Top

Clinical Oral Investigations

Published in:

01-04-2013 | Original Article

Overexpression of Smad proteins, especially Smad7, in oral epithelial dysplasias

Authors: Yuk-Kwan Chen, Anderson Hsien-Cheng Huang, Pei-Hsun Cheng, Shang-Hsun Yang, Li-Min Lin

Published in: Clinical Oral Investigations | Issue 3/2013

Abstract

Objective

Transforming growth factor β, via membrane-bound receptors and downstream Smad2–4, 7, can modulate tumorigenesis. Smad2 and Smad3 heterodimerize with Smad4, and the complex migrates to the nucleus to regulate the expression of target genes. Smad7 is a key negative regulator of this signaling pathway. This study aimed to examine Smad2–4, 7 expression and phosphorylated Smad2–3 (p-Smad2–3) in oral epithelial dysplasia and compared it with normal oral mucosa, hyperkeratosis/epithelial hyperplasia and squamous cell carcinoma (SCC).

Materials and methods

Immunohistochemical staining of Smad2–4, 7 and p-Smad2–3, was performed for 75 samples of human oral mucosa, including hyperkeratosis/epithelial hyperplasia (n = 20), mild epithelial dysplasia (n = 11), moderate to severe epithelial dysplasia (n = 11), and SCC (n = 43). Normal buccal mucosa samples (n = 9) were also included.

Results

A significant increase in Smad7 expression was observed in the ascending order of samples of normal oral mucosa, hyperkeratosis/epithelial hyperplasia/mild oral epithelial dysplasia, moderate to severe oral epithelial dysplasia, and well-differentiated oral SCC/moderately to poorly differentiated oral SCC. Additionally, significant increases in Smad7 expression were noted as compared with expression of Smad2–4 and p-Smad2–3 in lesions of hyperkeratosis/epithelial hyperplasia, mild oral epithelial dysplasia, moderate to severe oral epithelial dysplasia, well-differentiated oral SCC, and moderately to poorly differentiated oral SCC.

Conclusions

Our results indicate that Smad proteins, particularly Smad7, in oral epithelial dysplasia and SCC could contribute to the attenuation of Smads anti-proliferative signaling in cancer development.

Clinical relevance

Smad7 could be a marker for risk of malignant transformation of oral epithelial dysplasia.

Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55:74–108PubMedCrossRef

Chen YK, Huang HC, Lin LM, Lin CC (1999) Primary oral squamous cell carcinoma: an analysis of 703 cases in southern Taiwan. Oral Oncol 35:173–179PubMedCrossRef

Das BR, Nagpal JK (2002) Understanding the biology of oral cancer. Med Sci Monit 8:RA258–RA267PubMed

Zhang X, Liu Y, Gilcrease MZ et al (2002) A lymph node metastatic mouse model reveals alterations of metastasis-related gene expression in metastatic human oral carcinoma sublines selected from a poorly metastatic parental cell line. Cancer 95:1663–1672PubMedCrossRef

Deshpande AM, Wong DT (2008) Molecular mechanisms of head and neck cancer. Expert Rev Anticancer Ther 8:799–809PubMedCrossRef

Zimmerman CM, Padgett RW (2000) Transforming growth factor β signaling mediators and modulators. Gene 249:17–30PubMedCrossRef

Shi Y, Hata A, Lo RS, Massagué J, Pavletich NP (1997) Structural basis for mutational inactivation of the tumor suppressor Smad4. Nature 388:87–93PubMedCrossRef

Paterson IC, Matthews JB, Huntley S et al (2001) Decreased expression of TGF-β cell surface receptors during progression of human oral squamous cell carcinoma. J Pathol 193:458–467PubMedCrossRef

Qiu W, Schwnleben F, Li X, Su GH (2007) Disruption of transforming growth factor β-Smad signaling pathway in head and neck squamous cell carcinoma as evidenced by mutations of Smad2 and Smad4. Cancer Lett 245:163–170PubMedCrossRef

10.

