Skip to main content
Top
Published in: Diagnostic Pathology 1/2021

Open Access 01-12-2021 | Research

Key proteins of invadopodia are overexpressed in oral squamous cell carcinoma suggesting an important role of MT1-MMP in the tumoral progression

Authors: Geovanni Pereira Mitre, Karolyny Martins Balbinot, André Luis Ribeiro Ribeiro, Maria Sueli da Silva Kataoka, Sérgio de Melo Alves Júnior, João de Jesus Viana Pinheiro

Published in: Diagnostic Pathology | Issue 1/2021

Login to get access

Abstract

Background

Oral squamous cell carcinoma (OSCC) is the most relevant malignant neoplasm among all head and neck tumours due to its high prevalence and unfavourable prognosis. Tumour invasion and metastasis that affect prognosis are result of a set of complex events that cells with invasive potential use to spread to other regions. These cells use several mechanisms to invade tissues, including a type of finger-like membrane protrusion called invadopodia. This study aims to investigate the immunoexpression of invaopodia related-proteins TKs5, cortactin, TKs4 and MT1-MMP in OSCC and correlate it to clinicopathological data.

Methods

An immunohistochemical evaluation of fifty cases of OSCCs and 20 cases of oral mucosa (OM) were assessed. The expression of invadopodia proteins were analysed in comparison to normal tissue (OM) and correlated to different clinical-stage and histological grade of OSCC.

Results

TKs5, cortactin, TKs4 and MT1-MMP were significantly overexpressed in OSCC when compared to OM (p < 0.0001). Among tumour stages, TKs5 showed a statistical difference in immunolabelling between stage I and III (p = 0.026). Cortactin immunolabelling was statistically higher in grade I than in grade II and III. No differences were seen on TKs4 expression based on tumour staging or grading. MT1-MMP was higher expressed and showed statistical difference between stages I and III and grades I compared to II and III.

