一种新的分子标志物MS60在胃癌发生发展中的作用机制及临床意义

Gastric cancer (GC) is one of the most common malignancies of human digestive system worldwide, especially in China. Currently there are no good biomarkers with high specificity and sensitivity for early detection, screening, diagnosis and treatment of GC. The molecular mechanism of GC initiation and development is still unclear while some research works have been done attempted to elucidate it. Thus, the identification of novel functional biomarkers with specificity is pivotal and favorable for the early screening and clinical management of GC. Moreover, the better comprehension of specific and functional GC biomarkers will give a better understanding of molecular mechanisms underlying GC initiation and progression..In our preliminary works, the unique methodology, that is the hybridoma technology in combination with viable cell surface-based FACS screening, were used in our research and we generated MS40-3.1 monoclonal antibody (mAb) binding to conformational membrane protein of GC cells. Our further investigation showed membrane antigen targeted by mAb MS40-3.1 with highly specific expression in GC cells and tissues, not expressed in other human malignancies of digestive system and various normal tissues. Western Blot showed the molecular weight of target antigen was 60 kDa detected by MS40-3.1, so the corresponding antigen binding with MS40-3.1 antibody termed as MS60. To further identify the characteristic of MS60 protein, human protein microarray was fabricated and utilized to detect mAb MS40-3.1. The preliminary results demonstrated mAb MS40-3.1 specifically recognized human ODC1 (ornithine decarboxylase 1). ELISA results further confirmed that MS60 protein shared the same antigen epitope with ODC1..Our present results showed that MS60 is a novel molecular biomarker of GC and may have important role in the initiation and development of GC. Our next research will further elucidate the gene and protein characteristic of MS60, the clinical significance of MS60 expression in GC, the function and molecular mechanism of MS60 in proliferation or invasion and metastasis of GC. Our work will illuminate the utility of this novel biomarker as a potential target for GC early detection and antibody-mediated targeted therapy. In addition, the clarification of MS60 function in GC initiation and progression will bring a novel understanding of GC.

胃癌是我国最常见的消化系统恶性肿瘤之一，虽然近年来胃癌的筛查、诊断及治疗取得了一定成效，但是目前早期胃癌的筛查方法仍不完善，确诊手段仍较局限，进展期胃癌的治疗现状也不容乐观，主要原因在于缺乏理想的胃癌分子标志物。寻找胃癌特异性及功能性分子标志物，对于建立完善的早期胃癌筛查诊断方法及改善进展期胃癌治疗现状具有应用意义，对于探讨胃癌发生发展的可能机制具有指导意义。本课题前期研究鉴定了一种与鸟氨酸脱羧酶1有共同抗原表位的新胃癌分子标志物，命名为MS60。本课题拟进一步采用生物信息学、基因组学及蛋白质组学方法鉴定MS60基因及蛋白特性，采用免疫组化方法分析MS60在胃癌患者组织中表达的临床病理学意义，并在细胞及动物试验水平探讨MS60在胃癌发生发展中的促进或抑制作用机制。本研究将为胃癌的早期诊断或靶向治疗提供新靶标，并为胃癌发生发展机制研究提供新思路。

胃癌是最常见的消化系统恶性肿瘤之一，目前早期胃癌诊断及进展期胃癌治疗现状不容乐观，主要原因在于尚缺乏理想的分子标志物用于胃癌诊断及靶向治疗。本研究鉴定出新的胃癌分子标志物MS60，分析了MS60特性及其在胃癌组织中表达的临床意义，并明确了MS60在胃癌细胞增殖及转移中的作用，初步探讨了MS60在胃癌细胞生长中的作用机制。结果显示，MS60在胃癌组织中特异性表达，主要表现为肿瘤细胞膜表达，并与肿瘤预后相关；MS60蛋白与已知的胃癌标志物无同源性，而与人鸟氨酸脱羧酶1高度同源。因此将MS60定义为在胃癌诊断及预后评估中具有临床应用价值的新分子标志物。发现下调MS60表达可在体外抑制胃癌细胞增殖、迁移及侵袭，证实了MS60是一种具有生物学功能的新分子标志物，在胃癌细胞生长及转移过程中可能发挥了重要作用；同时也显示MS60具有成为治疗靶点的可能。进一步明确了本课题以独特的FACS-HTS方法制备的MS40-3.1单抗可作为拮抗型的功能性抗体特异性阻断MS60功能位点，从而抑制胃癌细胞增殖及转移。初步证实新的分子标志物MS60可能通过交互作用启动经典细胞信号通路（如EGFR信号通路、IL-6信号通路等）或者通过自身独特的下游细胞信号通路，从而在胃癌细胞增殖中发挥生物学功能。本课题鉴定获得了一个特异性的新胃癌分子标志物MS60，证实其可作为胃癌诊断及预后评估标志物；明确了MS60在胃癌发生发展中的生物学功能及部分可能机制，证实其可作为潜在治疗靶点；本课题同步筛选获得了功能性抗体MS40-3.1，可特异性阻断MS60功能位点，为制备靶向MS60的治疗性抗体提供了理想的候选抗体。本研究不仅鉴定出可用于胃癌诊断及治疗的全新的分子标志物，也为其它肿瘤分子标志物的鉴定研究提供了全新的技术参考。