2005 Fiscal Year Final Research Report Summary
Molecular mechanisms of progression and metastasis of hepatocellular carcinoma and their application on diagnosis and therapy.
| Project/Area Number |
15390118
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Human pathology
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| Research Institution | Keio University |
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Principal Investigator |
SAKAMOTO Michiie Keio University, Department of Pathology, Professor, 医学部, 教授 (40221270)
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| Co-Investigator(Kenkyū-buntansha) |
HASHIGUTI Akinori Keio University, Department of Medicine, Instructor, 医学部, 助手 (50276218)
DU Wenlin Keio University, Department of Medicine, Instructor, 医学部, 助手 (90348798)
SHIBATA Rie Keio University, Department of Medicine, Instructor, 医学部, 助手 (00365230)
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| Project Period (FY) |
2003 – 2005
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| Keywords | Hepatocellular carcinoma / Multistep carcinogenesis / Early hepatocellular carcinoma / Hepatitis C virus / Gene expression profile / HSP70 / Intrahepatic metastasis / Cortactin |
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| Research Abstract |
We retrospectively analyzed the relationship between multistep and multicentric development of HCC and the type of underlying chronic liver disease in a total of 980 HCC nodules. Of the 980 nodules, 369 (37.7%) met the criteria of multistep HCC. Of the 664 patients, 177(26.7%) had multiple nodules that met the criteria of multicentric HCC. Both the incidences of multistep and multicentric HCC were significantly higher in HCV-Ab-positive cases than in HBs-Ag-positive cases.
We compared expression profiles among 7 early components and 7 progressed components of "nodule-in-nodule"-type HCC tissues. Of the approximately 12600 genes that were analyzed, a set of 95 genes provided a molecular signature that distinguished between early HCC components and their non-cancerous liver tissues, and a set of 92 genes distinguished between progressed and early HCC components. Of these genes, the most abundantly upregulated gene in early HCC components was heat-shock protein 70 (HSP70). Real-time quanti
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tative RT-PCR confirmed this finding. Further immunohistochemical examination of HSP70 revealed its significant overexpression in early HCC compared with precancerous lesions, and in progressed HCC compared with early HCC, and its usefulness for the molecular diagnosis of early HCC.
We compared expression profiles among 2 highly metastatic HCC cell lines and 3 nonmetastatic HCC cell lines using oligonucleotide array. Of the approximately 12600 genes that were analyzed, we identified 39 genes whose expression levels were significantly correlated with metastatic ability. Of these genes, we further investigated cortactin. First, we demonstrated that overexpression of cortactin in nonmetastatic HCC cell line increased cell motility and silencing of cortactin in metastatic HCC cell line reduced cell motility, and overexpression of cortactin in nonmetastatic HCC cell line resulted in metastasis in vivo. Furthermore immunohistochemical examination of cortactin in human HCC samples revealed its significant overexpression in HCC with intrahepatic metastasis compared with HCC without intrahepatic metastasis. Less
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