Conclusions

The invadopodia related-proteins were found to be overexpressed in OSCC when compared to OM, suggesting invadopodia formation and activity. Besides overexpressed in OSCC, cortactin, TKs4 and TKs5 showed no or ambiguous differences in protein expression when compared among clinical-stages or histological grades groups. Conversely, the expression of MT1-MMP increased in advanced stages and less differentiated tumours, suggesting MT1-MMP expression as a promising prognostic marker in OSCC.
Literature
1.
go back to reference Kreppel M, Drebber U, Eich HT, et al. Combined-modality treatment in advanced oral squamous cell carcinoma: Primary surgery followed by adjuvant concomitant radiochemotherapy. Strahlenther Onkol. 2011;187:555–60.CrossRef Kreppel M, Drebber U, Eich HT, et al. Combined-modality treatment in advanced oral squamous cell carcinoma: Primary surgery followed by adjuvant concomitant radiochemotherapy. Strahlenther Onkol. 2011;187:555–60.CrossRef
2.
go back to reference Warnakulasuriya S. Global epidemiology of oral and oropharyngeal cancer. Oral Oncol. 2009;45:309–16.CrossRef Warnakulasuriya S. Global epidemiology of oral and oropharyngeal cancer. Oral Oncol. 2009;45:309–16.CrossRef
3.
go back to reference EL-Naggar A, Chan C, Grandis R, Takata T, Slootweg J. WHO Classification of Head and Neck Tumours. 4.ed. Lyon: IARC; 2017. EL-Naggar A, Chan C, Grandis R, Takata T, Slootweg J. WHO Classification of Head and Neck Tumours. 4.ed. Lyon: IARC; 2017.
4.
go back to reference Väyrynen O, Åström P, Nyberg P, et al. Matrix metalloproteinase 9 inhibits the motility of highly aggressive HSC-3 oral squamous cell carcinoma cells. Exp Cell Res. 2019;367:18–36.CrossRef Väyrynen O, Åström P, Nyberg P, et al. Matrix metalloproteinase 9 inhibits the motility of highly aggressive HSC-3 oral squamous cell carcinoma cells. Exp Cell Res. 2019;367:18–36.CrossRef
5.
go back to reference Yin M, Ma W, An L. Cortactin in cancer cell migration and invasion. Oncotarget. 2017;19:88232–43.CrossRef Yin M, Ma W, An L. Cortactin in cancer cell migration and invasion. Oncotarget. 2017;19:88232–43.CrossRef
6.
go back to reference Caldieri G, Ayala I, Attanasio F, et al. Cell and molecular biology of invadopodia. Int Rev Cell Mol Biol. 2009;275:1–34.CrossRef Caldieri G, Ayala I, Attanasio F, et al. Cell and molecular biology of invadopodia. Int Rev Cell Mol Biol. 2009;275:1–34.CrossRef
7.
go back to reference Hwang YS, Park KK, Chung WY. Invadopodia formation in oral squamous cell carcinoma: the role of epidermal growth factor receptor signalling. Arch Oral Biol. 2012;57:335–43.CrossRef Hwang YS, Park KK, Chung WY. Invadopodia formation in oral squamous cell carcinoma: the role of epidermal growth factor receptor signalling. Arch Oral Biol. 2012;57:335–43.CrossRef
8.
go back to reference Yilmaz M, Christofori G. EMT, the cytoskeleton, and cancer cell invasion. Cancer Metastasis Rev. 2009;28:15–33.CrossRef Yilmaz M, Christofori G. EMT, the cytoskeleton, and cancer cell invasion. Cancer Metastasis Rev. 2009;28:15–33.CrossRef
9.
go back to reference Millard TH, Sharp SJ, Machesky LM. Signalling to actin assembly via the WASP (Wiskott-Aldrich syndrome protein)-family proteins and the Arp2/3 complex. Biochem. 2004;15:1–17. Millard TH, Sharp SJ, Machesky LM. Signalling to actin assembly via the WASP (Wiskott-Aldrich syndrome protein)-family proteins and the Arp2/3 complex. Biochem. 2004;15:1–17.
10.
go back to reference Díaz B, Yuen A, Iizuka S, et al. Notch increases the shedding of HB-EGF by ADAM12 to potentiate invadopodia formation in hypoxia. J Cell Biol. 2013;201:279–92.CrossRef Díaz B, Yuen A, Iizuka S, et al. Notch increases the shedding of HB-EGF by ADAM12 to potentiate invadopodia formation in hypoxia. J Cell Biol. 2013;201:279–92.CrossRef
11.
go back to reference Jeannot P, Besson A. Cortactin function in invadopodia. Small GTPases. 2013;31:1–15. Jeannot P, Besson A. Cortactin function in invadopodia. Small GTPases. 2013;31:1–15.
12.
