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Updated: Jun 27, 2026
In vitro Organoid Culture of Primary Mouse Colon Tumors
Published on: May 17, 2013
Loss of PHLPP expression in colon cancer: role in proliferation and tumorigenesis
1Department of Biochemistry and Molecular Biology, West China Medical School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, Sichuan, PR China.
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.
Insights
PHLPP1 and PHLPP2 phosphatases are frequently lost in colorectal cancer. Restoring PHLPP levels suppresses colon cancer cell growth and tumor formation, indicating a tumor suppressor role.
Area of Science:
- Molecular Biology
- Oncology
- Biochemistry
Background:
- PHLPP (PH domain leucine-rich repeats protein phosphatase) is a novel Ser/Thr protein phosphatase family.
- PHLPP1 and PHLPP2 isoforms directly dephosphorylate and negatively regulate Akt and protein kinase C.
- Dysregulation of Akt signaling is implicated in various cancers, including colorectal cancer.
Purpose of the Study:
- To investigate the expression patterns of PHLPP1 and PHLPP2 in colorectal cancer.
- To determine the functional role of PHLPP isoforms in colon cancer cell proliferation and tumor growth.
Main Methods:
- Immunohistochemical staining of colorectal cancer tissues and adjacent normal mucosa.
- In vitro studies involving stable overexpression and shRNA-mediated knockdown of PHLPP isoforms in colon cancer cell lines.
- Assessment of cell proliferation, sensitivity to PI3K inhibitor LY294002, and Akt signaling pathway modulation.
- In vivo tumor growth assays in HCT116 cells with reexpressed PHLPP isoforms.
Main Results:
- Loss or decreased expression of PHLPP1 and PHLPP2 was observed in 78% and 86% of colorectal tumors, respectively.
- Overexpression of PHLPP1 or PHLPP2 reduced colon cancer cell proliferation and enhanced sensitivity to LY294002.
- Knockdown of PHLPP isoforms promoted DLD1 cell proliferation.
- PHLPP-mediated growth inhibition was reversed by active Akt.
- Reexpression of PHLPP isoforms inhibited tumor growth in vivo.
Conclusions:
- PHLPP1 and PHLPP2 exhibit significantly reduced expression in colorectal cancer.
- PHLPP isoforms act as tumor suppressors in colon cancer by inhibiting cell proliferation and tumor growth.
- PHLPP-mediated tumor suppression involves the Akt signaling pathway.
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