晚期胸腺癌的治疗是临床难题，研究发现KIT基因在胸腺癌患者过量表达，且以KIT为靶点的靶向药物Imatinib(伊马替尼)对KIT突变型胸腺癌患者有效，但是KIT在胸腺癌发病中的功能和Imatinib对非突变型患者无效的原因仍不清楚。本课题组利用前期临床积累的大量胸腺癌样本，也实验证实了KIT在胸腺癌中高表达，但是KIT高表达的分子机制仍不清楚，主要障碍在于缺乏大规模的临床标本研究。基于此，我们将利用积累的大量手术样本通过启动子甲基化、上游信号调控及启动子区转录因子结合实验，揭示KIT在胸腺癌中高表达的调控机制。并且，我们将通在胸腺癌细胞系中进行Knockdown和过表达实验，研究KIT的基因功能并揭示胸腺癌的发病机制。此外， 建立KIT为靶点的潜在化合物库，在细胞模型中筛选能够特异性抑制KIT野生型胸腺癌细胞增殖和促进其凋亡的化合物，以期找到对KIT野生型胸腺癌病人有效的临床药物。

Treatment of patients with advanced thymic carcinoma is an unsolved clinical problem and the study found that KIT gene overexpressed in patients of thymic carcinoma. Imatinib is only effective targeted drug for such patients with mutant KIT and its target is KIT. However the role of the KIT played in thymic carcinoma is still unclear. The main obstacle is the lack of surgical specimens. Our group have accumulated large amount of specimens and clinical data by pre-clinical studies and found that KIT is highly expressed in thymic carcinoma. We will conduct experiments on promoter methylation, upstream signal regulation and binding of transcription factors to promoter regions to explore the mechanisms governing the high expression of KIT in thymic carcinoma. Functions of the KIT gene will be investigated using knockdown experiments, KIT over-expression and suppression experiments to elucidate the role of KIT in the development of thymic carcinoma. In addition, by screening potential drugs targeting KIT in compound libraries, we hope to identify agents able to inhibit the proliferation of wild type cells and promote their apoptosis; these compounds can be used for future clinical research and provide clues for the development of potential drugs targeting KIT.

胸腺癌虽然发病率较低，但目前也有明显上升趋势。胸腺癌的侵袭力较强，容易转移，目前5年生存率为26-35%，容易复发。目前对于胸腺癌的发病分子机制不是非常清楚。因此找到可早期诊断胸腺癌的标志和治疗靶点对于胸腺癌的早期发现和治疗，提高生存期意义重大。本研究在对胸腺癌和癌旁组织进行microRNA芯片高通量数据分析时发现，mir-10b-5p 在胸腺癌组织中明显下调，并且用northern blot和qPCR的方法进行确认。在此基础上，我们通过在胸腺癌细胞系或原代胸腺癌细胞中过表达或者knockdown mir-10b-5p，在对相关肿瘤细胞进行一系列体内外相关功能检测中发现，mir-10b-5p对胸腺癌的发生发展起关键作用，影响胸腺癌细胞的增殖和侵袭能力。同时我们阐明了TIAM1和BCL6是mir-10b-5p影响胸腺癌增殖和侵袭转移的两个重要靶点。最后我们通过胸腺癌标本验证mir-10b-5p的表达与胸腺癌的病理分级和肿瘤分期成明显负相关。这一研究拓展了非编码RNA对于胸腺癌发生发展影响的理论，为后续将此非编码RNA作为胸腺癌的诊断标志和治疗靶点之一奠定了基础。