go back to reference Sung BH, Zhu X, Kaverina I, et al. Cortactin controls cell motility and lamellipodial dynamics by regulating ECM secretion. Curr Biol. 2011;21:1460–9.CrossRef Sung BH, Zhu X, Kaverina I, et al. Cortactin controls cell motility and lamellipodial dynamics by regulating ECM secretion. Curr Biol. 2011;21:1460–9.CrossRef
13.
go back to reference Burger KL, Learman BS, Boucherle AK, et al. Src-dependent TKs5 phosphorylation regulates invadopodia-associated invasion in prostate cancer cells. Prostate. 2014;74:134–48.CrossRef Burger KL, Learman BS, Boucherle AK, et al. Src-dependent TKs5 phosphorylation regulates invadopodia-associated invasion in prostate cancer cells. Prostate. 2014;74:134–48.CrossRef
14.
go back to reference Crimaldi L, Courtneidge SA, Gimona M. Tks5 recruits AFAP-110, p190RhoGAP, and cortactin for podosome formation. Exp Cell Res. 2013;315:2581–92.CrossRef Crimaldi L, Courtneidge SA, Gimona M. Tks5 recruits AFAP-110, p190RhoGAP, and cortactin for podosome formation. Exp Cell Res. 2013;315:2581–92.CrossRef
15.
go back to reference Abram CL, Seals DF, Pass I, et al. The adaptor protein fish associates with members of the ADAMs family and localizes to podosomes of Src-transformed cells. J Biol Chem. 2003;278:16844–51.CrossRef Abram CL, Seals DF, Pass I, et al. The adaptor protein fish associates with members of the ADAMs family and localizes to podosomes of Src-transformed cells. J Biol Chem. 2003;278:16844–51.CrossRef
16.
go back to reference Ongkeko WM, Altuna X, Weisman RA, et al. Expression of protein tyrosine kinases in head and neck squamous cell carcinomas. Am J Clin Pathol. 2005;124:71–6.CrossRef Ongkeko WM, Altuna X, Weisman RA, et al. Expression of protein tyrosine kinases in head and neck squamous cell carcinomas. Am J Clin Pathol. 2005;124:71–6.CrossRef
17.
go back to reference Buschman MD, Bromann PA, Cejudo-Martin P, et al. The novel adaptor protein Tks4 (SH3PXD2B) is required for functional podosome formation. Mol Biol Cell. 2009;20:1302–11.CrossRef Buschman MD, Bromann PA, Cejudo-Martin P, et al. The novel adaptor protein Tks4 (SH3PXD2B) is required for functional podosome formation. Mol Biol Cell. 2009;20:1302–11.CrossRef
19.
go back to reference Li YY, Zhou CX, Gao Y. Podoplanin promotes the invasion of oral squamous cell carcinoma in coordination with MT1-MMP and Rho GTPases. Am J Cancer Res. 2015;15:514–29. Li YY, Zhou CX, Gao Y. Podoplanin promotes the invasion of oral squamous cell carcinoma in coordination with MT1-MMP and Rho GTPases. Am J Cancer Res. 2015;15:514–29.
20.
go back to reference Courtneidge SA. Cell migration and invasion in human disease: the Tks adaptor proteins. Biochem Soc Trans. 2012;40:129–32.CrossRef Courtneidge SA. Cell migration and invasion in human disease: the Tks adaptor proteins. Biochem Soc Trans. 2012;40:129–32.CrossRef
21.
go back to reference Lebeau A, Nerlich AG, Sauer U, et al. Tissue distribution of major matrix metalloproteinases and their transcripts in human breast carcinomas. Anticancer Res. 1999;19:4257–64.PubMed Lebeau A, Nerlich AG, Sauer U, et al. Tissue distribution of major matrix metalloproteinases and their transcripts in human breast carcinomas. Anticancer Res. 1999;19:4257–64.PubMed
22.
go back to reference Shu J, Dolman GE, Duan J, et al. Statistical colour models: an automated digital image analysis method for quantification of histological biomarkers. Biomed Eng Online. 2016;27:15–46. Shu J, Dolman GE, Duan J, et al. Statistical colour models: an automated digital image analysis method for quantification of histological biomarkers. Biomed Eng Online. 2016;27:15–46.
23.
go back to reference Artym VV, Zhang Y, Seillier-Moiseiwitsch F, et al. Dynamic interactions of cortactin and membrane type 1 matrix metalloproteinase at invadopodia: defining the stages of invadopodia formation and function. Cancer Res. 2006;66:3034–43.CrossRef Artym VV, Zhang Y, Seillier-Moiseiwitsch F, et al. Dynamic interactions of cortactin and membrane type 1 matrix metalloproteinase at invadopodia: defining the stages of invadopodia formation and function. Cancer Res. 2006;66:3034–43.CrossRef
