新抑癌基因LMAN1在结直肠癌发生发展中的作用及分子机制研究

Colorectal cancer is one of the most common cancers in the world. Identification of new driver genes and characterization of associated pathways are important in understanding the disease mechanism and developing targeted treatment approaches. A recent report identified frequent biallelic mutations that result in the loss of LMAN1 expression in microsatellite unstable adenomas and carcinomas. To determine whether LMAN1 deficiency contributes to tumor development, we tested LMAN1 expression in human microsatellite stable colorectal cancer tissues, and found complete or partial loss of LMAN1 expression in 40% of them. Among patients with complete clinical records, we found that those lacking LMAN1 expression had significantly worse prognosis than those with normal LMAN1 expression. These results suggest that LMAN1 is a novel tumor suppressor gene in colorectal cancer. LMAN1 functions as a cargo receptor for the transport of certain glycoproteins from the endoplasmic reticulum to the Golgi. Our preliminary data showed that the IFNβ secretion is reduced in colorectal cancer cells lacking LMAN1 expression. We hypothesize that LMAN1 suppresses colorectal cancer by promoting IFNβ secretion. To test this hypothesis, we will use cancer cells and LMAN1 knockout mice to study the regulation of IFNβ secretion by LMAN1 and determine the molecular mechanism of LMAN1 deficiency in initiation and progression of colorectal cancer. We will also use mouse models and colorectal cancer patient samples to explore the effect of IFNβ as a treatment for LMAN1-deficient colorectal cancer, and also characterize the pathological and clinical features of this type of cancer. Results may lead to effective personalized medical care for a subset of patients whose cancer is deficient in LMAN1.

结直肠癌是最常见的恶性肿瘤之一，发现和阐明新驱动基因及通路对了解其机理和开发针对性治疗方法十分重要。最近报道近50%微卫星不稳定型结直肠癌存在LMAN1突变和表达缺失。我们发现40％微卫星稳定型结直肠癌也存在LMAN1表达缺失且这种患者预后更差，提示LMAN1是新结直肠癌抑制基因。鉴于LMAN1胞内转运蛋白功能，我们发现其表达缺失导致结直肠癌细胞IFNβ分泌显著下降。据此我们提出LMAN1可能通过介导IFNβ分泌抑制结直肠癌生长的假设。为验证该假设，本项目将利用LMAN1缺失细胞系和敲除小鼠开展癌细胞内LMAN1介导IFNβ分泌调控研究，从分子水平阐明LMAN1突变促进肿瘤起始和增生机制；同时用动物模型和人体标本验证IFNβ对LMAN1缺失型结直肠癌的抑制作用，并阐述LMAN1表达缺失型结直肠癌临床病理特点和预后意义，以期为LMAN1表达缺失型结直肠癌患者提供个性化治疗方案。

结直肠癌是最常见的恶性肿瘤之一，发现和阐明新驱动基因及通路对了解其机理和开发针对性治疗方法十分重要。前期研究发现结直肠癌存在LMAN1表达缺失且这种患者预后更差，提示LMAN1是新结直肠癌抑制基因。鉴于LMAN1胞内转运蛋白功能，我们发现其表达缺失可导致结直肠癌细胞IFNβ分泌显著下降。据此我们提出LMAN1可能通过介导IFNβ分泌抑制结直肠癌生长的假设。为验证该假设，本项目通过动物实验、临床样本、细胞实验三个层次阐明了LMAN1表达缺失导致IFNβ转运分泌下调从而促进结直肠癌发生发展的分子机制。细胞水平进一步深入研究阐明LMAN1通过糖结合位点与糖基化IFNβ结合而相互作用帮助IFNβ进入COPII包裹的出芽囊泡，完成从内质网到高尔基体的转运的分子机制。本项目研究结果将有助于为LMAN1表达缺失型结直肠癌患者提供有效的个性化治疗方案。