AZIN1基因RNA编辑在促进食管鳞癌发生发展中的分子机制及临床意义的研究

RNA editing, one of post-transcriptional modifications, introduces changes in the RNA sequences encoded by the genome, which completely changes our views on RNA and refutes the Central Dogma that DNA dictates each nucleotide in RNA. RNA editing may lead to tumor-specific "editing/epigenetic mutation", serving as the additional layer of informational alterations in parallel to somatic mutation. Previous study revealed that adenosine-to-inosine (A→I) RNA hyperediting of AZIN1 (encoding antizyme inhibitor 1) was frequently detected in human cancers, including hepatocellular carcinoma (HCC) and esophageal squamous cell carcinoma (ESCC). However, the role of AZIN1 RNA editing in ESCC is still unknown. ESCC is the major histologic form of esophageal cancer, is a hetero-geneous tumor displaying a complex variety of genetic and epigenetic changes. Aberrant RNA editing of adenosine-to-inosine (A-to-I), as it is catalyzed by adenosine deaminases acting on RNA (ADAR), represents a common posttranscriptional modi?cation in certain human diseases. In our earlier study, we investigated the status and role of ADARs and altered A-to-I RNA editing in ESCC tumorigenesis. Among the three ADAR enzymes expressed in human cells, only ADAR1 was overexpressed in primary ESCC tumors. ADAR1 overexpression was due to gene ampli?cation. Patients with ESCC with tumoral overexpression of ADAR1 displayed a poor prognosis. In vitro and in vivo functional assays established that ADAR1 functions as an oncogene during ESCC progression. Differential expression of ADAR1 resulted in altered gene-speci?c editing activities, as re?ected by hyperediting of AZIN1 messages in primary ESCC. Notably, the edited form of AZIN1 conferred a gain-of-function phenotype associated with aggressive tumor behavior. Our ?ndings revealed that altered gene-speci?c A-to-I editing events mediated by ADAR1 drive the development of ESCC, with potential implications in diagnosis, prognosis, and treatment of ESCC, indicating a critical role ADAR1 in the pathogenesis of ESCC. It has also been reported that ADAR1 contributes to the editing status of AZIN1 in ESCC. Taken together, in this proposal, we plan to further investigate the role of the ADAR1 edited target gene AZIN1 in ESCC. We will focus on the subcellular location, the bio-function of the gene and the associated apoptosis protein and downstream signaling pathway to verify the tumor-initiating potential and the tumorigenic ability of edt/AZIN1 gene. Our study would be of great importance to better individual management of ESCC patients.

RNA编辑是一种转录后修饰，能介导RNA序列编码基因组的多样性，对生物遗传信息由DNA决定RNA核苷酸序列的中心法则提出了挑战。RNA编辑可能导致肿瘤特异性的"编辑/表观遗传突变"，与体细胞突变一样引起遗传信息改变。我们的前期研究发现，在食管鳞癌中存在RNA腺苷脱氨酶（ADAR1）过表达并能介导编码抗酶抑制剂1（AZIN1）RNA(A→I)过度编辑，这种RNA编辑型AZIN1(edt/AZIN1)作为一种获得性功能表型有可能与食管鳞癌发生发展相关。为了进一步了解edt/AZIN1在食管鳞癌中的作用机制和生物学功能，本课题在前期研究的基础上拟通过亚细胞定位，基因生物学功能，相关凋亡蛋白，下游信号传导通路，阐明edt/AZIN1在食管鳞癌发生发展中的作用，这对于寻找新的生物标记物和基因靶点，开发潜在的治疗策略，实现个体化治疗具有重要意义。

RNA 编辑是一种转录后修饰，RNA 编辑可能导致肿瘤特异性的“编辑/表观遗传突变”，与体细胞突变一样引起遗传信息改变。食管鳞癌存在 RNA 腺苷脱氨酶（ADAR1）过表达并能介导编码抗酶抑制剂 1（AZIN1）RNA(A→I)过度编辑，提示 RNA 编辑型有可能与食管鳞癌发生发展相关。我们研究发现wt/AZIN1和 edt/AZIn1不同载体转染后细胞系细胞凋亡情况、迁移、侵袭等存在明显差异，提示Azin1可能与食管癌发生发展明确相关，使食管癌更易发生复发，侵袭和转移。发现食管鳞癌患者的AZIN1基因的RNA编辑有地区差异，在河南林州的食管鳞癌患者中可检测到T突变，而广东食管癌患者未检测到T突变。提示A到T的突变可能在不同地区食管癌患者癌变过程中发挥重要作用。同时发现TUSC7通过下调miR-224表达来调节DESC1/EGFR/AKT信号通路，进而抑制食管鳞状细胞癌的化疗耐药。阐明 edt/AZIN1 在食管鳞癌发生发展中的作用， 这对于寻找新的生物标记物和基因靶点，开发潜在的治疗策略，实现个体化治疗具有重要意义。