Abstract
βKlotho is a regulator in multiple metabolic processes, while its role in cancer remains unclear. We found the expression of βKlotho was down-regulated in human hepatocellular carcinoma tissues compared with that in paired adjacent non-tumourous liver tissues. Hepatoma cells also showed decreased expression of βKlotho compared with normal hepatocyte cells. Reintroduction of βKlotho into hepatoma cells inhibited their proliferation. The anti-proliferative effect of βKlotho might be linked with G1 to S phase arrest, which was mediated by Akt/GSK-3β/cyclin D1 signaling, since forced expression βKlotho reduced the phosphorylation level of Akt and GSK-3β and induced down-regulation of cyclin D1. Furthermore, βKlotho overexpression could inhibit tumorgenesis, while constitutively activated Akt could override the suppressive effects of βKlotho in vivo. These data suggest βKlotho suppresses tumor growth in hepatocellular carcinoma.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Aged
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Animals
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Carcinoma, Hepatocellular / genetics
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Carcinoma, Hepatocellular / metabolism*
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Carcinoma, Hepatocellular / pathology
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Cell Cycle Checkpoints / genetics
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Cell Line, Tumor
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Cell Proliferation
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Cyclin D1 / genetics
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Cyclin D1 / metabolism*
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Disease Models, Animal
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Female
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Gene Expression Regulation, Neoplastic
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Glucuronidase / genetics
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Glucuronidase / metabolism*
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Glycogen Synthase Kinase 3 / metabolism*
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Glycogen Synthase Kinase 3 beta
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Humans
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Klotho Proteins
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Liver Neoplasms / genetics
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Liver Neoplasms / metabolism*
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Liver Neoplasms / pathology
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Male
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Mice
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Middle Aged
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Proto-Oncogene Proteins c-akt / metabolism*
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Signal Transduction*
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Transplantation, Heterologous
Substances
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Cyclin D1
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GSK3B protein, human
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Glycogen Synthase Kinase 3 beta
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Gsk3b protein, mouse
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Proto-Oncogene Proteins c-akt
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Glycogen Synthase Kinase 3
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Glucuronidase
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Klotho Proteins
Grants and funding
This work was supported by grants from National Basic Research Program of China (973 Program, 2009CB522404,
http://www.973.gov.cn/), National Natural Science Foundation of China (30972915, 81170451 and U0932006,
http://www.nsfc.gov.cn), Science and Technology Planning Project of Guangdong Province (2011B031300016,
http://pro.gdstc.gov.cn) and Specialized Research Fund for the Doctoral Program of Higher Education (20110171120091,
http://www.cutech.edu.cn). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.