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Inactivation of RASSF1C during in vivo tumor growth identifies it as a tumor suppressor gene

Oncogene volume 23, pages 5941–5949 (2004)Cite this article

Abstract

RASSF1A, a major member of the RASSF1 gene family, is silenced by promoter methylation at a high frequency in a large number of human solid tumors. Controlled expression of RASSF1A reverts the tumorigenic phenotype of several human cancer cell lines. Here we investigated another main isoform, RASSF1C, and compared it with RASSF1A in the gene inactivation test (GIT), based on a tetracycline regulation system. In the small-cell lung cancer (SCLC) line U2020, only RASSF1A has shown growth inhibitory activity in vitro, while in the prostate cell line LNCaP and renal cell carcinoma (RCC) line KRC/Y both RASSF1A and RASSF1C showed similar (approximately 90%) suppressing activity in vitro. Both RASSF1C and RASSF1A suppressed the tumorigenicity of the KRC/Y RCC cell line in SCID mice. Mutations, deletions and loss of expression of RASSF1A and RASSF1C transgenes were identified in all 15 grown SCID tumors. In contrast, the mutant RASSF1A containing Cys65Arg and Val211Ala had reduced growth suppression activity both in vitro and in vivo and did not show any further changes in four grown SCID tumors. In addition, RASSF1C was shown to induce cell cycle arrest in KRC/Y cells. These results strongly imply that like RASSF1A the RASSF1C gene could serve a tumor suppressor function.

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Acknowledgements

We thank Ms Laura Geil for editing the manuscript. This work was supported by research grants from the Swedish Cancer Society, the Swedish Research Council, the Swedish Foundation for International Cooperation in Research and Higher Education (STINT), the Swedish Institute, the Royal Swedish Academy of Sciences, INTAS and Karolinska Institute. MIL was funded in toto with funds from the National Cancer Institute, National Institutes of Health, under Contract No. NO1-CO-56000. JDM was supported by Lung Cancer SPORE P50 CA70907, and CA71618.

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Author notes

  1. Jingfeng Li

    Present address: National Cancer Institute, Frederick, MD, 21702, USA

  2. Alexey Protopopov

    Present address: Dana-Farber Cancer Institute, M422, Boston, MA, 02115, USA

Authors and Affiliations

  1. Microbiology and Tumorbiology Center, Karolinska Institute, Stockholm, 171 77, Sweden

    Jingfeng Li, Fuli Wang, Alexey Protopopov, Alena Malyukova, Vladimir Kashuba, George Klein & Eugene Zabarovsky

  2. Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Kiev, 03143, Ukraine

    Vladimir Kashuba

  3. Hamon Center for Therapeutic Oncology, Research, University of Texas Southwestern Medical Center, Dallas, 75390, TX, USA

    John D Minna

  4. Cancer-Causing Genes Section, Laboratory of Immunobiology, Center for Cancer Research, National Cancer Institute, Frederick, 21702, MD, USA

    Michael I Lerman

  5. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991, Russia

    Eugene Zabarovsky

  6. Center for Genomics and Bioinformatics, Karolinska Institute, Stockholm, 171 77, Sweden

    Eugene Zabarovsky

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  1. Jingfeng Li
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  2. Fuli Wang
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Correspondence to Eugene Zabarovsky.

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Li, J., Wang, F., Protopopov, A. et al. Inactivation of RASSF1C during in vivo tumor growth identifies it as a tumor suppressor gene. Oncogene 23, 5941–5949 (2004). https://doi.org/10.1038/sj.onc.1207789

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