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RRM1-induced metastasis suppression through PTEN-regulated pathways

Oncogene volume 22, pages 2135–2142 (2003)Cite this article

Abstract

Lung cancer is the leading cause of cancer-related mortality in the United States. Only 15% of patients with this disease survive 5 years or longer. Early metastatic spread is the single most important reason for this poor outcome. The survival of patients with pathological stage I disease, that is, no evidence for metastatic spread, and molecular aberrations on chromosome 11p15.5 is equal to that of patients with stage II disease, that is, metastatic spread to hilar lymph nodes. RRM1 is a gene in this region, and it is haploinsufficient in at least 34% stage I patients. Here, we show that overexpression of RRM1 in human and mouse lung cancer cell lines induced PTEN expression, reduced phosphorylation of focal adhesion kinase (FAK), suppressed migration, invasion, and metastasis formation, and increased survival in an animal model. Increased PTEN expression was required for the RRM1-induced suppression of cell motility and FAK phosphorylation. We conclude that RRM1 functions as a metastasis suppressor gene through induction of PTEN expression.

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Acknowledgements

We thank Dr Norma Nowak, Dr Lesleyann Hawthorn, Julie Hughes, and Devin McQaid from the Roswell Park Cancer Institute Microarray Core facility for their help with the conduct of the oligonucleotide and cDNA microarray experiments. We are also grateful to Amy Beck, Sandy Livingston, and Mary Vaughan for technical assistance, to Dr Harry Slokum for help with the chemosensitivity assays, and to Dr Alan Cantor for statistical support. This research was supported in part by Grants R01-CA70317 and P30-CA16056 from the National Cancer Institute.

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  1. Contributed equally to this work

Authors and Affiliations

  1. Lung Cancer Program, Roswell Park Cancer Institute, Buffalo, New York, NY, USA

    Ashish Gautam, Zhan-Rong Li & Gerold Bepler

  2. Thoracic Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    Ashish Gautam & Gerold Bepler

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  1. Ashish Gautam
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Correspondence to Gerold Bepler.

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Gautam, A., Li, ZR. & Bepler, G. RRM1-induced metastasis suppression through PTEN-regulated pathways. Oncogene 22, 2135–2142 (2003). https://doi.org/10.1038/sj.onc.1206232

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