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01-02-2018 | Original Article

The role of epithelial-mesenchymal transition in squamous cell carcinoma of the oral cavity

Published in: Virchows Archiv | Issue 2/2018

Abstract

Epithelial-mesenchymal transition (EMT) has emerged as a possible mechanism of cancer metastasizing, but strong evidence for EMT involvement in human cancer is lacking. Our aim was to compare oral spindle cell carcinoma (SpCC) as an example of EMT with oral conventional squamous cell carcinoma (SCC) with and without nodal metastases to test the hypothesis that EMT contributes to metastasizing in oral SCC. Thirty cases of oral SCC with and without nodal metastasis and 15 cases of SpCC were included. Epithelial (cytokeratin, E-cadherin), mesenchymal (vimentin, N-cadherin), and stem cell markers (ALDH-1, CD44, Nanog, Sox-2) and transcription repressors (Snail, Slug, Twist) were analyzed immunohistochemically. We also analyzed the expression of microRNAs miR-141, miR-200 family, miR-205, and miR-429. SpCC exhibited loss of epithelial markers and expression of mesenchymal markers or coexpression of both up-regulation of transcription repressors and down-regulation of the investigated microRNAs. SCC showed only occasional focal expression of mesenchymal markers at the invasive front. No other differences were observed between SCC with and without nodal metastases except for a higher expression of ALDH-1 in SCC with metastases. Our results suggest that SpCC is an example of true EMT but do not support the hypothesis that EMT is involved in metastasizing of conventional SCC. Regarding oral SCC progression and metastasizing, we have been facing a shift from the initial enthusiasm for the EMT concept towards a more critical approach with “EMT-like” and “partial EMT” concepts. The real question, though, is, is there no EMT at all?

Thiery JP, Acloque H, Huang RY, Nieto MA (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139:871–890CrossRefPubMed

Nieto MA, Huang RY, Jackson RA, Thiery JP (2016) EMT: 2016. Cell 166:21–45CrossRefPubMed

De Wever O, Pauwels P, De Craene B, Sabbah M, Emami S, Redeuilh G et al (2008) Molecular and pathological signatures of epithelial-mesenchymal transitions at the cancer invasion front. Histochem Cell Biol 130:481–494CrossRefPubMedPubMedCentral

Kalluri R, Weinberg RA (2009) The basics of epithelial-mesenchymal transition. J Clin Invest 119:1420–1428CrossRefPubMedPubMedCentral

Thiery JP (2003) Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol 15:740–746CrossRefPubMed

Smith A, Teknos TN, Pan Q (2013) Epithelial to mesenchymal transition in head and neck squamous cell carcinoma. Oral Oncol 49:287–292CrossRefPubMed

Yilmaz M, Christofori G (2010) Mechanisms of motility in metastasizing cells. Mol Cancer Res 8:629–642CrossRefPubMed

Tsai JH, Donaher JL, Murphy DA, Chau S, Yang J (2012) Spatiotemporal regulation of epithelial-mesenchymal transition is essential for squamous cell carcinoma metastasis. Cancer Cell 22:725–736CrossRefPubMedPubMedCentral

Ocana OH, Córcoles R, Fabra A, Moreno-Bueno G, Acloque H, Vega S et al (2012) Metastatic colonization requires the repression of the epithelial-mesenchymal transition inducer Prrx1. Cancer Cell 22:709–724CrossRefPubMed

10.

Fischer KR, Durrans A, Lee S, Sheng J, Li F, Wong ST et al (2015) Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature 527:472–476CrossRefPubMedPubMedCentral

11.

Zheng X, Carstens JL, Kim J, Scheible M, Kaye J, Sugimoto H et al (2015) Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 527:525–530CrossRefPubMedPubMedCentral

12.

Chui MH (2013) Insights into cancer metastasis from a clinicopathologic perspective: epithelial-mesenchymal transition is not a necessary step. Int J Cancer 132:1487–1495CrossRefPubMed

13.

Tarin D (2005) The fallacy of epithelial mesenchymal transition in neoplasia. Cancer Res 65:5996–6000CrossRefPubMed

14.

Tarin D (2012) Inappropriate gene expression in human cancer and its far-reaching biological and clinical significance. Cancer Metastasis Rev 31:21–39CrossRefPubMed

15.

Tarin D (2013) The role of the host stroma in cancer and its therapeutic significance. Cancer Met Rev 32:553–566CrossRef

16.

Chaw SY, Majeed AA, Dalley AJ, Chan A, Stein S, Farah CS (2012) Epithelial to mesenchymal transition (EMT) biomarkers—E-cadherin, beta-catenin, APC and vimentin-in oral squamous cell carcinogenesis and transformation. Oral Oncol 48:997–1006CrossRefPubMed

17.

Pectasides E, Rampias T, Sasaki C, Perisanidis C, Kouloulias V, Burtness B et al (2014) Markers of epithelial to mesenchymal transition in association with survival in head and neck squamous cell carcinoma (HNSCC). PLoS One 9:e94273CrossRefPubMedPubMedCentral

18.

Zhang S, Zhou X, Wang B, Zhang K, Liu S, Yue K et al (2014) Loss of VHL expression contributes to epithelial-mesenchymal transition in oral squamous cell carcinoma. Oral Oncol 50:809–817CrossRefPubMed

19.

da Silva SD, Alaoui-Jamali MA, Soares FA, Carraro DM, Brentani HP, Hier M et al (2015) TWIST1 is a molecular marker for a poor prognosis in oral cancer and represents a potential therapeutic target. Cancer 120:352–362CrossRef

20.

da Silva SD, Morand GB, Alobaid FA, Hier MP, Mlynarek AM, Alaoui-Jamali MA et al (2015) Epithelial-mesenchymal transition (EMT) markers have prognostic impact in multiple primary oral squamous cell carcinoma. Clin Exp Metastasis 32:55–63CrossRefPubMed

21.

