Loss of PHLPP expression in colon cancer: role in proliferation and tumorigenesis.
Loss of PHLPP expression in colon cancer: role in proliferation and tumorigenesis.
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DOI：
10.1038/onc.2008.450
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发表时间：
2009-02-19
期刊：
影响因子：
8
通讯作者：
Gao, T.
中科院分区：
文献类型：
--
作者：
Liu, J.;Weiss, H. L.;Rychahou, P.;Jackson, L. N.;Evers, B. M.;Gao, T.
PHLPP（PH结构域富含亮氨酸重复序列蛋白磷酸酶）是一类新型的丝氨酸/苏氨酸蛋白磷酸酶家族。该家族中两个高度相关的异构体PHLPP1和PHLPP2已被确定通过直接使激酶去磷酸化而作为Akt和蛋白激酶C（PKC）的负调节因子。在本研究中，我们利用免疫组织化学（IHC）染色检测了PHLPP两种异构体在结直肠癌标本及相邻正常黏膜中的表达模式。我们发现PHLPP1或PHLPP2异构体在78%和86%的肿瘤组织中表达缺失或降低。在结肠癌细胞中稳定过表达任何一种PHLPP异构体都会降低细胞增殖速率，并使细胞对磷脂酰肌醇 - 3 - 激酶（PI3K）抑制剂LY294002诱导的生长抑制更加敏感，而通过shRNA敲低任何一种PHLPP异构体则促进了DLD1细胞的增殖。此外，我们证明在结肠癌细胞中PHLPP介导的生长抑制在很大程度上可通过组成型激活的Akt的过表达来挽救。而且，在HCT116细胞中重新表达任何一种PHLPP异构体都会抑制体内肿瘤生长。综上所述，我们的结果有力地支持了PHLPP在结肠癌中的肿瘤抑制作用。
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 (PKC) 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 (IHC) 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 (PI3K) 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, re-expression 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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