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ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 2  |  Page : 388-393

Expression of p53, epidermal growth factor receptor, c-erbB2 in oral leukoplakias and oral squamous cell carcinomas


Department of Pathology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India

Date of Web Publication8-Mar-2018

Correspondence Address:
Gaurav Singla
Department of Pathology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi - 110 029
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.191027

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 > Abstract 


Background: Oral cancer is a leading cause of cancer in India and contributes to 12% deaths worldwide. The identification of high-risk oral premalignant lesions such as leukoplakia and intervention at premalignant stages could result in significant loss of mortality and morbidity among these patients. The most frequently observed genetic aberrations in these lesions are of mutations in p53, c-erbB2, and epidermal growth factor receptor (EGFR). No specific tumor markers have been identified consistently in oral leukoplakias and the available studies show wide variations in their expression.
Materials and Methods: A total of eighty cases were taken up for study which included forty cases of leukoplakia and forty cases of squamous cell carcinomas (SCCs).
Results: There was a significant correlation between the expression of markers p53 and EGFR in leukoplakia and SCC. The expression of p53 was correlated between leukoplakia, SCC, and control and was found to be significant (P ≤ 0.001). Similarly, EGFR expression was significant (P ≤ 0.001) between cases of leukoplakia, SCCs, and controls. c-erbB2 was found to be negative though cytoplasmic positivity was observed in a few cases. Similarly, in SCCs, it was observed that lesser the differentiation, more is the expression of both p53 and EGFR. Similarly, a definite correlation was observed between p53 and EGFR (P ≤ 0.001) but not with c-erbB2 (P ≤ 1.000).
Conclusion: Thus, the author concludes that p53 and EGFR are useful biomarkers for the diagnosis of leukoplakia and their risk of malignant transformation.

Keywords: c-erbB2, epidermal growth factor receptor, leukoplakia, oral squamous cell carcinomas, p53


How to cite this article:
Singla S, Singla G, Zaheer S, Rawat DS, Mandal AK. Expression of p53, epidermal growth factor receptor, c-erbB2 in oral leukoplakias and oral squamous cell carcinomas. J Can Res Ther 2018;14:388-93

How to cite this URL:
Singla S, Singla G, Zaheer S, Rawat DS, Mandal AK. Expression of p53, epidermal growth factor receptor, c-erbB2 in oral leukoplakias and oral squamous cell carcinomas. J Can Res Ther [serial online] 2018 [cited 2020 Jun 1];14:388-93. Available from: http://www.cancerjournal.net/text.asp?2018/14/2/388/191027




 > Introduction Top


Oral cancer contributes to 12% of deaths worldwide and ranks among the top three cancers in India affecting 20 per 100,000 population.[1] It contributes to over 30% of all cancers in the country.[1] Despite therapeutic advances, the overall long-term survival has remained <50% for past 50 years because of late diagnosis. The prognosis for patients with oral squamous cell carcinoma (OSCC) that is treated early is much better, with 5-year survival rates as high as 80%.[2]

At least 95% of oral cancers are SCCs and commonly associated with premalignant lesions such as – leukoplakia, erythroplakia, and submucosal fibrosis. Of all these lesions, leukoplakia and submucosal fibrosis are the most prevalent in India.[3] Histological examination of tissue remains the gold standard for diagnosis and identification of malignant oral lesions. Molecular level changes in the lesion occur before clinical and histopathological changes.[2] The identification of high-risk oral premalignant lesions and intervention at premalignant stages could constitute one of the keys in reducing the mortality, morbidity, and cost of treatment associated with OSCC.

