MicroRNA markers of radioresistance in esophageal cancer: from radioresistant subline to animal model

Esophageal cancer is usually diagnosed at advanced stage due to lack of symptom and sign initially. Complete surgical resection is not usually feasible due to frequent invasion to adjacent vital organs. Thus, preoperative CRT is usually performed to improve resectability and tumor control. However, CRT has been shown to significantly improve survival only in patients who respond well to the CRT. On the other hand, if CRT is not effective—i.e., the tumor does not show chemoradiosensitivity—the patient has wasted valuable time, experienced severe toxicity, and lost an opportunity to have potentially curative surgery. Currently there are no clinically useful predictors of response prediction based on standard pathological assessment and immunohistochemistry. Thus, a reliable marker of radiosensitivity in esophageal cancer would be highly desirable and has long been sought. MicroRNAs (miRNAs) are a prevalent class of small single-stranded non-coading RNAs (19-25 nts). They serve widespread functions as regulatory molecules in post-transcriptional gene silencing for the regulation of cellular proliferation, differentiation, and apoptosis, which have great impacts on the malignant transformation. Recent investigation revealed that the expression of miRNA profile is closely associated with chemotherapy and radiotherapy response. Using miRNAs to alter the radiation response had been successfully reported in lung cancer cell line. The aim of this study is to investigate the potential roles of miRNA participating in cancer RR. Three phases of study will be designed: miRNA screening, function characterization using cellular models, and clinical association study. This knowledge will provide basic information for the potential applications of miRNA in esophageal cancer. The research design is briefly described follows. First year: Global screening of miRNA in RR Esophageal SCC cells. The RR ESCC subline cells will be established. Microarray and hiretical clustering analysis of miRNA will be apply to examine the differential profile of RR ESCC cells. Total of 10 miRNA will be selected. Functional investigation of candidate 6 miRNAs using cellular models. The candidate miRNA will be either overexpressed or knockdown in cells, and examine the phenoype alterations in Esophageal SCC cells. In this stage, 6 miRNA will be examined in cells. Xenograft animal model wil be used to further validate the function of six candidate miRNA. Second year: The candidate 6 miRNA will be validated in clinical association study. Tissue and plasma level of target miRNA from cancer patients will be tested to determine the consistency. Plasm level of miRNA from normal healthy patient will be compared with those from cancer patients to determine the specificity of certain target miRNA. Finally, plasma miRNA level in major and minor responders after CRT will be determined and correlated with treatment response and survival outcome.

Project ID:PC10202-0716
External Project ID:NSC101-2314-B182-094-MY2