hBD-1在口腔黏膜癌变过程中调控角质形成细胞分化的分子机制及其临床意义研究

Elucidating the molecular mechanisms of oral carcinogenesis is the focus of research in this field. Previous studies by our group indicated that human beta-defensin-1(hBD-1) might play an important role in oral carcinogenesis by regulating the differentiation of oral keratinocytes. This process is probably mediated by RhoA/MRTF/SRF pathway, which has recently been proved to be closely related with the differentiation of keratinocytes. The following studies are designed to prove that hypothesis: ①Expression pattern of hBD-1, markers of oral keratinocyte differentiation and key molecules of RhoA/MRTF/SRF pathway in the clinical samples at different stages of oral carcinogenesis, as well as the relationship between these proteins and clinicophathalogical characteristics and prognosis of oral squamous cell carcinoma (OSCC); ②In vitro validation of the regulation of oral keratinocyte differentiation by hBD-1 via RhoA/MRTF/SRF pathway; ③In vivo validation of the regulation of OSCC differentiation by hBD-1 via RhoA/MRTF/SRF pathway, as well as the possibility of hBD-1 and key molecules of RhoA/MRTF/SRF pathway as potential targets for the prevention of oral carcinogenesis. The results of this research will help with the understanding of the molecular mechanism of oral carcinogenesis, thus facilitate the development of new therapeutic strategies to treat and prevent OSCC.

阐明关键分子在口腔黏膜癌变中的作用机制是目前的研究热点。本课题组前期发现人beta-防御素-1(hBD-1)可能通过调控口腔角质形成细胞的分化，参与口腔黏膜癌变的发生、发展，其分子机制尚不明确，但可能与RhoA/MRTF/SRF信号通路有关。为印证该假设，拟进行以下研究：①hBD-1、口腔角质形成细胞分化标志物、RhoA/MRTF/SRF信号通路关键分子在临床样本中的表达及其相关性；②体外实验验证hBD-1通过RhoA/MRTF/SRF信号通路调控口腔角质形成细胞分化；③动物实验验证hBD-1通过RhoA/MRTF/SRF信号通路调控口腔鳞癌体内生长、分化和转移；以及以hBD-1及RhoA/MRTF/SRF信息通路关键节点蛋白为靶点早期阻断口腔黏膜癌变的可行性。结果有助于阐明hBD-1在口腔黏膜癌变过程中的作用机制，为靶向防治口腔黏膜癌变提供依据。

本课题组既往研究发现人β-防御素-1(human beta defensin-1, hBD-1)在口腔黏膜癌变的过程中，可能通过抑制口腔角质形成细胞迁移和侵袭，抑制口腔黏膜癌变的进展。为进一步阐明相关机制，本研究拟探讨hBD-1是否通过调控血清反应性因子(serum response factor, SRF)/心肌心肌素相关转录因子(myocardin-related transcription factor, MRTF)发挥其对口腔角质形成细胞的作用。研究发现：①hBD-1除了可以抑制口腔角质形成细胞迁移和侵袭外，还可促进口腔角质形成细胞的分化；②SRF/MRTF对口腔角质形成细胞生物学行为的调控作用与hBD-1有一定的相似性， SRF/MRTF和hBD-1均可以抑制口腔鳞癌(oral squamous cell carcinoma, OSCC)细胞的迁移和侵袭，SRF和hBD-1均与OSCC患者的预后相关，并可作为OSCC患者预后风险评估的独立因素，高表达SRF和hBD-1的患者预后较好，但未发现二者之间的相互调控关系；③SRF/MRTF对OSCC细胞迁移和侵袭的调控可能是通过促进OSCC细胞由间质表型向上皮表型转变而实现的。.上述研究提示，hBD-1和SRF/MRTF信号轴对口腔角质形成细胞生物学行为和口腔黏膜癌变进程的影响具有一定的相似性，但二者之间是否具有内在联系，是否具有相似的调控机制，还有待进一步探索。