Leukoplakia is a common lesion of the oral mucosa, which is defined as a white patch or plaque that cannot be characterized clinically or pathologically as any other diseases. The percentage of leukoplakias that progress to invasive SCC is accepted to be directly related to the severity of the dysplastic changes and it ranges from 5% to 43%.[4] The most frequently observed genetic aberrations in these lesions are of mutations in p53, c-erbB2, and epidermal growth factor receptor (EGFR). No specific tumor markers have been identified consistently in oral leukoplakias, and the available studies show wide variations in their expression.

p53 is a tumor suppressor gene located on the short arm (p) of chromosome 17. It encodes a protein TP53, whose mutation is one of the most common events in oral carcinogenesis. The gene mutation produces an accumulation of p53 protein, which can be detected by immunohistochemical (IHC) methods and its overexpression has been associated with poor survival of patients with OSCCs. Alterations in the p53 tumor suppressor gene are among the most common genetic aberrations in the spectrum of oral cancers.[5]

EGFR is a tyrosine kinase receptor located at the cell membrane. This cell membrane tyrosine kinase receptor is involved in a variety of cellular activities including proliferation, differentiation, survival, and death and activating multiple downstream cell signaling pathways. Overactivation of this pathway is considered an etiological factor in human cancer, which contributes to cancer development, metastasis, and resistance to chemotherapy.[6] It has been shown that the EGFR is involved in both normal and abnormal proliferations of epithelial tissues.

c-erbB2 (also known as Her2/neu) is a proto-oncogene located on human chromosome-17. The amplification of Her2/neu oncogene or overexpression of its protein has been demonstrated in several malignant neoplasms.[7] Yet, diverse results regarding the overexpression of Her2/neu in OSCCs have been reported.[8]


 > Materials and Methods Top


A total of eighty cases were taken up for study which included forty cases of leukoplakia and forty cases of SCCs. The ethical clearance was obtained from the institution where the study took place. The procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional or regional) and with the Helsinki Declaration of 1975 as revised in 2000. This was a cross-sectional study, with a sample size of minimum eighty cases.

Inclusion criteria

  • Histologically proven cases of oral leukoplakias and OSCCs.


Exclusion criteria

  1. Other premalignant lesions such as:


    • Submucosal fibrosis
    • Erythroplakia
    • Lichen planus


  2. All non-SCCs of oral cavity.


Forty samples of normal oral epithelia were also evaluated as controls. The samples were subjected to routine histological processing followed by hematoxylin and eosin staining. The lesions were then divided into leukoplakia with no, mild, moderate, and severe dysplasia. Similarly, OSCCs were further divided into well, moderately, and poorly differentiated SCCs. Sections of 3-μm thickness were prepared for each specimen, and IHC analysis was done for p53, EGFR, and cerb-B2.

Assessment of immunostaining

The slides were stained for p53, EGFR, and cerb-B2 and observed under the light microscope. The tissue samples were thoroughly examined, and a total number of 100 cells were counted. Then, among the 100 cells, the number of cells which had taken up the stain was counted. A brown precipitate seen within the nucleus confirmed the presence of p53 protein. EGFR was evaluated on the basis of extent and intensity of EGFR immunolabeling in tumor cell membranes. Distinct membrane staining was considered as a positive reaction in c-erbB2. Cytoplasmic staining was considered negative.

The p53-positive samples were graded as follows:[9]

  • Negative: <10% of the cells showed positive staining
  • Positive: >10% of the cells showed positive staining


  • o 1+: 10–30% of cells showed positive staining

    o 2+: 30–50% of cells showed positive staining

    o 3+: >50% of cells showed positive staining.


EGFR-positive samples were graded as follows:[10]

  • Negative: <10% of tumor cells show labeling
  • Positive: >10% of cells show labeling


  • o 1+: Weak labeling, homogeneous or patchy, in >10% of tumor cells

    o 2+: Moderate labeling, homogeneous or patchy, in >10% of tumor cells

    o 3+: Intense labeling, homogeneous or patchy, in >10% of tumor cells.


c-erbB2 was graded as follows:[11]

  • Negative: No staining
  • +: <10% cells stained
  • 2+: 10–50% cells stained
  • 3+: >50% cells stained.


