KLF5调控细胞不对称分裂促进肿瘤发生的机制

The association of abnormities of asymmetric cell division with tumorigenesis has been one of the important cell biology findings in the past 10 years. While, how asymmetric cell division is regulated and contributes to tumorigenesis is largely unclear. Our study identified that KLF5 is a critical regulator of asymmetric cell division in squamous epithelial cells. And increased expression of KLF5 in progenitor cells locating at basal layer of squamous epithelium was identified to be positively correlated with squamous cell cancer initiation and progression by analysis of pathological samples from patient. These results indicated that KLF5 may be a critical gene involves in squamous cell carcinogenesis, and it likely could promote squamous cell carcinogenesis through regulation of asymmetric cell division. In present study, this hypothesis will be tested by using cultured squamous cells, KLF5 knockout mice and pathological samples from patients. This study will provide important insights in understanding the mechanism of asymmetric cell division and its roles in squamous cell carcinogenesis, which is useful in the diagnosis and treatment of squamous cell carcinoma

细胞不对称分裂的异常与肿瘤发生的关联是近十年来最重要的细胞生物学发现之一，但是目前对参与其调控的关键基因的研究，以及对它们在肿瘤发生中扮演角色的探索尚待深入。我们的研究发现KLF5是鳞状上皮KRT5阳性前体细胞不对称分裂的重要调控基因。且临床样本研究显示KLF5在鳞状上皮基底层前体细胞中表达的增高与鳞状上皮癌的起始和进展成正相关。这些发现提示KLF5很可能通过调控细胞的不对称分裂促进鳞癌的发生，是鳞癌发生的重要调控基因。该研究将利用体外细胞培养、KLF5鳞状上皮特异性敲除的动物模型以及鳞癌组织样本，深入探讨KLF5调控不对称分裂的机制，探索其表达异常在鳞癌发生中的作用及其相关的分子机制，为深入认识鳞癌发生的机制及鳞癌的诊疗提供理论依据和分子靶向。

肿瘤是危害人类健康的重大疾病。目前越来越多的证据显示成人的组织干细胞或前体细胞是多种癌细胞的重要来源，他们不对称分裂的调控异常是肿瘤发生的重要促进因素，具体机制研究尚待深入阐明。在前期研究的基础上，我们利用鳞状上皮体外培养体系、基因敲除小鼠、皮肤鳞癌动物模型和鳞状上皮癌前病变到癌的病理标本，发现了KLF5是调控细胞不对称分裂的关键基因，其在复层鳞状上皮肿瘤发生过程中起重要作用。重要发现主要有以下两个方面：1. KLF5是调控皮肤角细胞不对称分裂的关键基因，其通过抑制Notch1信号，促进对称分裂；2.KLF5在多种复层鳞状上皮来源的肿瘤组织中高表达，且与疾病进程密切相关。KLF5缺失可抑制DMBA/TPA诱导的皮肤肿瘤形成。