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Downregulation of tumor suppressor Pdcd4 promotes invasion and activates both β-catenin/Tcf and AP-1-dependent transcription in colon carcinoma cells

Oncogene volume 27, pages 1527–1535 (2008)Cite this article

Abstract

Programmed cell death 4 (Pdcd4) is a tumor suppressor that inhibits neoplastic transformation and tumor invasion. Tissue microarray analysis showed that Pdcd4 expression is downregulated in colon adenocarcinoma and carcinoma relative to adjacent normal tissues. To address the issue of whether reduced Pdcd4 expression is sufficient to promote tumor progression, we knocked down Pdcd4 expression in colon tumor HT29 cells using pdcd4 short hairpin RNA (shRNA). Pdcd4 knockdown results in a fibroblast-like transition, while the control cells (expressing LacZ shRNA) remain as clumped similar to the parental cells. In addition, expression of pdcd4 shRNA in HT29 cells promotes invasion. In an effort to characterize the molecular mechanism underlying these observations, we discovered that knockdown of Pdcd4 results in reduction of E-cadherin expression, and accumulation of active β-catenin in the nucleus. The active β-catenin binds with T-cell factor 4 (Tcf4) and activates β-catenin/Tcf-dependent transcription. Furthermore, Pdcd4 knockdown dramatically increases AP-1-dependent transcription. Thus, the mechanism by which reduced Pdcd4 expression promotes invasion appears to involve the activation of β-catenin/Tcf and AP-1-dependent transcription.

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Acknowledgements

We thank Drs Eun Lee (University of Kentucky) for examination of immunohistochemical staining of Pdcd4 in colon tissues, Mary Vore (University of Kentucky) and Chou-Chi Li (SAIC-Frederick) for reading the article and helpful comments.

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  1. Z Sun

    Present address: 3Present address: School of Chinese Pharmacy, Beijing University of Chinese Medicine, 6 Wangjing Zhonghuan Nanlu, Beijing 100102, PR China,

Authors and Affiliations

  1. Graduate Center for Toxicology, College of Medicine, University of Kentucky, Lexington, KY, USA

    Q Wang, Z Sun & H-S Yang

  2. Markey Cancer Center, College of Medicine, University of Kentucky, Lexington, KY, USA

    H-S Yang

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  1. Q Wang
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Correspondence to H-S Yang.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Wang, Q., Sun, Z. & Yang, HS. Downregulation of tumor suppressor Pdcd4 promotes invasion and activates both β-catenin/Tcf and AP-1-dependent transcription in colon carcinoma cells. Oncogene 27, 1527–1535 (2008). https://doi.org/10.1038/sj.onc.1210793

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