Statistical analysis

The data were collected, and the association between different groups was analyzed by Chi-square test and Kruskal–Wallis test.


 > Results Top


A total of eighty cases were registered for the study which included forty cases of leukoplakia, forty cases of SCC, and forty controls. Of forty cases of leukoplakia, 31 cases (77.5%) consisted of leukoplakia with no dysplasia [Figure 1]a, seven cases (17.5%) had mild dysplasia [Figure 1]d while two cases (5%) had moderate dysplasia [Figure 2]a. SCCs consisted of 12 cases (30%) of well-differentiated SCCs [Figure 2]d, 19 cases (47.5%) of moderately differentiated [Figure 3]a, and nine cases (22.5%) of poorly differentiated SCCs [Figure 3]d.
Figure 1: (a) Leukoplakia with acanthosis and hyperkeratosis (H and E, ×200), (b) p53 nuclear positivity in leukoplakia (IHC, ×200), (c) membranous epidermal growth factor receptor staining in leukoplakia (IHC, ×200), (d) leukoplakia with mild dysplasia (H and E, ×200), (e) p53 nuclear positivity in leukoplakia with mild dysplasia (IHC, ×400), (f) membranous epidermal growth factor receptor staining in leukoplakia with mild dysplasia (IHC, ×200)

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Figure 2: (a) Leukoplakia with moderate dysplasia (H and E, ×200), (b) p53 nuclear positivity in leukoplakia with moderate dysplasia (IHC, ×400), (c) membranous epidermal growth factor receptor staining in leukoplakia with moderate dysplasia (IHC, ×200), (d) well-differentiated squamous cell carcinoma with formation of squamous pearls (H and E, ×400), (e) p53 nuclear positivity in well-differentiated squamous cell carcinoma (IHC, ×400), (f) membranous epidermal growth factor receptor staining with mild intensity in well-differentiated squamous cell carcinoma (IHC, ×400)

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Figure 3: (a) Moderately differentiated squamous cell carcinomas (H and E, ×400), (b) p53 nuclear positivity in moderately differentiated squamous cell carcinoma (IHC, ×400), (c) membranous epidermal growth factor receptor staining with moderate intensity in moderately differentiated squamous cell carcinoma (IHC, ×400), (d) poorly differentiated squamous cell carcinomas (H and E, ×400), (e) p53 nuclear positivity in poorly differentiated squamous cell carcinoma (IHC, ×400) (f) membranous epidermal growth factor receptor staining with severe intensity in poorly differentiated squamous cell carcinoma (IHC, ×400)

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The most common age group diagnosed with leukoplakia was 31–40 years while it was 51–60 years in SCCs. The male: female ratio in leukoplakia and SCC was 4.7:1 and 4:1, respectively. A definite correlation was observed when we compared the age groups in leukoplakia and SCCs (P ≤ 0.001, Pearson's Chi-square test).

Similarly, the expression of p53 was correlated between leukoplakia, SCC, and control and was found to be significant (P ≤ 0.001, Pearson's Chi-square test) [Table 1]. That is the expression of p53 increased with progression toward malignancy. Similarly, EGFR expression was significant (P ≤ 0.001, Pearson's Chi-square test) [Table 2] between cases of leukoplakia, SCCs, and controls. c-erbB2 was found to be negative though cytoplasmic positivity was observed in a few cases.
Table 1: Comparison of p53 between leukoplakia, oral squamous cell carcinoma, and control

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Table 2: Comparison of epidermal growth factor receptor between leukoplakia, oral squamous cell carcinoma, and control

