新的潜在抑癌基因CMTM8在膀胱癌发生及进展中的作用及机制研究

CMTM8 is a new gene which was cloned by Peking University Center for Human Disease Genomics(PUCHDG). PUCHDG posseses the independent intellectual property right of CMTM8 and has formed a stable research direction of it. The previously study confirmed that tumor cell proliferation and metastasis could be inhibited by CMTM8, and in variety of tumors there is a relatively low expression of CMTM8 compared with normal tissues. In this study, we intend to carry out research about the effects and mechanisms of CMTM8 in tumorigenesis and progression of bladder cancer. The preliminary experiments showed that the level of CMTM8 in human bladder cancer tissues was down-regulated, and was negatively correlated with tumor stage and grade. On the other hand, the expression of CMTM8 in bladder cancer was positively correlated with the survival rate of patients. In this project, we intend to investigate the following contents: we will make use of pathological tissue samples and follow-up data to analysis the correlation between the expression of CMTM8 and proliferation, apoptosis, invasion, metastasis and prognosis of bladder cancer.We will establish the bladder cancer cell lines whose CMTM8 are regulated, and use variety of experimental methods to reveal the role of CMTM8 in proliferation, apoptosis, invasion and metastasis.The mechanisms of CMTM8 on signaling pathway will also be studied. Furthermore, the tumor in situ mouse model will be used to study the effect of CMTM8 on tumor growth, invasion, metastasis and chemosensitivity in vivo.This project is expected to elucidate the role of CMTM8 in tumorigenesis and progression of bladder cancer, and to make a foundation for further functional mechanism and clinical application.

CMTM8是北京大学人类疾病基因研究中心在国际上首次克隆，具有自主知识产权，已形成稳定研究方向的新基因。已有体外研究证实CMTM8能够抑制肿瘤细胞增殖和转移，在多种肿瘤组织中表达下调。本课题拟首次开展CMTM8在膀胱癌发生进展中的作用及机制研究。预实验显示CMTM8在人膀胱癌组织中表达下调，与肿瘤分期和分级呈负相关，与患者生存率呈正相关。CMTM8上调明显抑制膀胱癌细胞增殖和侵袭性，增强化疗敏感性。本课题拟进一步利用临床病理组织标本及随访资料，分析CMTM8表达与膀胱癌增殖、凋亡、浸润及转移的相关性，以及与患者预后的相关性；采用多种实验方法研究CMTM8对膀胱癌细胞增殖、凋亡、浸润及转移的影响及作用机制；利用膀胱癌原位动物模型研究CMTM8在体内对肿瘤发生、生长、侵袭、转移及化疗敏感性的影响。本课题可望首次阐明CMTM8在膀胱癌发生进展中的作用及分子机制，具有创新性、理论意义和应用价值。

膀胱癌是泌尿系统最常见的肿瘤。在过去几十年间，膀胱癌的发生率逐渐上升，因此，更需要研究出用于早期诊断和有效治疗的分子标志物。趋化素样因子超家族8（CMTM8）的表达在几种肿瘤中均下调，并且与肿瘤进展相关。然而，CMTM8在膀胱癌中的表达尚无研究。通过免疫组织化学的方法，我们发现CMTM8在62.2%（46/74例膀胱癌组织）中低表达。CMTM8的下调与膀胱肿瘤的分级、分期相关。利用慢病毒在EJ和T24细胞系中稳定过表达CMTM8，细胞功能实验提示上调CMTM8后细胞增殖能力、迁徙能力以及转移能力均下降。在移植瘤中上调CMTM8的表达，能抑制肿瘤生长和淋巴结转移。总的来说，膀胱癌中过表达的CMTM8能提示细胞增殖、迁移和侵袭能力的下降，CMTM8可以作为膀胱癌潜在的治疗靶点。