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Originally published In Press as doi:10.1074/mcp.M300094-MCP200 on October 30, 2003.
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Molecular & Cellular Proteomics 3:73-81, 2004.
© 2004 by The American Society for Biochemistry and Molecular Biology, Inc.

Research

From Proteomic Analysis to Clinical Significance

Overexpression of Cytokeratin 19 Correlates with Hepatocellular Carcinoma Metastasis *

Shi-Jian Ding{ddagger},§, Yan Li§,¶, Ye-Xiong Tan§,||, Man-Rong Jiang{ddagger}, Bo Tian, Ying-Kun Liu, Xiao-Xia Shao{ddagger}, Sheng-Long Ye, Jia-Rui Wu{ddagger}, Rong Zeng{ddagger}, Hong-Yang Wang||,**, Zhao-You Tang,** and Qi-Chang Xia{ddagger},**

From the {ddagger} Research Center for Proteome Analysis, Key Laboratory of Proteomics, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, CAS, Shanghai 200031, People’s Republic of China; Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, People’s Republic of China; and || Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, People’s Republic of China

To better understand the mechanism underlying the hepatocellular carcinoma (HCC) metastasis and to search potential markers for HCC prognosis, differential proteomic analysis on two well-established HCC cell strains with high and low metastatic potentials, MHCC97-H and MHCC97-L, was conducted using two-dimensional gel electrophoresis followed by matrix-assisted laser desorption/time-of-flight mass spectrometry. Cytokeratin 19 (CK19) was identified and found to be overexpressed in MHCC97-H as compared with MHCC97-L. This result was further confirmed by two-dimensional Western blot analysis and immunofluorescence assay. Furthermore, one-dimensional Western blot analysis showed consistently increased CK19 expression in progressively more metastatic cells. Immunohistochemical study on 102 human HCC specimens revealed that more patients in the CK19-positive group had overt intrahepatic metastases (satellite nodules, p < 0.05; vascular tumor emboli, p < 0.001; tumor node metastatis staging, p < 0.001). CK19 fragment CYFRA 21-1 levels measured in sera from nude mice model of human HCC metastasis with radioimmunoassay increased in parallel with tumor progression and rose remarkably when pulmonary metastases occurred. The results demonstrated that overexpression of CK19 in HCC cells is related to metastatic behavior. Serum CK19 level might reflect the pathological progression in some HCC and may be a useful marker for predicting tumor metastasis and a therapeutic target for the treatment of HCC patients with metastases.

§ S.-J. D., Y. L., and Y.-X. T. contributed equally to this paper

** To whom correspondence should be addressed: Qi-Chang Xia, Shanghai Institute of Biochemistry and Cell Biology, Yueyang Road, Shanghai 200031, China. Tel.: 86-21-54920160; Fax: 86-21-54920171; E-mail: xiaqc{at}sibs.ac.cn; Hong-Yang Wang, Eastern Hepatobiliary Surgery Hospital, No. 225, Changhai Road, Shanghai 200438, China. Tel.: 86-21-25070856; Fax: 86-21-65566851; E-mail: hywangk{at}online.sh.cn; or Zhao-You Tang, Liver Cancer Institute & Zhongshan Hospital of Fudan University, 136 Yixueyuan Road, Shanghai 200032, China. Tel.: 86-21-64037181; Fax: 86-21-64037181; E-mail: zytang{at}scrap.stc.sh.cn


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