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The role of growth regulatory aberrations in progression of human colon carcinoma

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Summary

Colon carcinoma is a multistage disease. Most malignancies arise from pre-existing benign tumors. Multiple chromosomal defects affecting oncogene and tumor suppressor gene function are associated with disease progression. These aberrations result in an imbalance between the normal positive and negative growth effectors, which contribute further to disease progression. We have studied how changes in the expression of TGFα and TGFβ affect colon carcinoma cell behavior. Overexpression of the stimulatory factor TGFα in a relatively benign cell line with weak TGFα autocrine activity converted the cell type to an aggressive, progressed phenotypein vivo andin vitro. In contrast, disruption of TGFα expression by constitutive expression of TGFα antisense RNA in a progressed cell line with a strong, internalized autocrine loop resulted in the development of clones with decreased tumorigenicityin vitro andin vivo. Suppression of the inhibitory effects of TGFβ by constitutive expression of TGFβ antisense RNA increased the tumorigenicity of the cell linesin vitro andin vivo. None of these alterations in TGFα or TGFβ expression affected the doubling time of the cells. The changes in tumorigenicity were due to effects on the lag phase of growth. We conclude that TGFβ functions to maintain the cells in a quiescent state while TGFα drives reentry into the cell cycle. We have identified a unique cis-element that mediates TGFα autoregulation. The transcription factor binding this element is also involved in the cell-cycle regulation of TGFα expression. We hypothesize that this factor may be a convergent point TGFα and TGFβ interact in controlling movement into and out of quiescence.

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  1. Department of Biochemistry and Molecular Biology, Medical College of Ohio, P.O. Box 10008, 43699, Toledo, Ohio, USA

    Gillian M. Howell, LuZhe Sun, Barry L. Ziober, Shao Ping Wu & Michael G. Brattain

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  1. Gillian M. Howell
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  2. LuZhe Sun
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Howell, G.M., Sun, L., Ziober, B.L. et al. The role of growth regulatory aberrations in progression of human colon carcinoma. Cancer Metast Rev 12, 275–286 (1993). https://doi.org/10.1007/BF00665958

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