The long-term objective of our research is to contribute to the early detection and prevention of esophageal cancer (EC). We have been conducting long-term studies on the etiology, pathogenesis, and nutritional intervention of esophageal cancers in a high incidence area of Henan Province in northern China. In recent studies on the early molecular events in esophageal carcinogenesis, we have observed p53 protein accumulation and gene mutations in esophageal dysplasia and hyperplasia, and even in near-normal epithelia. In this proposal, we plan to determine the molecular basis for the p53 protein accumulation and the biological consequence of p53 accumulation/mutation in human subjects, and to study other molecular events which are important in esophageal carcinogenesis.
The specific aims of this project are as follows: 1. To determine the molecular basis of p53 accumulation at different stages of esophageal carcinogenesis. Using esophageal biopsy samples and resected tissues from Henan, China, we will test the hypothesis that there are two types of p53 protein accumulation in near-normal and hyperplastic epithelia: one type due to wild-type p53 protein and the other type due to mutant p53 protein; the sites of mutation will be analyzed. 2. To examine the biological consequences of wt p53 elevation and p53 mutations in cell cycle control and related molecular events in esophageal carcinogenesis. For this aim, we will use specific cell cycle markers in multiparameter flow cytometry and cell sorting, and will study the expression of WAF1(Cip1) and other molecular changes. 3. To test, in follow-up studies, the hypothesis that p53 mutation makes the host prone to esophageal carcinogenesis and to explore the practical application of our findings in the early detection and prognosis of EC. Our ability to study molecular changes in human esophageal biopsy samples and to conduct follow-up studies in this high EC risk area enables us to test the above hypotheses directly. The project is expected to provide important new information on the early molecular events in human esophageal carcinogenesis. This information is important for the prevention, early detection, and prognosis of EC not only in this high incidence area but also in other areas, including the United States.
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