2016-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/644765摘要：食道癌為快速成長且預後極不佳之疾病。食道癌中有95 % 為食道鱗狀上皮細胞癌 (esophagealsquamous cell carcinoma，ESCC)。細胞激素(cytokine)與生長因子(growth factor)如IL-6 及EGF 與ESCC的癌化與預後有高度相關。由於細胞因子信號轉導抑制蛋白(Suppressor of cytokine signaling，SOCS)是回饋調節細胞激素與生長因子表現的重要因子, 因此我們認為SOCS 蛋白的缺乏於ESCC 的癌化與預後上可能扮演重要角色，然而缺乏相關的探討。SOCS 家族包含八個成員，SOCS1、SOCS2、SOCS3、SOCS4、SOCS5、SOCS6、 SOCS7 及 CISH。我們初步的研究發現SOCS5 的3 個基因多型性，SOCS5:rs3814039、SOCS5:rs3738890 及 SOCS5: rs3768720 與ESCC 的預後有顯著相關。而在附基因(epigenetic)的調控中，我們發現SOCS2 與SOCS7 在食道正常與癌組織中的甲基化程度有顯著的不同，顯示SOCS2 與SOCS7 的表現可能與ESCC 癌化有關。在本三年計畫中，我們將以前瞻性臨床研究與細胞模型更深入地探討這些SOCS 蛋白作用於ESCC 癌化與預後的可能機轉。本計畫的研究目標如下:臨床研究:1) 於100 組食道癌組織中，偵測SOCS2、SOCS5 及 SOCS7 的表現量，並分析其與基因型、甲基化程度、腫瘤期數與預後的關係。2) 於100 位食道癌病人血清與組織中，偵測EGF/EGFR、IL-6 及Insulin 的表現量，並分析其與SOCS蛋白表現量的關係。細胞模型:1) 探討ESCC 細胞中，是否SOCS5:rs3814039 多型性會影響啟動子的活性。2) 研究ESCC 細胞中，是否SOCS5:rs3768720 多型性會影響RNA 的穩定或蛋白轉譯的效率。3) 探討ESCC 細胞中，SOCS2、SOCS5 及 SOCS7 與他們的目標因子是否有回饋調控的關係。我們相信這些機轉研究的結果，將提供ESCC 癌化的重要資訊與ESCC 預後改善的新方向。<br> Abstract: Esophageal cancer is a fast-growing deadly disease worldwide with poor prognosis. The major cell typeof primary esophageal cancer, esophageal squamous cell carcinoma (ESCC), is accounting for 95 % of thedisease worldwide. The expressions of cytokine and growth factors such as interleukin 6 (IL-6) and EGFhave been known to highly correlated with carcinogenesis and adverse prognosis of ESCC. Becausesuppressor of cytokine signaling (SOCS) family of proteins are the key factors to feedback regulate theexpressions of cytokines and growth factors in cells, we suggest loss of SOCS proteins may play crucial rolesin the carcinogenesis and prognosis of ESCC. However, the roles of SOCS proteins in ESCC are hardlyinvestigated. The SOCS family contains 8 members, including SOCS1, SOCS2, SOCS3, SOCS4, SOCS5,SOCS6, SOCS7, CISH. We have preliminarily observed 3 SNPs at SOCS5, the SOCS5:rs3814039,SOCS5:rs3738890, and SOCS5: rs3768720, were significantly associated with the clinical outcome of ESCCpatients. In the epigenetic study, we have also observed the methylation levels of SOCS2 and SOCS7displaying evidently difference between the levels in normal and tumor tissues which revealing SOCS2 andSOCS7 might be correlated with the carcinogenesis of ESCC. Based on the preliminary observations, incurrent 3-year project, we intend to further clarify the underlying mechanism of these SOCS proteins in thecarcinogenesis and prognostic relevance of ESCC by a prospectively clinical study and cell model. Thespecific aims of the projects in the three years will be:In clinical study:1) To detect the protein expression levels of SOCS2, SOCS5, and SOCS7 from the tissue samples of 100ESCC patients and correlated the expression levels with the genotypes (in SOCS5 study) or methylationprofiles (in SOCS5 and SOCS7 study), tumor stage, and the prognosis of patients.2) To detect the expressions of EGF/EGFR, IL-6, and Insulin in 100 ESCC patients and correlate theexpression profile with the level of SOCSs protein of these ESCC patients.In cell model:1) To analyze whether SOCS5:rs3814039 effects on the promoter activity of SOCS5 gene in ESCC cells.2) To investigate whether SOCS5: rs3768720 function mediated by modulating RNA stability or translationefficiency in ESCC cells.3) To demonstrate the feedback regulation of SOCS2, SOCS5, and SOCS7 protein and their target factors,including EGF/EGFR, IL-6, and Insulin in ESCC cells.We believe providing the mechanistic evidence of the SOCS function in ESCC will provide valuableinformation for the study of ESCC carcinogenesis and novel direction for improving the clinical outcome ofESCC.食道癌食道鱗狀上皮細胞癌細胞因子信號轉導抑制蛋白甲基化基因多型性Esophageal cancerEsophageal squamous cell carcinoma (ESCC)Suppressor of cytokine signaling (SOCS)MethylationGenetic polymorphism