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Similarly, the expression of p53, EGFR, and c-erbB2 was compared in cases of leukoplakia. It was observed that the expression of both p53 (P ≤ 0.001, Pearson's Chi-square test) [Table 3] and [Figure 1]b and [Figure 1]e, [Figure 2]b and EGFR increased (P ≤ 0.013, Pearson's Chi-square test) [Table 4] and [Figure 1]c and [Figure 1]f, [Figure 2]c as the lesion progressed from leukoplakia with no dysplasia toward moderate dysplasia. c-erbB2 was negative though cytoplasmic staining was observed in a few cases [Figure 4]. Similarly, in SCCs, it was observed that lesser the differentiation, more the expression of both p53 [Table 5] and [Figure 2]e, [Figure 3]b and [Figure 2]e and EGFR [Table 6] and [Figure 2]f, [Figure 3]c and [Figure 3]f. c-ebB2 was negative as above though cytoplasmic staining was observed [Figure 5]. Similarly, a definite correlation was observed between p53 and EGFR (P ≤ 0.001, Kruskal–Wallis test) but not with c-erbB2 (P ≤ 1.000, Kruskal–Wallis test) [Table 7].
Table 3: Comparison of p53 between leukoplakia with no, mild, and moderate dysplasia

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Table 4: Comparison of epidermal growth factor receptor between leukoplakia with no, mild, and moderate dysplasia

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Figure 4: Cytoplasmic staining of c-erbB2 in leukoplakia

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Table 5: Comparison of p53 between well, moderately, and poorly differentiated oral squamous cell carcinoma

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Table 6: Comparison of epidermal growth factor receptor between well, moderately, and poorly differentiated oral squamous cell carcinoma

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Figure 5: Cytoplasmic staining of c-erbB2 in squamous cell carcinomas

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Table 7: Comparison between p53, epidermal growth factor receptor, and c-erbB2 in leukoplakia, squamous cell carcinoma, and control

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 > Discussion Top


In the present study, the most common age group in patients with leukoplakia was 31–40 years with the mean age of 42.03 ± 13.16 years which was consistent with the findings of Gupta et al.[12] The most common age group diagnosed with SCC was 51–60 years with the mean age of 52.85 ± 11.92 years which was similar to the findings of Bernardes et al.[13]

A significant correlation was observed between the age groups of leukoplakia and SCCs which shows that the premalignant conditions such as leukoplakia develop in younger age group as compared to OSCC which develops in slightly higher age group. This is important because these premalignant lesions with time progress to malignancy and their early detection may prevent the patients developing malignancy.

The male:female ratio found in our study was 4.7:1 in cases of leukoplakia while 4:1 in cases of SCC. Monteiro et al.[14] reported a higher incidence in males as compared to females in cases of leukoplakia[13] and OSCCs.

A higher incidence among males occurs because of heavier indulgence in both tobacco and alcohol habits in most countries. In India, the highest rates of intraoral cancer may be found in women who chew tobacco heavily.[15] Tobacco chewing accounts for nearly 50% of cancers of the oral cavity in men and over 90% in women.

In our study, 27.5% cases of leukoplakia were positive for p53 while 55% cases were positive for p53 in SCCs. We observed that the expression of p53 increased as the lesion progressed from leukoplakia to carcinoma. These results are in accordance with the previous studies.[16],[17] Saranath et al. showed that the overexpression of p53 protein was seen in 27% samples of leukoplakia and 37% samples of oral cancer.[5] All normal tissue specimens were negative for mutant p53 expression. p53 encodes a protein TP53, whose mutation is one of the most common events in oral carcinogenesis. The gene mutation produces an accumulation of p53 protein, which can be detected by IHC methods, and its overexpression has been associated with poor survival of patients with OSCCs. Normal tissue expresses wild-type p53 which has a short half-life and most of it is not detected IHC. By contrast, mutations of p53 result in a greatly extended protein half-life, thus permitting IHC detection. Unlike the proteins of nontransformed cells, the mutant protein is likely to form complexes leading to the acquisition of a stable conformation than the wild-type protein. It is suggested that the overexpression of p53 is a common event in the multistep carcinogenesis in OSCCs.[16]

We also observed that in leukoplakias, the p53 expression increased with increase in grades of dysplasia. This can also be explained similarly by the fact that with increasing grades of dysplasia, there is a greater degree of p53 mutation which prolongs the half-life of p53 and is detected IHC. Similarly, in SCCs, we observed that with a decrease in grade of differentiation, the expression of p53 protein increased. Monteiro et al.[14] also reported increased expression of p53 in moderately and poorly differentiated carcinomas as compared to well-differentiated carcinomas.