24.
go back to reference Ng JH, Iyer NG, Tan MH, et al. Changing epidemiology of oral squamous cell carcinoma of the tongue: A global study. Head Neck. 2017;39:297–304.CrossRef Ng JH, Iyer NG, Tan MH, et al. Changing epidemiology of oral squamous cell carcinoma of the tongue: A global study. Head Neck. 2017;39:297–304.CrossRef
25.
go back to reference Castro-Castro A, Marchesin V, Monteiro P, et al. Cellular and Molecular Mechanisms of MT1-MMP-Dependent Cancer Cell Invasion. Annu Rev Cell Dev Biol. 2016;32:555–76.CrossRef Castro-Castro A, Marchesin V, Monteiro P, et al. Cellular and Molecular Mechanisms of MT1-MMP-Dependent Cancer Cell Invasion. Annu Rev Cell Dev Biol. 2016;32:555–76.CrossRef
26.
go back to reference Oser M, Yamaguchi H, Mader CC, et al. Cortactin regulates cofilin and N-WASp activities to control the stages of invadopodium assembly and maturation. J Cell Biol. 2009;186:571–87.CrossRef Oser M, Yamaguchi H, Mader CC, et al. Cortactin regulates cofilin and N-WASp activities to control the stages of invadopodium assembly and maturation. J Cell Biol. 2009;186:571–87.CrossRef
27.
go back to reference Clark ES, Weaver AM. A new role for cortactin in invadopodia: regulation of protease secretion. Eur J Cell Biol. 2008;87:581–90.CrossRef Clark ES, Weaver AM. A new role for cortactin in invadopodia: regulation of protease secretion. Eur J Cell Biol. 2008;87:581–90.CrossRef
28.
go back to reference Stylli SS, Stacey TT, Verhagen AM, et al. Nck adaptor proteins link Tks5 to invadopodia actin regulation and ECM degradation. J Cell Sci. 2009;122:2727–40.CrossRef Stylli SS, Stacey TT, Verhagen AM, et al. Nck adaptor proteins link Tks5 to invadopodia actin regulation and ECM degradation. J Cell Sci. 2009;122:2727–40.CrossRef
29.
go back to reference Stylli SS, Luwor RB, Kaye AH1, et al. Expression of the adaptor protein Tks5 in human cancer: prognostic potential. Oncol Rep. 2014;32:989–1002.CrossRef Stylli SS, Luwor RB, Kaye AH1, et al. Expression of the adaptor protein Tks5 in human cancer: prognostic potential. Oncol Rep. 2014;32:989–1002.CrossRef
30.
go back to reference Rothschild BL, Shim AH, Ammer AG, et al. Cortactin overexpression regulates actin-related protein 2/3 complex activity, motility, and invasion in carcinomas with chromosome 11q13 amplification. Cancer Res. 2006;66:8017–25.CrossRef Rothschild BL, Shim AH, Ammer AG, et al. Cortactin overexpression regulates actin-related protein 2/3 complex activity, motility, and invasion in carcinomas with chromosome 11q13 amplification. Cancer Res. 2006;66:8017–25.CrossRef
31.
go back to reference Hofman P, Butori C, Havet K, et al. Prognostic significance of cortactin levels in head and neck squamous cell carcinoma: comparison with epidermal growth factor receptor status. Br J Cancer. 2008;98:956–64.CrossRef Hofman P, Butori C, Havet K, et al. Prognostic significance of cortactin levels in head and neck squamous cell carcinoma: comparison with epidermal growth factor receptor status. Br J Cancer. 2008;98:956–64.CrossRef
32.
go back to reference Hsu NY, Yeh KT, Chiang IP, et al. Cortactin overexpression in the esophageal squamous cell carcinoma and its involvement in the carcinogenesis. Dis Esophagus. 2008;21(5):402–8.CrossRef Hsu NY, Yeh KT, Chiang IP, et al. Cortactin overexpression in the esophageal squamous cell carcinoma and its involvement in the carcinogenesis. Dis Esophagus. 2008;21(5):402–8.CrossRef
33.
go back to reference Ribeiro Ribeiro AL, da Costa NM, de Siqueira AS, et al. Keratocystic odontogenic tumor overexpresses invadopodia-related proteins, suggesting invadopodia formation. Oral Surg Oral Med Oral Pathol Oral Radiol. 2016;122:500–8.CrossRef Ribeiro Ribeiro AL, da Costa NM, de Siqueira AS, et al. Keratocystic odontogenic tumor overexpresses invadopodia-related proteins, suggesting invadopodia formation. Oral Surg Oral Med Oral Pathol Oral Radiol. 2016;122:500–8.CrossRef
