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A REIC gene shows down-regulation in human immortalized cells and human tumor-derived cell lines
T Tsuji1, M Miyazaki, M Sakaguchi
1Department of Cell Biology, Institute of Molecular and Cellular Biology, Okayama University Medical School, Shikata-cho 2-5-1, Okayama, 700-8558, Japan.
Abstract:
Normal human cells stop proliferation after a certain number of cell divisions. This phenomenon is called cellular aging. The fact that the senescence phenotype is dominant and the immortal one is recessive indicates that immortalization of human cells may be caused by loss of functions of certain genes in normal cells. Based on this evidence, several cDNA clones whose expression was down-regulated during the immortalization process of human cells were isolated by the representative difference analysis (RDA) system in our laboratory. One of them, which was named REIC, was expressed to a lower degree in three human immortalized cell lines as compared with their parental normal counterparts. In addition, the expression of REIC was markedly lower in eight human tumor-derived cell lines (Hep3B and HuH-7 hepatocellular carcinomas, HuH-6 Clone 5 hepatoblastoma, HuCCT-1 cholangiocarcinoma, A549 lung cancer, HaCaT immortalized keratinocyte, HeLa cervical carcinoma, and Saos-2 osteosarcoma). In contrast, among the human tissues examined, the heart and brain, which contain a large number of post-mitotic cells, showed the highest expression of REIC. The full-length REIC cDNA revealed that the predicted protein is 350 amino acids in length and possesses coiled-coil tertiary structures in each of the amino- and carboxyl-termini. Furthermore, a search of the protein database revealed a match of this gene product with Dkk-3, which is a novel inhibitor of Wnt oncogene. These results indicate that the REIC cloned by us may function as a tumor suppressor.
Insights
Researchers identified REIC, a gene downregulated during cellular aging and cancer. REIC, also known as Dkk-3, shows higher expression in heart and brain tissues, suggesting its role as a potential tumor suppressor.
Area of Science:
- Molecular Biology
- Cell Biology
- Oncology
Background:
- Cellular aging, or senescence, limits normal human cell proliferation.
- Immortalization of cells involves recessive genetic changes, suggesting loss-of-function mutations.
Purpose of the Study:
- To identify genes downregulated during human cell immortalization.
- To investigate the function of the identified REIC gene in cellular aging and cancer.
Main Methods:
- Representative Difference Analysis (RDA) to isolate differentially expressed cDNA clones.
- Quantitative analysis of REIC gene expression in normal, immortalized, and tumor-derived cell lines.
- Bioinformatic analysis to identify the REIC gene product and its potential function.
Main Results:
- REIC expression was significantly lower in immortalized and tumor-derived cell lines compared to normal cells.
- REIC expression was highest in post-mitotic tissues like the heart and brain.
- REIC protein shares homology with Dickkopf-3 (Dkk-3), a Wnt pathway inhibitor.
Conclusions:
- REIC (Dkk-3) expression is reduced during cellular immortalization and tumorigenesis.
- REIC may function as a tumor suppressor by inhibiting the Wnt oncogene pathway.
- REIC's expression pattern suggests a role in maintaining cellular homeostasis in non-proliferating tissues.