Fang Tao, Cui Meiling, Sun Ji, Ge Chao, Zhao Fangyu, Zhang Lin, Tian Hua, Zhang Lixing, Chen Taoyang, Jiang Guoping, Xie Haiyang, Cui Ying, Yao Ming, Li Hong, Li Jinjun
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Shanghai Medical Colloge, Fudan University, Shanghai, China.
Oncotarget. 2015 Jun 30;6(18):16106-19. doi: 10.18632/oncotarget.3867.
Cancer metastasis is a complex process, and the incidence of metastasis is influenced by many biological factors. Orosomucoid 2 (ORM2) is an important glycoprotein that is mainly biosynthesized and secreted by hepatocytes. As an acute-phase protein, ORM2 likely plays important roles in anti-inflammation, immunomodulation and drug delivery. However, little is known regarding the function of ORM2 in hepatocellular carcinoma (HCC). In this study, we determined that ORM2 expression in HCC tissues was negatively associated with intrahepatic metastasis and histological grade. Moreover, the ectopic overexpression of ORM2 decreased HCC cell migration and invasion in vitro and intrahepatic metastasis in vivo, whereas silencing ORM2 expression resulted in increased tumor cell migration and invasion in vitro. The CCAAT/enhancer binding protein β (C/EBPβ) upregulated ORM2 expression, while only the LAP1/2 (C/EBPβ isoforms) possessed transcription-promoting activity on the ORM2 promoter. Subsequently, we found that LAP1 repressed HCC cell migration and invasion via the induction of ORM2 expression. Consistently, the protein expression of C/EBPβ was negatively associated with histological grade and positively correlated with ORM2 protein expression in HCC tissues. Collectively, our findings indicate that ORM2 is a functional downstream target of C/EBPβ and functions as a tumor suppressor in HCC.
癌症转移是一个复杂的过程，转移的发生率受多种生物学因素影响。血清类黏蛋白2（ORM2）是一种重要的糖蛋白，主要由肝细胞生物合成并分泌。作为一种急性期蛋白，ORM2可能在抗炎、免疫调节和药物递送中发挥重要作用。然而，关于ORM2在肝细胞癌（HCC）中的功能知之甚少。在本研究中，我们确定HCC组织中ORM2的表达与肝内转移和组织学分级呈负相关。此外，ORM2的异位过表达在体外降低了HCC细胞的迁移和侵袭能力，并在体内减少了肝内转移，而沉默ORM2表达则导致体外肿瘤细胞迁移和侵袭增加。CCAAT/增强子结合蛋白β（C/EBPβ）上调ORM2的表达，而只有LAP1/2（C/EBPβ同工型）对ORM2启动子具有转录促进活性。随后，我们发现LAP1通过诱导ORM2表达来抑制HCC细胞的迁移和侵袭。一致地，C/EBPβ的蛋白表达与HCC组织的组织学分级呈负相关，与ORM2蛋白表达呈正相关。总体而言，我们的研究结果表明，ORM2是C/EBPβ的功能性下游靶点，在HCC中发挥肿瘤抑制作用。