34.
go back to reference Iizuka S, Abdullah C, Buschman MD, et al. The role of Tks adaptor proteins in invadopodia formation, growth and metastasis of melanoma. Oncotarget. 2016;29:78473–86.CrossRef Iizuka S, Abdullah C, Buschman MD, et al. The role of Tks adaptor proteins in invadopodia formation, growth and metastasis of melanoma. Oncotarget. 2016;29:78473–86.CrossRef
35.
go back to reference Mak KM, Mei R. Basement Membrane Type IV Collagen and Laminin: An Overview of Their Biology and Value as Fibrosis Biomarkers of Liver Disease. Anat Rec. 2017;300:1371–90.CrossRef Mak KM, Mei R. Basement Membrane Type IV Collagen and Laminin: An Overview of Their Biology and Value as Fibrosis Biomarkers of Liver Disease. Anat Rec. 2017;300:1371–90.CrossRef
36.
go back to reference Itoh Y. MT1-MMP: a key regulator of cell migration in tissue. IUBMB Life 58:589–596. Itoh Y. MT1-MMP: a key regulator of cell migration in tissue. IUBMB Life 58:589–596.
37.
go back to reference Turunen SP, Tatti-Bugaeva O, Lehti K. Membrane-type matrix metalloproteases as diverse effectors of cancer progression. Biochim Biophys Acta Mol Cell Res. 2017;1864:1974–88.CrossRef Turunen SP, Tatti-Bugaeva O, Lehti K. Membrane-type matrix metalloproteases as diverse effectors of cancer progression. Biochim Biophys Acta Mol Cell Res. 2017;1864:1974–88.CrossRef
38.
go back to reference Lodillinsky C, Infante E, Guichard A, et al. p63/MT1-MMP axis is required for in situ to invasive transition in basal-like breast cancer. Oncogene. 2016;35:344–57.CrossRef Lodillinsky C, Infante E, Guichard A, et al. p63/MT1-MMP axis is required for in situ to invasive transition in basal-like breast cancer. Oncogene. 2016;35:344–57.CrossRef
39.
go back to reference Knapinska AM, Fields GB. The Expanding Role of MT1-MMP in Cancer Progression. Pharmaceuticals (Basel). 2019;12(2):77.CrossRef Knapinska AM, Fields GB. The Expanding Role of MT1-MMP in Cancer Progression. Pharmaceuticals (Basel). 2019;12(2):77.CrossRef
40.
go back to reference Miyazawa Y, Uekita T, Ito Y, et al. CDCP1 regulates the function of MT1-MMP and invadopodia-mediated invasion of cancer cells. Mol Cancer Res. 2013;11:628–37.CrossRef Miyazawa Y, Uekita T, Ito Y, et al. CDCP1 regulates the function of MT1-MMP and invadopodia-mediated invasion of cancer cells. Mol Cancer Res. 2013;11:628–37.CrossRef
41.
go back to reference Ali A, Soares AB, Eymael D, et al. Expression of invadopodia markers can identify oral lesions with a high risk of malignant transformation. J Pathol Clin Res. 2021;7(1):61–74.CrossRef Ali A, Soares AB, Eymael D, et al. Expression of invadopodia markers can identify oral lesions with a high risk of malignant transformation. J Pathol Clin Res. 2021;7(1):61–74.CrossRef
42.
go back to reference Goertzen C, Mahdi H, Laliberte C, et al. Oral inflammation promotes oral squamous cell carcinoma invasion. Oncotarget. 2018;9(49):29047–63.CrossRef Goertzen C, Mahdi H, Laliberte C, et al. Oral inflammation promotes oral squamous cell carcinoma invasion. Oncotarget. 2018;9(49):29047–63.CrossRef
43.
go back to reference Augoff K, Hryniewicz-Jankowska A, Tabola R. Invadopodia: clearing the way for cancer cell invasion. Ann Transl Med. 2020;8(14):902.CrossRef Augoff K, Hryniewicz-Jankowska A, Tabola R. Invadopodia: clearing the way for cancer cell invasion. Ann Transl Med. 2020;8(14):902.CrossRef
Metadata
Title
Key proteins of invadopodia are overexpressed in oral squamous cell carcinoma suggesting an important role of MT1-MMP in the tumoral progression
Authors
Geovanni Pereira Mitre
Karolyny Martins Balbinot
André Luis Ribeiro Ribeiro
Maria Sueli da Silva Kataoka
Sérgio de Melo Alves Júnior
João de Jesus Viana Pinheiro
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Diagnostic Pathology / Issue 1/2021
Electronic ISSN: 1746-1596
DOI
https://doi.org/10.1186/s13000-021-01090-7

Other articles of this Issue 1/2021

Diagnostic Pathology 1/2021 Go to the issue