Iamaroon A, Pattamapun K, Piboonniyom SO (2006) Aberrant expression of Smad4, a TGF-β signaling molecule, in oral squamous cell carcinoma. J Oral Sci 48:105–109PubMedCrossRef

11.

Pindborg JJ, Daftary DK, Mehta FS (1997) A follow-up study of sixty-one oral dysplastic precancerous lesions in Indian villagers. Oral Surg Oral Med Oral Pathol 43:383–390CrossRef

12.

Lumerman H, Freedman P, Kerpel S (1995) Oral epithelial dysplasia and the development of invasive squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 79:321–329PubMedCrossRef

13.

Wright A, Shear M (1985) Epithelial dysplasia immediately adjacent to oral squamous cell carcinoma. J Oral Pathol 14:559–564PubMedCrossRef

14.

Kramer IR, Lucas RB, Pindborg JJ, Sobin LH (1978) Definition of leukoplakia and related lesions: an aid to studies on oral precancer. Oral Surg Oral Med Oral Pathol 46:518–539PubMedCrossRef

15.

World Health Organization (1988) International classification of diseases for oncology. World Health Organization, Geneva

16.

Hsu SM, Raine L, Fanger H (1981) Use of avidin–biotin–peroxidase complex (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabelled antibody (PAP) procedures. J Histochem Cytochem 29:577–580PubMedCrossRef

17.

Chen YK, Yang SH, Huang AH, Hsue SS, Lin LM (2011) Aberrant expression in multiple components of the transforming growth factor-β1-induced Smad signaling pathway during 7,12-dimethylbenz[a]anthracene-induced hamster buccal-pouch squamous-cell carcinogenesis. Oral Oncol 47:262–267PubMedCrossRef

18.

Landis JR, Koch GG (1977) The measurement of observer agreement for categorical data. Biometrics 33:159–174PubMedCrossRef

19.

Kleeff J, Ishiwata T, Maruyama H et al (1999) The TGF-beta signaling inhibitor Smad7 enhances tumorigenicity in pancreatic cancer. Oncogene 18:5363–5372PubMedCrossRef

20.

Boulay JL, Mild G, Lowy A et al (2003) SMAD7 is a prognostic marker in patients with colorectal cancer. Int J Cancer 104:446–449PubMedCrossRef

21.

Shen JL, Yan CH, Liu Y et al (2003) Studies of TGF-beta/Smads expression in lung cancer. Yi Chuan Xue Bao 30:681–686PubMed

22.

Pring M, Prime S, Parkinson EK, Paterson I (2006) Dysregulated TGF-beta1-induced Smad signaling occurs as a result of defects in multiple components of the TGF-beta signaling pathway in human head and neck carcinoma cell lines. Int J Oncol 28:1279–1285PubMed

23.

Ginos MA, Page GP, Michalowicz BS et al (2004) Identification of a gene expression signature associated with recurrent disease in squamous cell carcinoma of the head and neck. Cancer Res 64:55–63PubMedCrossRef

24.

Pyeon D, Newton MA, Lambert PF et al (2007) Fundamental differences in cell cycle deregulation in human papillomavirus-positive and human papillomavirus-negative head/neck and cervical cancers. Cancer Res 67:4605–4619PubMedCrossRef

25.

Cromer A, Carles A, Millon R et al (2004) Identification of genes associated with tumorigenesis and metastatic potential of hypopharyngeal cancer by microarray analysis. Oncogene 23:2484–2498PubMedCrossRef

26.

Toruner GA, Ulger C, Alkan M et al (2004) Association between gene expression profile and tumor invasion in oral squamous cell carcinoma. Cancer Genet Cytogenet 154:27–35PubMedCrossRef

27.

Heikkinen PT, Nummela M, Jokilehto T, Grenman R, Kähäri VM, Jaakkola PM (2010) Hypoxic conversion of SMAD7 function from an inhibitor into a promoter of cell invasion. Cancer Res 70:5984–5993PubMedCrossRef

28.

van der Waal I (2009) Potentially malignant disorders of the oral and oropharyngeal mucosa; terminology, classification and present concepts of management. Oral Oncol 45:317–323PubMedCrossRef

29.

