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Dinucleotide repeats negatively modulate the promoter activity of Cyr61 and is unstable in hepatocellular carcinoma patients

Oncogene volume 24, pages 3999–4008 (2005)Cite this article

Abstract

Cyr61 is a secreted, cysteine-rich, heparin-binding protein that mediates diverse functions including extracellular matrix formation, differentiation, cell proliferation, adhesion, migration, survival, as well as angiogenesis and tumorigenesis. In this study, we found that Cyr61 gene expression is significantly downregulated in the tumors of hepatocellular carcinoma (HCC) patients. To elucidate its mechanism of gene regulation, we examined the promoter of Cyr61 which contains two long stretches of repeats, each comprising d(CA) dinucleotide repeats downstream of HNF3β- and ATF-binding sites. We hypothesized that the d(CA) repeats may play an important role in regulating Cyr61 promoter activity and performed promoter reporter assays to examine this. We found that a greater number of d(CA) repeats resulted in significantly lower promoter activity of the Cyr61 gene in the KB3-1 and HepG2 cell lines, but not in the MCF-7 cell line. In addition, the d(CA) repeats, but not other random sequences, were found to be important for Cyr61 promoter activity. We further demonstrate that the ATF- and HNF3β-binding sites upstream the d(CA) repeats positively and negatively modulate Cyr61 promoter activity, respectively. An examination of the d(CA) dinucleotide patterns in the Cyr61 promoter in HCC patients revealed that ∼32% of these patients exhibited either loss of heterozygosity or somatic mosaicism in either the tumors, adjacent normal liver tissues or both.

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Acknowledgements

This work is supported by block grants from the National Medical Research Council, Singapore and the SingHealth Cluster Research Fund through the National Cancer Center to CGL Lee and an academic research grant from the National University of Singapore to CGL Lee.

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Authors and Affiliations

  1. Department of Biochemistry, National University of Singapore, Singapore

    Baoshuang Wang & Caroline G L Lee

  2. Division of Medical Sciences, National Cancer Center, Singapore

    Jianwei Ren & Caroline G L Lee

  3. Department of Surgical Oncology, National Cancer Center, Singapore

    London L P J Ooi

  4. Department of Surgery, Singapore General Hospital, Singapore

    London L P J Ooi

  5. Department of Pediatrics and Obstetrics & Gynecology, National University of Singapore, Singapore

    Samuel S Chong

  6. Departments of Pediatrics and Gynecology & Obstetrics, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Samuel S Chong

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  1. Baoshuang Wang
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Correspondence to Caroline G L Lee.

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Wang, B., Ren, J., Ooi, L. et al. Dinucleotide repeats negatively modulate the promoter activity of Cyr61 and is unstable in hepatocellular carcinoma patients. Oncogene 24, 3999–4008 (2005). https://doi.org/10.1038/sj.onc.1208550

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