Dickkopf-3/REIC functions as a suppressor gene of tumor growth.
To identify putative tumor suppressor genes in hepatocarcinogenesis, we combined the representational difference analysis and reverse northern blot identifying downregulated genes in human hepatoma tissues. One of them was Dkk-3/REIC. Dkk-3/REIC was downregulated in 11 out of the 20 human hepatoma tissues as compared to their counterparts of noncancerous liver tissues by northern blot analysis. It was also downregulated in 29 out of 48 human cancer samples including the kidney, urinary bladder, prostate, pancreas and lung cancers. Its gene product, Dkk-3/REIC, was found to be N-glycosylated and have two isoforms, the 55 kDa in the cytosol and 50 kDa secreted in the medium. Ectopic expression of Dkk-3/REIC in HeLa, Hep3B and Huh 7 cells led to suppression of cell growth, which was primarily attributable to induction of cell apoptosis. The suppression phenomenon was found to be cell-type related (most prominent in HeLa and least in Hep3B cells) and cell-density dependent (attenuated as the cell density increased). Transduction of Dkk-3/REIC into HeLa and Hep3B cells caused suppression on colony formation in vitro and reduced tumor growth rate in inoculated athymic nude mice. In conclusion, these data indicate that Dkk-3/REIC functions as a suppressor for human tumor growth.
Hsieh
Sen-Yung
SY
Liver Research Unit, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan. siming@adm.sgmh.org.tw
Hsieh
Pei-Shan
PS
Chiu
Cheng-Tang
CT
Chen
Wai-Ying
WY
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology*; D002455:Cell Division / Q000235:genetics; D045744:Cell Line, Tumor; D018925:Chemokines; D017931:DNA Primers; D016147:Genes, Tumor Suppressor; D006031:Glycosylation; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology*; D019656:Loss of Heterozygosity; D008969:Molecular Sequence Data; D011506:Proteins / Q000235:genetics* / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D018925:Chemokines; C498624:DKK3 protein, human; D017931:DNA Primers; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins