Loss of PHLPP expression in colon cancer: role in proliferation and tumorigenesis (original) (raw)

• Original Article
• Published: 15 December 2008

Oncogene volume 28, pages 994–1004 (2009)Cite this article

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Abstract

PHLPP (PH domain leucine-rich repeats protein phosphatase) represents a family of novel Ser/Thr protein phosphatases. Two highly related isoforms in this family, PHLPP1 and PHLPP2, have been identified to serve as negative regulators of Akt and protein kinase C by dephosphorylating the kinases directly. In this study, we examined the expression pattern of both PHLPP isoforms in colorectal cancer specimens and the adjacent normal mucosa using immunohistochemical staining. We found that the expression of PHLPP1 or PHLPP2 isoform was lost or decreased in 78 and 86% of tumor tissues, respectively. Stable overexpression of either PHLPP isoform in colon cancer cells decreased the rate of cell proliferation and sensitized the cells to growth inhibition induced by the phosphoinositide-3 kinase inhibitor, LY294002, whereas knockdown of either PHLPP isoform by shRNA promoted the proliferation of DLD1 cells. In addition, we demonstrated that the PHLPP-mediated growth inhibition in colon cancer cells was largely rescued by overexpression of a constitutively active Akt. Moreover, reexpression of either PHLPP isoform in HCT116 cells inhibited tumor growth in vivo. Taken together, our results strongly support a tumor suppressor role of PHLPP in colon cancer.

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Acknowledgements

We thank UTMB flow cytometry core for assistance with the flow cytometry analysis, and Dr Alexandra Newton at University of California San Diego for providing the wild-type and mutant Akt and PKC βII expression constructs. This work was supported by NIH K01 CA10209-05 (TG), American Cancer Society RSG0822001TBE (TG) and R01CA104748 (BME).

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Authors and Affiliations

1. Department of Biochemistry and Molecular Biology, West China Medical School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, Sichuan, PR China
   J Liu
2. Sealy Center for Cancer Cell Biology, University of Texas Medical Branch, Galveston, TX, USA
   J Liu, H L Weiss, B M Evers & T Gao
3. Department of Preventive Medicine and Community Health, University of Texas Medical Branch, Galveston, TX, USA
   H L Weiss
4. Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA
   P Rychahou, L N Jackson & B M Evers
5. Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA
   T Gao

Authors

1. J Liu
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2. H L Weiss
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3. P Rychahou
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4. L N Jackson
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5. B M Evers
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6. T Gao
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Corresponding author

Correspondence toT Gao.

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Liu, J., Weiss, H., Rychahou, P. et al. Loss of PHLPP expression in colon cancer: role in proliferation and tumorigenesis.Oncogene 28, 994–1004 (2009). https://doi.org/10.1038/onc.2008.450

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• Received: 16 July 2008
• Revised: 30 September 2008
• Accepted: 01 November 2008
• Published: 15 December 2008
• Issue Date: 19 February 2009
• DOI: https://doi.org/10.1038/onc.2008.450

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