Similarly, EGFR was evaluated on the basis of extent and intensity of EGFR immunolabeling in oral leukoplakias and SCCs. In our study, 95% cases of leukoplakia showed positivity. 97.5% cases of SCC were EGFR positive. A significant correlation was observed between the EGFR cell staining in leukoplakia, SCC, and controls. The result is in concordance with Rubin Grandis et al.[18] and Shin et al.[19] who have demonstrated increased EGFR expression in oral leukoplakias and SCCs. Similarly, we found that the EGFR expression was significantly higher in cases of SCCs as compared to leukoplakias. This is because EGFR is found in an abnormally high number on the surface of cancer cells; hence, these cells may divide excessively in the presence of epidermal growth factor. Malignant oral keratinocytes possess from 5 to 50 times more EGFR than their normal counterparts.[20] Another possible reason may be due to the production of continuous ligand-independent mitogenic signal leading to cell proliferation.

Similarly, the intensity of EGFR expression increased with increasing grades of dysplasia. This may again be possibly explained due to increased EGFR expression with increasing grades of dysplasia. Similarly, the overexpression of EGFR correlated with poor tumor differentiation in our study. Few authors have found the EGFR gene to correlate with a lower degree of differentiation[21] whereas others have reported an opposite effect.[22]

The expression of c erbB2 was studied in cases of leukoplakia and OSCCs and was found to be negative although few cases showed cytoplasmic positivity, the significance of which is still unclear though few studies have postulated it to represent incomplete receptor degradation.[11] One possible reason can be the inactivation of cerb-B2 in Indian population. In literature, the results of c-erbB2 immunostaining have been reported to be extremely variable since both cytoplasmic staining and membranous staining have been taken positive.[23]

Similarly, a definite correlation was observed between p53 and EGFR. This may possibly be explained by the fact that both p53 and EGFR are interlinked to each other at a molecular level and may augment each other in cases of dysplasia and carcinogenesis. This is supported by Wang et al.[24] who showed that the mutant p53 binds to promote a sustained EGF-induced extracellular signal–regulated kinase 1/2 activation, thereby facilitating cell proliferation and tumorigenesis.

Both p53 and EGFR play an important role in identifying those premalignant oral lesions which may progress to oral carcinoma. They also help in classifying the severity of OSCCs. The ability to identify oral leukoplakia patients at increased risk of cancer development is critical for improving control of oral cancer. Once identified, the highest risk individuals could be offered more aggressive treatment options and more intensive follow-up. Furthermore, the significance of cytoplasmic staining of c-erbB2 in patients with leukoplakias and SCCs should be evaluated further.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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Sankaranarayanan R, Ramadas K, Thomas G, Muwonge R, Thara S, Mathew B, et al. Effect of screening on oral cancer mortality in Kerala, India: A cluster-randomised controlled trial. Lancet 2005;365:1927-33.  Back to cited text no. 1
    
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Saranath D, Tandle AT, Teni TR, Dedhia PM, Borges AM, Parikh D, et al. p53 inactivation in chewing tobacco-induced oral cancers and leukoplakias from India. Oral Oncol 1999;35:242-50.  Back to cited text no. 5
    
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Shintani S, Nakahara Y, Li C, Mihara M, Nakashiro KI. HER2/neu expression in oral squamous cell carcinoma. Asian J Oral Maxillofac Surg 2004;16:172-6.  Back to cited text no. 7
    
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Xia W, Lau YK, Zhang HZ, Liu AR, Li L, Kiyokawa N, et al. Strong correlation between c-erbB-2 overexpression and overall survival of patients with oral squamous cell carcinoma. Clin Cancer Res 1997;3:3-9.  Back to cited text no. 8
    
