癌/睾丸基因MAEL调控结肠癌上皮间质转化和肿瘤干细胞的作用机制研究

Cancer-testis genes exhibit normal expression in germ cells of male testis but aberrant expression in a variety of malignant tumor tissues, the underlying mechanism of which remain poorly understood. We previously found that MAEL, which is specifically expressed in sperm cell and play important role in the development of testis germ cell, is a predictive marker for metastasis of colon cancer patients and promote invasion and metastasis through epithelialmesenchymal transition(EMT) in colon cancer. Furthermore, we showed that MAEL could maintain the colon cancer stem cell(cCSC) property. Additionally, MAEL may serve as a key modulator of signalling cross talk between EMT and cCSC possibly. In this study, we aim to elucidate the precise mechanism of MAEL involved in colon cancer tumorigenesis and metastasis through transactivation of cCSC with EMT property, which has important theoretical significance and clinical value in screening biomarkers for prognosis and targeted therapy.

在肿瘤组织中高表达、但在正常组织中的表达仅限于睾丸精细胞的基因被称为癌—睾丸基因(cancer-testis genes) ，目前对该类基因的功能机制尚缺乏深入了解。MAEL基因是在睾丸精细胞发育中发挥重要作用的生殖细胞特异表达基因，我们前期发现：（一）MAEL是结肠癌病人转移预测指标，介导上皮间质转化促进结肠癌侵袭转移；（二）MAEL可调控结肠癌干细胞干性；（三）MAEL可能通过介导Wnt/β-catenin通路调控EMT和CSC的内在转化，扮演两者信号串话（cross talk）的关键“角色”，进而参与结肠癌发生和转移过程。据此，本课题组拟在前期研究基础上以分子生物学、细胞生物学实验和基因敲除小鼠模型等作为主要研究手段，深入阐明MAEL参与结肠癌发生和恶性转归的生物学过程，揭示上下游关键信号调控机制，这对于筛选干预靶标和预后分子标记物具有重要的转化应用价值。

MAEL通过抑制转座因子并阻止其动员，在精子发生过程中发挥核心作用，然而，其在癌症中的作用尚不清楚。在本项目研究中，发现MAEL在185例结肠癌病人原发癌灶样本中异常过表达，而在正常肠粘膜上皮中表达缺失。MAEL高表达与结肠癌的病期、侵犯深度和淋巴结转移显著正相关；MAEL是病人术后出现远处转移的风险因子，MAEL高表达病人术后总体生存时间和无疾病进展时间较阴性组显著降低。体内外研究表明MAEL表达与上皮-间质转化有关，可以诱导结肠癌细胞的细胞增殖，侵袭和耐药的特征。从机制上讲，我们的研究表明MAEL与Snail相互作用并抑制E-cadherin启动子活性。总的来说，MAEL是一种致癌基因，在结肠癌进展中起着重要作用。