非经典NF-kB信号通路在涎腺肿瘤发生过程中的功能研究

Salivary gland tumors are the second most common tumors in oral and maxillofacial region. It represents about 2.3% of all tumors in human. Malignancy proportions are different in three major glands, where the incidence rate in mandibular gland is 45%. The recurrence and metastasis of salivary gland tumors often appear after surgery due to the lack of specific treatment. Therefore, an in-depth understanding of the pathogenesis and metastasis mechanism of salivary glands tumors especially mandibular gland malignancies is crucial for the development of targeted therapeutic drugs. In our preliminary data, we found that transgenic NIK gene in myeloid cells in mice specifically induced tumors in mandibular gland. Base on this observation, our further research will focus on the carcinogenic mechanism of noncanonical NF-kB signaling both in NIK transgenic mice and clinic specimens. The research will additionally identify the relationship between immune cells and epithelial cells in salivary glands. We are also interested in clarifying the specific genes regulated by the noncanonical NF-kB in salivary glans tumors compare to the wild-type mice. At last, we will evaluate the resistant effect of noncanonical NF-kB adenviral shRNA on the tumor growth and proliferation. Our research will contribute to the development of new therapeutic targets of salivary gland tumors, while further improving the level of anti-tumors treatment in China.

涎腺肿瘤是口腔颌面部所特有的第二大类肿瘤，约占人体全部肿瘤的2.3%。恶性肿瘤在涎腺不同腺体中发生比例也有所不同，其中下颌腺的恶性肿瘤发病率为45%。涎腺恶性肿瘤因缺乏特异性治疗手段，常出现术后复发、转移，因此更好的了解涎腺的涎腺尤其是下颌腺恶性肿瘤的发病和转移机理，对于开发有针对性的治疗类药物具有重要的意义。申请人在前期工作中发现，在小鼠髓系免疫细胞中过表达非经典NF-kB核心激酶NIK会在小鼠涎腺的下颌腺位置特异性的诱导肿瘤的产生。本研究将结合转基因小鼠和临床涎腺肿瘤标本，继续探索非经典NF-kB信号通路的致癌机理，明确免疫细胞与涎腺上皮细胞间的作用关系，阐明非经典NF-kB特异性调控的基因。在小鼠涎腺肿瘤细胞及NIK转基因小鼠模型上评估非经典NF-kB腺病毒shRNA是否能够阻断涎腺肿瘤的发生和增殖。我们的研究将为涎腺恶性肿瘤的治疗探索新的治疗靶点，进一步提高我国涎腺肿瘤的治疗水平。

涎腺肿瘤是由分泌唾液的唾液腺组织所长出的肿瘤，其是口腔颌面部肿瘤中较为常见的肿瘤之一。由于目前对涎腺肿瘤发生发展的精确分子机制尚不完全清楚，因此尚未发现非常有效的化疗药物。本项目揭示了非经典NF-kB通过促进涎腺部位髓系免疫细胞增殖，引发涎腺多形性腺瘤的发生。非经典NF-kB通过特异性上调IL-23的表达，进而诱发IL-17信号通路的异常表达导致肿瘤的发生。髓系免疫细胞活化中，下调的细胞周期相关分子CRL4DCAF2导致非经典NF-kB通路中关键激酶NIK的累积，进而促进p100加工成p52。本研究为解析非经典NF-kB在髓系免疫细胞及腺肿瘤发生中的作用，提供了理论基础。发现了非经典NF-kB新型的负调控机制，为开发涎腺肿瘤治疗药物和提高治疗效果提供新策略，进一步提高我国涎腺肿瘤的治疗水平。在项目实施期间，已发表5篇相关文章（其中4篇影响因子大于10分，其中包括一篇Cell），负责人获得一项国家自然科学基金面上项目资助，一项优秀青年科学基金。培养了博士研究生3名。