Expression of Smad2 and Smad7 Proteins in Cutaneous Squamous Cell Carcinomas and its Clinical Significance
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Objective To detect the expression of Smad2 and Smad7 in cutaneous squamous cell carcinomas(SCC) and normal squamous epithelia of skins,analyze the relationship of two Smad expressions in SCC of differentiation grades and clinical stages,thus explore the role of Smad2 and Smad7 in the pathogenesis of SCC.Methods Paraffin-embedded tissue sections containing normal squamous epithelia,well differentiated,moderately differentiated and poorly differentiated SCC were stained by SABC immunohistochemistry technique to detect the expression and location of Smad2 and Smad7.Protein immunoexpression was quantified by image analysis in the context of histopathological parameters.The different expressions of Smad2 and Smad7 among all the tissue sections were compared.Expression of Smad2 and Smad7 in different clinical stages of SCC was also analyzed. Results Expression of Smad2 and Smad7 located in cytoplasm in normal squamous epithelia and SCC of skins.There was statistically significant difference of Smad2 and Smad7 expression between normal skin and SCC(P0.05).Compared with normal group,expression of Smad2 was down-regulated and Smad7 was up-regulated in SCC. Obvious difference of expression of Smad2 demonstrated in stage Ⅰ or Ⅱ compared with stage Ⅲ(P0.05).However,there was no statistic difference of Smad7 though gradually increasing from stage I to stage Ⅲ. Conclusions Down-regulation of Smad2 and up-regulation of Smad7 contribute to relieve the inhibition effect mediated by TGF β of cellular proliferation,which results in losing of cell growth suppression mediated by TGF β and contribute to tumor development or progression.Down-regulation of expression of Smad2,down-stream molecular of TGF β signaling pathway,was associated with invasion and metastasis of SCC.Keywords:
Pathogenesis
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Transforming growth factor (TGF)-beta is a potent regulator of growth and differentiation in normal squamous epithelium. TGF-beta exerts its antiproliferative effect via the TGF-beta type II receptor (TbetaR-II). A decrease in TbetaR-II expression is believed to be responsible, in part, for the resistance of squamous cell carcinoma (SqCC) to the anti-proliferative effects of TGF-beta. In the present study, we used immunohistochemistry and in situ hybridization to analyze the expression of TbetaR-II along the successive oncogenic stages of head and neck squamous neoplasia, from normal epithelium to dysplasia to carcinoma. Quantitation of TbetaR-II expression in 38 SqCCs was assessed on a visual scale ranging from negative (absence of staining) to 3+ (strong staining). Normal squamous epithelium and squamous epithelium in the vicinity of the tumors showed homogenous receptor expression with moderate intensity. Dysplastic epithelium and carcinoma in situ showed a mild decrease in receptor expression intensity. Well-differentiated to moderately differentiated carcinomas showed heterogeneous expression of variable intensity, and poorly differentiated carcinomas were completely devoid of TbetaR-II. In every tumor, the superficial component showed more intense receptor expression than the invasive component. These results indicate that TbetaR-II expression inversely correlates with disease aggressiveness and suggest that aberrant TbetaR-II expression is a contributing factor to the pathogenesis of SqCC.
Squamous carcinoma
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To investigate the patterns of expression of transforming growth factor alpha (TGF-alpha) and epidermal growth factor receptor (EGFR) in squamous metaplasia and squamous cell carcinomas of the urinary bladder with and without schistosomiasis.Immunohistochemical study of the expression of TGF-alpha and EGFR in squamous metaplasias (n = 12) and various grades of squamous cell carcinomas (n = 21) of the bladder with and without schistosomiasis.Focal cytoplasmic and membranous positivity for EGFR and TGF-alpha was seen in all cases of squamous metaplasia. The markers were diffusely coexpressed in a concordant pattern in areas of hyperplastic keratinising squamous metaplasia. A similar pattern of positivity was seen in verrucous carcinomas (n = 2) and well differentiated squamous carcinomas (n = 6). Progressive loss of differentiation was associated with increasing loss of EGFR staining while TGF-alpha staining was retained. Squamous cell carcinoma in situ (n = 2) showed focal positivity for TGF-alpha and EGFR. There were no differences in staining patterns between cases with and without schistosomiasis.The coexpression of TGF-alpha and EGFR by well differentiated squamous cell carcinomas and hyperplastic keratinising squamous metaplasia is consistent with the active regulatory role exerted by this autocrine loop. There is regional absence of expression of EGFR but not of TGF-alpha in squamous cell carcinomas of lesser differentiation, suggesting heterogeneity of such control in these tumours. The focal expression of the two markers in squamous cell carcinomas in situ indicates a possible second pathway of oncogenesis for less differentiated tumours. These observations may have important implications for the effectiveness of putative growth factor based treatments.
