| Effective biomarkers are needed to supplement conventional morphological diagnosis for improving the management, treatment and prevention of human cancer. In the present study, we performed immunohistochemistry (IHC) to examine the expression of the candidate proteins, which may be abnormal during the development and progression of esophageal squamous cell carcinoma (ESCC), in order to provide clinically applicable biomarkers for early diagnosis, prognosis and prediction of the disease.The candidate molecules in this study included not only the proteins with abnormal expression in ESCC in our previous studies by array-comparative genomic hybridization (aCGH) and proteomics analysis, but also overexpressed proteins from the literature and the key nodes in the important signaling pathway during the development of esophageal cancer.We first tested226candidate proteins in the ESCC and adjacent normal tissues by a small sample size, and found12proteins with highly expressed in tumors, but only low or no expression in adjacent normal tissues, such as P53, EGFR, PI3K-p85a and ANO1were detected in43.0%(232/539),36.6%(185/506),57.1%(303/531) and26.5%(140/529) of tumors, whereas in2.9%(11/382),3.5%(13/372),1.4%(5/368) and0%(0/401) of adjacent normal tissues. And the combination of9proteins, including P53, EGFR, PI3K-p85a and ANO1, et cetera, could detect90%of ESCCs at stage I with a specificity of100%, suggesting that this9-protein combination may be of value for early diagnosis.Kaplan-Meier analysis indicated that the overall survival (OS) of patients was shorter when ANO1(P=0.00007), PI3K-p85a (P=0.00111), P53(P=0.00426), EGFR (P=0.00001), PTP1B (P=0.00617), P62(P=0.024) and SKP2(P=0.027) were positive expression in ESCC tissues. Multivariate Cox regression model determined that ANO1(P=0.0003), P53(P=0.021), PI3K-p85a (P=0.00002), EGFR (P=0.00003), PTP1B (P=0.005), P62(P=0.014) and pN were independent prognostic factors. When three of the six factors, pN, ANO1, PI3K-p85a, EGFR, PTP1B and P62were positive, the panel could significantly divide patients into better and poorer subgroups (P=0.0000000004), suggesting that the panel of ANO1/PI3K-p85α/EGFR/PTPlB/P62/pN could be useful for prognosis in patients with ESCC.We further investigated the correlation between the dysregulations of the above12proteins in a cohort population with precancerous lesions collected from ESCC screening in2005-2007at high-incidence area. P53, EGFR, SKP2, CHK2, PTP1B and ANO1were observed more specific with a higher positive rate. When analyzed the progression of precancerous lesions after5-7years with positive of these proteins detected in initial biopsy specimens in2005-2007, we found that ANO1was of higher expression in progress group than progress-free group (P=0.0000001). Further validation for the correlation between positive expression of ANO1and the risk of developing a cancer was carried out in another independent cohort population with precancerous lesions collected from ESCC screening in1996-2002, and the data revealed that ANO1also presented higher expression in progress group than progress-free group (P=0.004), consistent with the results from the specimens in2005-2007. ANO1is probably a promising biomarker for predicting a higher risk of developing a cancer for precancerous lesions.In conclusion, we identified potential biomarkers for the prognosis, early detection of ESCC and risk prediction of esophageal precancerous lesions, to which further multicentre validation with large sample is required. |
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