干细胞相关基因Hiwi在口腔潜在恶性病变癌变中的作用机制研究

The stem cell-associated gene Hiwi is a human member of the piwi family, which play an improtant role in stem cell self-renewal and divition. Overexpression of Hiwi has been found in various malignant tumors and to be related with the poor prognosis. Our previous studies also showed that Hiwi protein expression was elevated in the oral PMD and oral cancer lesions, indicating its possible involvement in the pathogenesis and malignant transformation of oral PMD. The objective of this study is to investigate the role of Hiwi in the malignant transformation of oral PMD. First, we are going to investigate the gene and protein expression patterns of Hiwi in multiple stages of oral PMD and to evaluate the clinical relevance. Next, the effect of up or down-regulation of Hiwi gene on the biological behavior of normal, dysplastic and malignant oral epithelial cell lines and its potential mechanism are to be explored. Further, an oral carcinogenesis animal model are to be used to assese the effect of Hiwi gene-regulation on oral PMD malignant transformation in vivo. Taken together, the present study is aiming to understand the biological role of Hiwi in the development of oral PMD, and to find out novel biomarkers and therapeutic targets for the prevention and treatment of malignant transformation of oral PMD.

Hiwi基因是参与调控干细胞自我更新和分裂的Piwi家族中的一员，在多种恶性肿瘤组织中均表达增高，且与临床预后有关。本课题组前期研究发现，Hiwi蛋白在口腔潜在恶性病变（PMD）及口腔癌组织中的表达显著增高，提示Hiwi基因很可能参与了口腔PMD的发生与癌变进程并在此过程中发挥重要的调控作用。为此，本研究拟以临床病理研究、细胞生物学研究与动物模型研究相结合的策略，研究Hiwi在口腔PMD癌变各阶段的表达规律，探讨Hiwi用于口腔PMD癌变早期诊断的可行性；了解Hiwi参与调控口腔PMD癌变各阶段细胞生物学行为的内在分子机制；利用动物模型，研究以Hiwi为治疗靶点对口腔PMD癌变进行干预的效果并探讨其对口腔PMD癌变防治的价值。研究成果将为阐明Hiwi参与调控口腔PMD癌变的分子机制提供理论依据，并有助于找寻口腔PMD癌变早期诊断标志物和防治新靶标。

Hiwi基因是参与调控干细胞自我更新和分裂的Piwi家族中的一员，在多种恶性肿瘤组织及癌前病损中均表达增高，然而其在口腔潜在恶性病变（PMD）癌变过程的表达规律及作用尚不明确。本课题研究发现，Hiwi蛋白在口腔PMD癌变的各个阶段均有表达，其在口腔鳞癌组织中的表达较之正常口腔黏膜组和口腔上皮异常增生组织显著降低，提示其表达缺失可能参与了口腔PMD癌变的发展进程。同时，在本课题的资助下，我们还发现了抗吞噬蛋白CD47在口腔黏膜癌变的进程中表达显著升高，高浓度的抗CD47抗体能明显抑制口腔鳞癌细胞的增殖，细胞衰老标记分子p16INK4a、p15 INK4b、DEC1和DCR2在正常口腔黏膜、低危型及高危型口腔白斑以及口腔鳞癌组织的细胞胞核和胞浆中呈现不同的表达模式。另外，我们还成功构建了优化的4NQO饮水诱导小鼠口腔黏膜癌变模型，以及建立了口腔PMD的临床研究队列。上述研究结果可为进一步探索口腔PMD癌变的发病机制提供一定理论线索，并为将来口腔PMD癌变相关的临床及分子机制研究提供基础条件。