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Agarwal S, Mathur M, Srivastava A, Ralhan R. MDM2/p53 co-expression in oral premalignant and malignant lesions: Potential prognostic implications. Oral Oncol 1999;35:209-16.  Back to cited text no. 9
    
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Kumar P, Kane S, Rathod GP. Coexpression of p53 and Ki 67 and lack of c-erbB2 expression in oral leukoplakias in India. Braz Oral Res 2012;26:228-34.  Back to cited text no. 11
    
12.
Gupta S, Gupta OP, Srivastava S. Role of CYP2E1 genetic polymorphism in the development of oral leukoplakia among tobacco users in North Indian population. Indian J Cancer 2014;51:154-8.  Back to cited text no. 12
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Bernardes VF, Gleber-Netto FO, Sousa SF, Silva TA, Aguiar MC. Clinical significance of EGFR, Her-2 and EGF in oral squamous cell carcinoma: A case control study. J Exp Clin Cancer Res 2010;29:40.  Back to cited text no. 13
    
14.
Monteiro LS, Diniz-Freitas M, Garcia-Caballero T, Warnakulasuriya S, Forteza J, Fraga M. Combined cytoplasmic and membranous EGFR and p53 overexpression is a poor prognostic marker in early stage oral squamous cell carcinoma. J Oral Pathol Med 2012;41:559-67.  Back to cited text no. 14
    
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Franceschi S, Bidoli E, Herrero R, Muñoz N. Comparison of cancers of the oral cavity and pharynx worldwide: Etiological clues. Oral Oncol 2000;36:106-15.  Back to cited text no. 15
    
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Warnakulasuriya KA, Johnson NW. Expression of p53 mutant nuclear phosphoprotein in oral carcinoma and potentially malignant oral lesions. J Oral Pathol Med 1992;21:404-8.  Back to cited text no. 16
    
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Murti PR, Warnakulasuriya KA, Johnson NW, Bhonsle RB, Gupta PC, Daftary DK, et al. p53 expression in oral precancer as a marker for malignant potential. J Oral Pathol Med 1998;27:191-6.  Back to cited text no. 17
    
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Rubin Grandis J, Tweardy DJ, Melhem MF. Asynchronous modulation of transforming growth factor alpha and epidermal growth factor receptor protein expression in progression of premalignant lesions to head and neck squamous cell carcinoma. Clin Cancer Res 1998;4:13-20.  Back to cited text no. 18
    
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Shin DM, Ro JY, Hong WK, Hittelman WN. Dysregulation of epidermal growth factor receptor expression in premalignant lesions during head and neck tumorigenesis. Cancer Res 1994;54:3153-9.  Back to cited text no. 19
    
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Fong Y, Chou SJ, Hung KF, Wu HT, Kao SY. An investigation of the differential expression of Her2/neu gene expression in normal oral mucosa, epithelial dysplasia, and oral squamous cell carcinoma in Taiwan. J Chin Med Assoc 2008;71:123-7.  Back to cited text no. 21
    
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Yamada T, Takagi M, Shioda S. Evaluation of epidermal growth factor receptor in squamous cell carcinoma of the oral cavity. Oral Surg Oral Med Oral Pathol 1992;73:67-70.  Back to cited text no. 22
    
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Del Sordo R, Angiero F, Bellezza G, Cavaliere A, Mameli MG, Stefani M, et al. HER family receptors expression in squamous cell carcinoma of the tongue: Study of the possible prognostic and biological significance. J Oral Pathol Med 2010;39:79-86.  Back to cited text no. 23
    
24.
Wang W, Cheng B, Miao L, Mei Y, Wu M. Mutant p53-R273H gains new function in sustained activation of EGFR signaling via suppressing miR-27a expression. Cell Death Dis 2013;4:e574.  Back to cited text no. 24
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]



 

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