Danielsson K, Wahlin YB, Coates PJ, Nylander K (2010) Increased expression of Smad proteins, and in particular Smad3, in oral lichen planus compared to normal oral mucosa. J Oral Pathol Med 39:639–644PubMedCrossRef

30.

He W, Cao T, Smith DA, Myers TE, Wang XJ (2001) Smads mediate signaling of the TGFbeta superfamily in normal keratinocytes but are lost during skin chemical carcinogenesis. Oncogene 20:471–483PubMedCrossRef

31.

Xie W, Bharathy S, Kim D, Haffty BG, Rimm DL, Reiss M (2003) Frequent alterations of Smad signaling in human head and neck squamous cell carcinomas: a tissue microarray analysis. Oncol Res 14:61–73PubMed

32.

Báez A, Cantor A, Fonseca S et al (2005) Differences in Smad4 expression in human papillomavirus type 16-positive and human papillomavirus type 16-negative head and neck squamous cell carcinoma. Clin Cancer Res 11:3191–3197PubMedCrossRef

33.

Bornstein S, White R, Malkoski S et al (2009) Smad4 loss in mice causes spontaneous head and neck cancer with increased genomic instability and inflammation. J Clin Invest 119:3408–3419PubMed

34.

Korc M (2009) (2009) Smad4: gatekeeper gene in head and neck squamous cell carcinoma. J Clin Invest 119:3208–3211PubMed

35.

Xie W, Aisner S, Baredes S, Sreepada G, Shah R, Reiss M (2012) Alterations of Smad expression and activation in defining 2 subtypes of human head and neck squamous cell carcinoma. Head Neck. doi:10.1002/hed.22924

36.

Bennett KL, Romigh T, Eng C (2009) Disruption of transforming growth factor-beta signaling by five frequently methylated genes leads to head and neck squamous cell carcinoma pathogenesis. Cancer Res 69:9301–9305PubMedCrossRef

37.

Bennett KL, Karpenko M, Lin MT et al (2008) Frequently methylated tumor suppressor genes in head and neck squamous cell carcinoma. Cancer Res 68:4494–4499PubMedCrossRef

38.

Derynck R, Akhurst RJ, Balmain A (2001) TGF-beta signaling in tumor suppression and cancer progression. Nat Genet 29:117–129PubMedCrossRef

Title: Overexpression of Smad proteins, especially Smad7, in oral epithelial dysplasias
Authors: Yuk-Kwan Chen
Anderson Hsien-Cheng Huang
Pei-Hsun Cheng
Shang-Hsun Yang
Li-Min Lin
Publication date: 01-04-2013
Publisher: Springer-Verlag
Published in: Clinical Oral Investigations / Issue 3/2013
Print ISSN: 1432-6981
Electronic ISSN: 1436-3771
DOI: https://doi.org/10.1007/s00784-012-0756-7

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Overexpression of Smad proteins, especially Smad7, in oral epithelial dysplasias

Abstract

Objective

Materials and methods

Results

Conclusions

Clinical relevance

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Objective

Materials and methods

Results

Conclusions

Clinical relevance

Please log in to get access to this content

Other articles of this Issue 3/2013

A micro-computed tomography study of the root canal morphology of the mandibular first premolar in a population from southwestern China

Levels of salivary IgA in patients with minor recurrent aphthous stomatitis: a matched case–control study

Transconjunctival versus subciliary approach for orbital fracture repair—an anthropometric evaluation of 221 cases

Clinical longevity of ceramic laminate veneers bonded to teeth with and without existing composite restorations up to 40 months

Effects of long-term water storage on the microtensile bond strength of five experimental self-etching adhesives based on surfactants rather than HEMA

Postoperative failure of platelet recovery is an independent risk factor for poor survival in patients with oral and oropharyngeal cancer