NF-κB信号通路调控溶酶体相关4次跨膜蛋白质B (LAPTM4B)促人肝细胞癌增殖作用的研究

Our research team have reported " FXR inhibiting hepatocellular carcinoma cell proliferation (Su H, 2012)". In the subsequent experiments we found the mechanism of FXR inhibiting hepatocellular carcinoma cell proliferation may be related to down-regulated expression of LAPTM4B, and found that NF-κB signaling pathway may be involved in the regulatory mechanism. LAPTM4B was a novel gene overexpressed in HCC. LAPTM4B was involved in the cellular activities, including cell differentiation, proliferation, adhesion and migration, and was closely related to cellular malignant transformation through forming signaling complexes with a few cell surface signal molecules. Our preliminary experiment showed that LAPTM4B mRNA and protein expression levels in HCC tissues were significantly higher than those in adjacent noncancerous liver tissues and normal liver tissues. LAPTM4B mRNA expression level was negatively related to the FXR expression level, and was positively related to the serum AFP Protein level and the BCLC staging of liver cancer, and was up-regulated in the HBsAg positive patients. This project intends to solve three problems: 1. Is LAPTM4B the key gene to the regulation of liver cancer cell proliferation? 2. LAPTM4B promote liver cancer cell proliferation whether through regulating the NF-κB signal pathway. 3. LAPTM4B expression level will be detected in a large number of HCC tissue samples ,and it will be assessed whether LAPTM4B is help for the diagnosis and prognosis of HCC.

课题组前期曾报道“核受体FXR抑制肝癌细胞增殖(Su H,2012)”, 并在后续实验中发现FXR抑制肝癌细胞增殖的机制可能与下调LAPTM4B基因表达有关，LAPTM4B可能参与调控NF-κB信号通路。LAPTM4B 是在肝癌组织中上调表达的新基因，参与细胞分化、增殖、粘附和迁移，并与细胞的癌变过程有关。我们检测了HCC组织标本中LAPTM4B的表达情况，其在肝癌组织中高表达，与FXR表达负相关，并与肝癌BCLC分期和血清AFP蛋白表达正相关，在HBsAg阳性患者中上调表达。本项目拟解决三个问题： 1. LAPTM4B是否为调控肝癌细胞增殖的关键基因? 2. LAPTM4B与炎症致癌的关系，其是否通过调控NF-κB信号转导通路促进肝癌细胞增殖？3.通过大规模HCC组织标本验证LAPTM4B在肝癌组织的表达情况，评估LAPTM4B是否可作为HCC辅助诊断和预后判断的新生物学指标。

肝细胞癌是最常见的恶性肿瘤之一，发展迅速、预后差。人新基因溶酶体相关4次跨膜蛋白质B（LAPTM4B）是近年来发现的一种新基因，在多种肿瘤中呈上调表达。我们研究发现LAPTM4B在肝细胞癌组织中高表达，其表达水平与血清甲胎蛋白水平、肝癌巴塞罗那分期呈正相关，在HBsAg 阳性患者高表达，与患者年龄呈负相关。通过肝癌细胞株体外实验，我们发现LAPTM4B能够促进肝癌细胞的增殖、侵袭和转移能力，还发现白介素增强因子2（ILF2）是LAPTM4B发挥促肝癌作用的重要的下游靶基因。通过ILF2干扰实验，发现LAPTM4B可能通过下游靶基因ILF2上调细胞周期蛋白CyclinD1、CyclinE、CyclinA、E2F1的表达从而促进肝癌细胞的增殖，上调ACK1和MTDH表达影响AKT信号通路，促进肝癌细胞的侵袭迁移。 LAPTM4B基因与肝癌细胞发生和恶性进展相关，提示其有望成为肝癌诊断和治疗的新靶点。