Orosomucoid 2 inhibits tumor metastasis and is upregulated by CCAAT/enhancer binding protein β in hepatocellular carcinomas
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Tao Fang1, Meiling Cui1, Ji Sun2, Chao Ge1, Fangyu Zhao1, Lin Zhang2, Hua Tian1, Lixing Zhang1, Taoyang Chen3, Guoping Jiang4, Haiyang Xie4, Ying Cui5, Ming Yao1, Hong Li1 and Jinjun Li1
1 State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
2 Shanghai Medical Colloge, Fudan University, Shanghai, China
3 Qi Dong Liver Cancer Institute, Qi Dong, Jiangsu Province, China
4 Department of General Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
5 Cancer Institute of Guangxi, Nanning, China
Hong Li, email:
Jinjun Li, email:
Keywords: hepatocellular carcinoma, ORM2, C/EBPβ, metastasis
Received: February 10, 2015 Accepted: March 31, 2015 Published: April 19, 2015
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.
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