Hydroxylase Activity of ASPH Promotes Hepatocellular Carcinoma Metastasis Through Epithelial-to-Mesenchymal Transition Pathway

Qifei Zou; Ying Hou; Haibo Wang; Kui Wang; Xianglei Xing; Yong Xia; Xuying Wan; Jun Li; Binghua Jiao; Jingfeng Liu; Aimin Huang; Dong Wu; Hongjun Xiang; Timothy M Pawlik; Hongyang Wang; Wan Yee Lau; Yizheng Wang; Feng Shen

doi:10.1016/j.ebiom.2018.05.004

Hydroxylase Activity of ASPH Promotes Hepatocellular Carcinoma Metastasis Through Epithelial-to-Mesenchymal Transition Pathway

EBioMedicine. 2018 May:31:287-298. doi: 10.1016/j.ebiom.2018.05.004.

Authors

Qifei Zou¹, Ying Hou², Haibo Wang¹, Kui Wang¹, Xianglei Xing¹, Yong Xia¹, Xuying Wan¹, Jun Li¹, Binghua Jiao³, Jingfeng Liu⁴, Aimin Huang⁴, Dong Wu¹, Hongjun Xiang¹, Timothy M Pawlik⁵, Hongyang Wang⁶, Wan Yee Lau⁷, Yizheng Wang⁸, Feng Shen⁹

Affiliations

¹ Department of Hepatic Surgery, The Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
² Department of Hepatic Surgery, The Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China; Laboratory of Neural Signal Transduction, Institute of Neuroscience, Chinese Academy of Science, Shanghai, China.
³ Department of Biochemistry and Molecular Biology, Second Military Medical University, Shanghai, China.
⁴ Department of Hepatobiliary Surgery, The Mengchao Hepatobiliary Surgery Hospital, Fujian Medical University, Fuzhou, China.
⁵ Department of Surgery, The Ohio State University, Wexner Medical Center, Columbus, OH, USA.
⁶ National Scientific Center for Liver Cancer, Shanghai, China.
⁷ Department of Hepatic Surgery, The Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China; Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, SAR, China.
⁸ Laboratory of Neural Signal Transduction, Institute of Neuroscience, Chinese Academy of Science, Shanghai, China. Electronic address: yzwang@ion.ac.cn.
⁹ Department of Hepatic Surgery, The Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China. Electronic address: shenfengehbh@sina.com.

Abstract

Over-expression of aspartyl (asparagynal)-β-hydroxylase (ASPH) contributes to hepatocellular carcinoma (HCC) invasiveness, but the role of ASPH hydroxylase activity in this process remains to be defined. As such, the current study investigated the role of ASPH hydroxylase activity in downstream signalling of HCC tumorgenesis and, specifically, metastasis development. Over-expression of wild-type ASPH, but not a hydroxylase mutant, promoted HCC cell migration in vitro, as well as intrahepatic and distant metastases in vivo. The enhanced migration and epithelial to mesenchymal transition (EMT) activation was notably absent in response to hydroxylase activity blockade. Vimentin, a regulator of EMT, interacted with ASPH and likely mediated the effect of ASPH hydroxylase activity with cell migration. The enhanced hydroxylase activity in tumor tissues predicted worse prognoses of HCC patients. Collectively, the hydroxylase activity of ASPH affected HCC metastasis through interacting with vimentin and regulating EMT. As such, ASPH might be a promising therapeutic target of HCC.

Keywords: ASPH; Epithelial-mesenchymal transition; Hepatocellular carcinoma; Hydroxylase; Metastasis; Vimentin.

MeSH terms

Calcium-Binding Proteins / metabolism*
Carcinoma, Hepatocellular / enzymology*
Carcinoma, Hepatocellular / pathology
Cell Line, Tumor
Epithelial-Mesenchymal Transition
HEK293 Cells
Humans
Liver Neoplasms / enzymology*
Liver Neoplasms / pathology
Membrane Proteins / metabolism*
Mixed Function Oxygenases / metabolism*
Muscle Proteins / metabolism*
Neoplasm Metastasis
Neoplasm Proteins / metabolism*

Substances

Calcium-Binding Proteins
Membrane Proteins
Muscle Proteins
Neoplasm Proteins
Mixed Function Oxygenases
ASPH protein, human

Grants and funding

P30 CA016058/CA/NCI NIH HHS/United States