domain. Oncogene 17:313–325. https://doi.org/10.1038/sj.onc.1201947
Fan CD, Lum MA, Xu C et al (2013) Ubiquitin-dependent regulation of phospho-AKT dynamics by the ubiquitin E3 LIGASE, NEDD4-1, in the insulin-like growth factor-1 response. J Biol Chem 288:1674–1684. https://doi.org/10.1074/jbc.M112.416339
Martelli AM, Tabellini G, Bressanin D et al (2012) The emerging multiple roles of nuclear Akt. Biochim Biophys Acta Mol Cell Res 1823:2168–2178. https://doi.org/10.1016/j.bbamcr.2012.08.017
Zhou J, Du T, Li B et al (2015) Crosstalk between MAPK/ERK and PI3K/AKT signal pathways during brain ischemia/reperfusion. ASN Neuro 7(5):1759091415602463. https://doi.org/10.1177/1759091415602463
Aggarwal BB, Shishodia S (2004) Suppression of the nuclear factor-kappaB activation pathway by spice-derived phytochemicals: Reasoning for seasoning. Ann N Y Acad Sci 1030:434–441. https://doi.org/10.1196/annals.1329.054
Joyce D, Albanese C, Steer J et al (2001) NF-κB and cell-cycle regulation: the cyclin connection. Cytokine Growth Factor Rev 12:73–90. https://doi.org/10.1016/S1359-6101(00)00018-6
Vivanco I, Sawyers CL (2002) The phosphatidylinositol 3-kinase—AKT pathway in human cancer. Nat Rev Cancer 2:489–501. https://doi.org/10.1038/nrc839
Ma B, Hottiger MO (2016) Crosstalk between wnt/β-catenin and NF-κB signaling pathway during inflammation. Front Immunol. https://doi.org/10.3389/fimmu.2016.00378
Testa JR, Bellacosa a (2001) AKT plays a central role in tumorigenesis. Proc Natl Acad Sci USA 98:10983–10985. https://doi.org/10.1073/pnas.211430998
Pitt SC, Davis R, Kunnimalaiyaan M, Chen H (2009) AKT and PTEN expression in human gastrointestinal carcinoid tumors. Am J Transl Res 1:291–299
Hafner C, Houben R, Baeurle A et al (2012) Activation of the PI3K/AKT pathway in merkel cell carcinoma. PLoS One 7(2):e31255. https://doi.org/10.1371/journal.pone.0031255
Scrima M, de Marco C, Fabiani F et al (2012) Signaling networks associated with AKT activation in non-small cell lung cancer (NSCLC): new insights on the role of phosphatydil-inositol-3 kinase. PLoS One 7(2):e30427. https://doi.org/10.1371/journal.pone.0030427
Brembeck FH, Rosário M, Birchmeier W (2006) Balancing cell adhesion and Wnt signaling, the key role of β-catenin. Curr Opin Genet Dev 16:51–59. https://doi.org/10.1016/j.gde.2005.12.007
Polakis P (2007) The many ways of Wnt in cancer. Curr Opin Genet Dev 17:45–51. https://doi.org/10.1016/j.gde.2006.12.007
Chandrashekar C, Angadi PV, Krishnapillai R (2011) Β-Catenin expression in benign and malignant salivary gland tumors. Int J Surg Pathol 19:433–440. https://doi.org/10.1177/1066896909346366
Schneider S, Thurnher D, Seemann R et al (2016) The prognostic significance of β-catenin, cyclin D1 and PIN1 in minor salivary gland carcinoma: β-catenin predicts overall survival. Eur Arch Otorhinolaryngol 273:1283–1292. https://doi.org/10.1007/s00405-015-3609-6
Shtutman M, Zhurinsky J, Simcha I et al (1999) The cyclin D1 gene is a target of the beta-catenin/LEF-1 pathway. Proc Natl Acad Sci USA 96:5522–5527. https://doi.org/10.1073/pnas.96.10.5522
Ramos-García P, Gil-Montoya J, Scully C et al (2017) An update on the implications of cyclin D1 in oral carcinogenesis. Oral Dis 23:897–912. https://doi.org/10.1111/odi.12620
Greenhough A, Smartt HJM, Moore AE et al (2009) The COX-2/PGE2 pathway: key roles in the hallmarks of cancer and adaptation to the tumour microenvironment. Carcinogenesis 30:377–386. https://doi.org/10.1093/carcin/bgp014
Liao Y, Hung MC (2010) Physiological regulation of Akt activity and stability. Am J Transl Res 2:19–42
Yin Y, Shen WH (2008) PTEN: a new guardian of the genome. Oncogene 27:5443–5453. https://doi.org/10.1038/onc.2008.241
Yasumatsu R, Kuratomi Y, Nakashima T et al (2004) Cyclin D1 expression does not effect cell proliferation in adenoid cystic carcinoma of the salivary gland. Eur Arch Otorhinolaryngol 261:526–530. https://doi.org/10.1007/s00405-003-0724-6
Fouad YA, Aanei C (2017) Revisiting the hallmarks of cancer. Am J Cancer Res 7:1016–1036. https://doi.org/10.1016/j.jmwh.2009.11.004
Deng J, Xia W, Miller SA et al (2004) Crossregulation of NF-κB by the APC/GSK-3β/β-catenin pathway. Mol Carcinog 39:139–146. https://doi.org/10.1002/mc.10169
Karim RZ, Tse GMK, Putti TC et al (2004) The significance of the Wnt pathway in the pathology of human cancers. Pathology 36:120–128. https://doi.org/10.1080/00313020410001671957
Zhang G, Zhou X, Xue L et al (2005) Accumulation of cytoplasmic beta-catenin correlates with reduced expression of E-cadherin, but not with phosphorylated Akt in esophageal squamous cell carcinoma: immunohistochemical study. Pathol Int 55:310–317. https://doi.org/10.1111/j.1440-1827.2005.01840.x
Cao Y, Prescott SM (2002) Many actions of cyclooxygenase-2 in cellular dynamics and in cancer. J Cell Physiol 190:279–286. https://doi.org/10.1002/jcp.10068
Sobolewski C, Cerella C, Dicato M et al (2010) The role of cyclooxygenase-2 in cell proliferation and cell death in human malignancies. Int J Cell Biol 2010:1–21. https://doi.org/10.1155/2010/215158
Chun KS, Surh YJ (2004) Signal transduction pathways regulating cyclooxygenase-2 expression: potential molecular targets for chemoprevention. Biochem Pharmacol 68:1089–1100. https://doi.org/10.1016/j.bcp.2004.05.031
Hinz B (2002) Cyclooxygenase-2–10 years later. J Pharmacol Exp Ther 300:367–375. https://doi.org/10.1124/jpet.300.2.367
Acknowledgements
The author Andre Luis Ribeiro Ribeiro is grateful to CAPES Foundation, Ministry of Education of Brazil, for funding his PhD scholarship (Grant no. 0698130).
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This study was approved by the ethics committee of the Institute of Health Sciences at the Federal University of Pará (protocol number: 0047.0.073.000-11) and all procedures performed were in accordance with the ethical standards of the national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
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Branco, K.F.C.C., Ribeiro, A.L.R., de Mendonça, R.P. et al. Abnormal activation of the Akt signaling pathway in adenoid cystic carcinoma. Eur Arch Otorhinolaryngol 275, 3039–3047 (2018). https://doi.org/10.1007/s00405-018-5182-2
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DOI: https://doi.org/10.1007/s00405-018-5182-2