Squamous metaplasia
Squamous carcinoma
Metaplasia
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Objective To explore the role of COX-2 and p53 genes in the carcinogenesis of esophageal epithelia, and its use in the early diagnosis and as a chemopreventional indicator of esophageal carcinoma. Methods The samples of esophageal epithelial cells were collected from the population living in the high risk area of esophageal carcinoma, and the specimens of esophageal squamous cell carcinoma (SCC) and its precancerous lesions were collected from the patients after esophagectomy. The proteins of COX-2 and p53 were labeled by indirect immunofluorescence technique and detected by flow cytometry. Results The expression of COX-2 gene increased in the exfoliated epithelial cells of the esophagus as its progression from normal to carcinoma, and the fluorescence index (FI) reached peak in carcinoma cell group (FI=1.62±0.23); The expression of COX-2 was the highest in the well differentiated SCC (FI=2.37±0.71) and then decreased from well to poorly differentiated SCC. The expression of p53 gene was also increased in the exfoliated epithelial cells of the esophagus as its progression to carcinoma, (F1=2.28±0.20) and was the highest in poorly differentiated SCC (FI=2.70±0.82).The overexpressions of COX-2 and p53 had positive correlation ( r=0.424, P =0.002) as the progression from normal epithelia to well differentiated SCC, and they had a negative correlation in different degree of differentiation. Conclusion The expressions of COX-2 and p53 are up-regulated in the early carcinogenesis of esophageal epithelial cells,and shows a positive correlation. COX-2 alone or both COX-2 and p53 may be a good molecular marker for the early diagnosis of esophageal SCC and used as a chemopreventional indicator of esophageal carcinoma in high-risk area.
Immunofluorescence
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OBJECTIVES: To evaluate the expression of E‐cadherin, a calcium‐dependent cell adhesion molecule, in a retrospective analysis of paraffin embedded tissue specimens of oral squamous cell carcinoma and relationship with the clinical TNM stage and histochemical differentiation. DESIGN: Paraffin embedded tissue sections of normal oral mucosa ( n = 6), oral squamous cell carcinoma (SCC, n = 18) and metastatic lymph nodes ( n = 2) were immunostained by a three‐stage streptoavidin‐biotin immunoperoxidase method using monoclonal antibody. The TNM staging and histochemical grading were done according to the standard criteria. RESULTS: Normal oral epithelium showed a strongly positive pericellular distribution of E‐cadherin in basal, parabasal and spinous layers and no staining was observed in the parakeratinized and cornified layerS. In well differentiated SCCs, the centrally located cells in tumour islands showed no staining, but peripheral basally located tumour cells showed positive staining. Poorly differentiated SCCs were devoid of staining. In moderately differentiated SCCs, the staining pattern was found to be one of the following three types: (1) a pattern similar to that of well differentiated SCC; (2) central cells of tumour aggregates were reactive but peripheral cells showed weak to negative reaction; and (3) all cells showed a negative reaction, resembling the poorly differentiated SCC.Fischer exact test showed a statistically significant correlation with loss of E‐cadherin and grades of tumour differentiation as well as an advancing T and N stage. CONCLUSION: The loss of E‐cadherin may correlate with advancing T and N stages of the tumour and a poor tumour cell differentiation in oral squamous cell carcinomas.
Oral mucosa
Grading (engineering)
Immunoperoxidase
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Objective To investigate the expression and possible role of human arrest defective 1(hARD1) in squamous epithelium and squamous cell carcinoma(SCC).Methods Firstly,polyclonal anti-hARD1 antibody was prepared and characterized. Then,the expression of hARD1 in various differentiated SCC and squamous epithelium(control tissues) which were from skins, lungs,oesophaguses and cervices was detected by immunohistochemical method and was compared with each other.Results Compared with control tissues,the expression of hARD1 was significantly down-regulated in squamous cell carcinoma,especially in poor differentiated carcinoma(P0.001) and was positively associated with the differentiation of squamous cell(r=0.493,P0.001). Conclusion The expression of hARD1 was positively associated with the differentiation of squamous cell.Namely,Poorer differentiation tended to show lower hARD1 expression.