Angadi PV, Patil PV, Angadi V, Mane D, Shekar S, Hallikerimath S et al (2016) Immunoexpression of epithelial mesenchymal transition proteins E-cadherin, β-catenin, and N-cadherin in oral squamous cell carcinoma. Int J Surg Pathol 24:696–703CrossRefPubMed

22.

Kimura I, Kitahara H, Ooi K, Kato K, Noguchi N, Yoshizawa K et al (2016) Loss of epidermal growth factor receptor expression in oral squamous cell carcinoma is associated with invasiveness and epithelial-mesenchymal transition. Oncol Lett 11:201–207CrossRefPubMed

23.

Zidar N, Gale N, Kojc N, Volavšek M, Cardesa A, Alos L et al (2008) Cadherin-catenin complex and transcription factor Snail-1 in spindle cell carcinoma of the head and neck. Virchows Arch 453:267–274CrossRefPubMed

24.

Kojc N, Zidar N, Gale N, Poljak M, Fujs Komlos K, Cardesa A et al (2009) Transcription factors Snail, Slug, Twist, and SIP1 in spindle cell carcinoma of the head and neck. Virchows Arch 454:549–555CrossRefPubMed

25.

Zidar N, Boštjančič E, Gale N, Kojc N, Poljak M, Glavač D et al (2011) Down-regulation of microRNAs of the miR-200 family and miR-205, and an altered expression of classic and desmosomal cadherins in spindle cell carcinoma of the head and neck-hallmark of epithelial-mesenchymal transition. Hum Pathol 42:482–488CrossRefPubMed

26.

Díaz-López A, Moreno-Bueno G, Cano A (2014) Role of microRNA in epithelial to mesenchymal transition and metastasis and clinical perspectives. Cancer Manag Res 6:205–216PubMedPubMedCentral

27.

Díaz-Martín J, Díaz-López A, Moreno-Bueno G, Castilla MÁ, Rosa-Rosa JM, Cano A, Palacios J (2014) A core microRNA signature associated with inducers of the epithelial-to-mesenchymal transition. J Pathol 232:319–329CrossRefPubMed

28.

Cano A, Pérez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG et al (2000) The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol 2:76–83CrossRefPubMed

29.

Bracken CP, Gregory PA, Kolesnikoff N, Bert AG, Wang J, Shannon MF et al (2008) A double-negative feedback loop between ZEB1-SIP1 and the microRNA-200 family regulates epithelial-mesenchymal transition. Cancer Res 68:7846–7854CrossRefPubMed

30.

Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G et al (2008) The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol 10:593–601CrossRefPubMed

31.

Lamouille S, Subramanyam D, Blelloch R et al (2013) Regulation of epithelial-mesenchymal and mesenchymal-epithelial transitions by microRNAs. Curr Opin Cell Biol 25:200–207CrossRefPubMedPubMedCentral

32.

Zidar N, Boštjančič E, Jerala M, Kojc N, Drobne D, Štabuc B et al (2016) Downregulation of microRNAs of the miR-200 family and up-regulation of Snail and Slug in inflammatory bowel diseases—hallmark of epithelial-mesenchymal transition. J Cell Mol Med 20:1813–1820CrossRefPubMedPubMedCentral

33.

Latham GJ (2010) Normalization of microRNA quantitative RT-PCR data in reduced scale experimental designs. Methods Mol Biol 667:19–31CrossRefPubMed

34.

Bryne M (1998) Is the invasive front of an oral carcinoma the most important area for prognostication? Oral Dis 4:70–77CrossRefPubMed

35.

Du L, Yang Y, Xiao X, Wang C, Zhang X, Wang L et al (2011) Sox2 nuclear expression is closely associated with poor prognosis in patients with histologically node-negative oral tongue squamous cell carcinoma. Oral Oncol 47:709–713CrossRefPubMed

36.

Kokko LL, Hurme S, Maula SM, Alanen K, Grénman R, Kinnunen I et al (2011) Significance of site-specific prognosis of cancer stem cell marker CD44 in head and neck squamous-cell carcinoma. Oral Oncol 47:510–516CrossRefPubMed

37.

Watanabe M, Ohnishi Y, Inoue H, Wato M, Tanaka A, Kakudo K et al (2014) NANOG expression correlates with differentiation, metastasis and resistance to preoperative adjuvant therapy in oral squamous cell carcinoma. Oncol Lett 7:35–40CrossRefPubMed

38.

Zhou C, Sun B (2014) The prognostic role of the cancer stem cell marker aldehyde dehydrogenase 1 in head and neck squamous cell carcinomas: a meta-analysis. Oral Oncol 50:1144–1148CrossRefPubMed

39.

Chou MY, Hu FW, Yu CH, Yu CC (2015) Sox2 expression involvement in the oncogenicity and radiochemoresistance of oral cancer stem cells. Oral Oncol 51:31–39CrossRefPubMed

Title: The role of epithelial-mesenchymal transition in squamous cell carcinoma of the oral cavity
Publication date: 01-02-2018
Published in: Virchows Archiv / Issue 2/2018
Print ISSN: 0945-6317
Electronic ISSN: 1432-2307
DOI: https://doi.org/10.1007/s00428-017-2192-1

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The role of epithelial-mesenchymal transition in squamous cell carcinoma of the oral cavity

Abstract

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