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Antiproliferative activity of REIC/Dkk-3 and its significant down-regulation in non-small-cell lung carcinomas
T Tsuji1, I Nozaki, M Miyazaki
1Department of Cell Biology, Okayama University Graduate School of Medicine and Dentistry, Shikata-cho 2-5-1, Okayama 700-8558, Japan. tsujit01@popmail.med.nyu.edu
Abstract:
We recently reported the cloning of the REIC/Dkk-3 gene, whose expression was shown to be down-regulated in many human immortalized and tumor-derived cell lines [T. Tsuji et al. (2000) Biochem. Biophys. Res. Commun. 268, 20-24]. In the present study, we demonstrated that expression of the exogenous REIC/Dkk-3 gene in tumor cells inhibited cell growth. Furthermore, the level of REIC/Dkk-3 mRNA in normal human cells was lowest in the late G(1) phase during the cell cycle. Then we found that the expression of REIC/Dkk-3 was significantly down-regulated in surgically resected non-small-cell lung carcinomas. We determined the REIC/Dkk-3 locus on chromosome 11p15, where loss of heterozygosity has frequently been observed in human tumors. These findings indicate that REIC/Dkk-3 may function as a tumor suppressor.
Insights
The REIC/Dkk-3 gene, found to be downregulated in tumors, inhibits tumor cell growth when introduced exogenously. Its low expression in normal cells during the G1 phase suggests a role in cell cycle regulation and tumor suppression.
Area of Science:
- Molecular Biology
- Cancer Genetics
Background:
- The REIC/Dkk-3 gene was previously cloned and found to be downregulated in immortalized and tumor-derived cell lines.
- Tumorigenesis is often associated with the downregulation of specific genes.
Purpose of the Study:
- To investigate the functional role of REIC/Dkk-3 in tumor cells.
- To determine the expression pattern of REIC/Dkk-3 during the normal human cell cycle.
- To assess the relevance of REIC/Dkk-3 in non-small-cell lung carcinomas.
Main Methods:
- Transfection of tumor cells with exogenous REIC/Dkk-3 gene.
- Quantitative analysis of REIC/Dkk-3 mRNA levels during the cell cycle.
- Analysis of REIC/Dkk-3 expression in non-small-cell lung cancer tissues.
- Chromosomal localization of the REIC/Dkk-3 gene.
Main Results:
- Exogenous REIC/Dkk-3 gene expression inhibited tumor cell growth.
- REIC/Dkk-3 mRNA levels were lowest in normal human cells during the late G(1) phase.
- REIC/Dkk-3 expression was significantly downregulated in non-small-cell lung carcinomas.
- The REIC/Dkk-3 gene maps to chromosome 11p15, a region frequently showing loss of heterozygosity in tumors.
Conclusions:
- REIC/Dkk-3 functions as a tumor suppressor gene.
- Downregulation of REIC/Dkk-3 may contribute to the development of non-small-cell lung cancer.
- REIC/Dkk-3 plays a role in regulating cell proliferation and the cell cycle.