| Objective To invastigate the different expressions of cellular senescence associated proteins in the normal esophageal epithelia, esophageal squamous cell carcinoma (ESCC) and its precursor lesions (intraepithelial neoplasias), then to assess the roles of those proteins in the development and progression of ESCC, and finally to identify the value biomarkers for early diagnosis and prognosis of ESCC.Methods (1)Esophagectomy samples from 241 patients with different pTNM stage ESCC combined with adjacent precursor lesions were collected to construct tissue microarrays (TMAs). Every case on the TMAs contained tumour, different grades of intraepithelial neoplasias and normal squamous epithelia at the margins of resection. (2) Immunohistochemistry was performed on the TMAS to analyze the expressions of 15 cellular senescence associated proteins (PML, DEC1, DCR2, H3K9mel, HPlβ, p53, Rb, P95 NBS1, CDC2, HMGA1, HMGA2, P21WAF, P27Kipl, P161NK4a and P38MAPK). Different expression patterns of those proteins were analyzed among normal epithelia, intraepithelial neoplasia and ESCC. The correlations between the proteins and the clinicopathological parameters were also analyzed statistically.Results (1) Compared with normal epithelia, the expression levels of PML, DEC1, HP1β, P21WAF, p53, Rb, CDC2, HMGA2, P95NBS1 and P38MAPK in intraepithelial neoplasia showed up-regulation, while the expressions of H3K9mel and DCR2 showed down-regulation. (2) In contrast to high grade intraepithelial neoplasia, the expression levels of PML, DEC1, HP1β, P21WAF, p53, P95NBS1 and P38MAPK in ESCC significantly decreased, and the expression levels of H3K9mel and DCR2 decreased further. (3) The expression level of DEC1 in ESCC was correlated with the age of patients (x2=7.364, P=0.025), with lower expression in the patients<60 years old than those>60 years old. The expression level of HMGA2 was correlated with the gender (X2=13.489, P=0.001), with higher expression in the male patients. The lower expressions of PML, DEC1, P21WAF, H3K9mel, and the higher expression of P38MAPK were correlated with the occurrence of angiolymphatic invasion (x2, P value were 6.07,0.048; 16.162,<0.001; 7.758,0.021; 6.285,0.043 and 7.042,0.030 respectively). The lower expressions of PML, DEC1, P21WAF, H3K9mel, HP1β, and the higher expression of CDC2 were correlated with the increase depth of ESCC invasion(x2,P value were 29.461,0.001; 81.590,<0.001; 42.974, <0.001; 13.012, 0.011; 10.118,0.038 and 28.743, 0.001, respectively). The lower expressions of PML, DEC1, P21WAF and the higher expression of CDC2 were correlated with lymph metastasis (x2, P value were 15.226,<0.001; 20.422,<0.001; 6.829,0.033 and 22.268, <0.001, respectively). The lower expressions of PML, DEC1 P21WAF, HP1β, and higher expessions of CDC2, HMGA2 were correlated with late pTNM stage(x2, P value were 26.956, 0.001; 70.693, 0.001; 31.884,<0.001; 10.660,0.031; 37.983,<0.001 and 21.260,<0.001, respectively). (4) Kaplan-Meier method analysis revealed that the expression levels of DEC1, CDC2, HMGA2, P38MAPK and Rb were significantly correlated with the survival of ESCC patients after surgery (P<0.05). Cox proportional hazard regression model multivariate analysis suggested that pTNM stage, CDC2, HMGA2, and Rb were correlated with the prognosis of ESCC independently (P<0.05).Conclusions Different expressions of PML, DEC1, HP1β, P21WAF, P27Kipl, p53, Rb, CDC2, HMGA2, P95NBS1, P38MAPK, H3K9mel and DCR2 were found among ESCC, introepithelial neoplasia and normal squamous cell epithelia, which suggested that cellular senescence pathway may take place synchronously with the progression of carcinogenesis; Abnormal expressions of some senescence associated proteins were correlated with clinicopathological features, which give a hint that cellular senescence may play an important role in the development and progression of ESCC. Some senescence associated proteins possibly could act as candidate biomarkers for predicting premalignant lesions, which may be helpful in the early diagnosis of ESCC.
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