Polyclonal antibodies
Squamous carcinoma
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Smad4 is a member of the Smad proteins, which are needed for mediating signals of transforming growth factor beta from the cell surface to the nucleus. Smad4 is also a tumor suppressor gene for cancers of the pancreas, colon, and lung. The aim of this study was to investigate the expression and prognostic significance of this gene product in endometrial cancer. Immunohistochemical staining for Smad4 was performed on formalin-fixed, paraffin-embedded specimens of endometrial tumors with an anti-Smad4 monoclonal antibody (clone B8): 97 primary endometrial carcinomas, 20 cases of endometrial hyperplasia, and 26 cases of metastases from endometrial carcinoma. The immunoreactivity of each tumor was correlated with the clinical and histopathologic parameters of the patients. Diffusely positive expression of Smad4 protein was detected in all 20 cases of endometrial hyperplasia and in most of the primary and metastatic endometrial cancers. The frequency of positive expression decreased progressively with tumor grade. Clinically, however, it was not associated with tumor progression, nor did it predict patient outcome. Although loss of heterozygosity at chromosome 18q21 (the location of the Smad4 gene) is frequent in endometrial carcinomas, the authors show in this immunohistochemical study that inactivation of this gene occurs infrequently in this tumor.
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Keratoacanthoma
Epidermoid carcinoma
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Objective To observe the expression and role of HSP70 in human epidermis and cutaneous neoplasms.Methods 56 cases of epidermis tumors,including 29 biopsy samples from basal cell carcinoma, 27 from squamous cell carcinoma,and 30 from normal human skin were investigated. HSP70 expression was examined by immunohistochemical SABC staining with specific monoclonal antibodies.Results The expression of HSP70 was detectable in the cytoplasm throughout the epidermal cell layers in normal human epidermis,HSP70 expression in the tumor cells in basal and squamous cell carcinomas was reduced (P0 01). The nucleus of part tumor cells in basal and squamous cell carcinomas had moderate HSP70 expression.Conclusions Reduction of HSP70 expression is significantly correlated with cutaneous neoplasms. Nucleus positive expression of HSP70 could contribute to the malignant growth of keratinocytes.
Epidermis (zoology)
Basal (medicine)
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Objective:To investigate the different expression of CK and PCNA proteins of squamous cell carcinoma(SCC)in various tissues.Methods:The expression of CK and PCNA antigen proteins was examined by immunohistochemical staining in 69 cases SCC(9 skin,10 laryngeal,12 nasopharyngeal,14 esophageal,12 cervical and 12 lung SCC).Result:well differentiated SCC was mainly found in epidermal esophageal SCC,whereas poorly differentiated SCC was mainly found in nasopharyngeal and lung SCC.The strength of CK expression was as follows:skin,esophageal,laryngeal,cervical,nasopharyngeal and lung SCC.The number of CK proteins positive cells increased gradually in epidermal and esophageal SCC from the edge to the center of the cell nest,whereas diffused in nasopharyngeal and lung SCC.Significantly higher expression of PCNA proteins was found in nasopharyngeal and lung SCC compared with skin and esophageal SCC(P0 05).PCNA positive cells were observed mainly on the edge of the cell nest in epidermal and esophageal SCC,whereas diffused in nasopharyngeal and lung SCC.Conclusion:These results suggest that enviroment may play an important role in differentiation and proliferation of squamous cell carcinoma.
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Objective To evaluate the difference of the clinical,biological and histopathological features in two kinds of elders,skin carcinoma BCC and SCC.Methods We investigated desmoglein1 and E-cadherin expression in 26 SCC and 30 BCC with monoclonal antibodies to desmoglein1 and E-cadherin used immunohistochemistry staining.Results In SCC the expression of desmoglein1 and E-cadherin markedly reduced or absent in tumor cells.In BCC the expression of desmoglein1 markedly reduced or absent in tumor cells also,but E-cadherin was strongly expressed.Conclusion These results suggest the reduction or absence of desmoglein1 expression may be related to invasiveness of skin carcinomas,the reduction or absence of E-cadherin expression may be related to the metastasis of SCC.
Positive staining
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