Liu J, Weiss H L, Rychahou P, Jackson L N, Evers B M, Gao T
Department of Biochemistry and Molecular Biology, West China Medical School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, Sichuan, PR China.
Oncogene. 2009 Feb 19;28(7):994-1004. doi: 10.1038/onc.2008.450. Epub 2008 Dec 15.
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.
PHLPP（含PH结构域富亮氨酸重复蛋白磷酸酶）代表一类新型的丝氨酸/苏氨酸蛋白磷酸酶。该家族中有两种高度相关的亚型，即PHLPP1和PHLPP2，已被确定可通过直接使激酶去磷酸化而作为Akt和蛋白激酶C的负调节因子。在本研究中，我们使用免疫组织化学染色检测了PHLPP两种亚型在结直肠癌标本及相邻正常黏膜中的表达模式。我们发现，在78%和86%的肿瘤组织中，PHLPP1或PHLPP2亚型的表达分别缺失或降低。在结肠癌细胞中稳定过表达任一PHLPP亚型均可降低细胞增殖速率，并使细胞对磷酸肌醇-3激酶抑制剂LY294002诱导的生长抑制敏感，而通过短发夹RNA敲低任一PHLPP亚型则可促进DLD1细胞的增殖。此外，我们证明，组成型活性Akt的过表达在很大程度上挽救了PHLPP介导的结肠癌细胞生长抑制。而且，在HCT116细胞中重新表达任一PHLPP亚型均可在体内抑制肿瘤生长。综上所述，我们的结果有力地支持了PHLPP在结肠癌中发挥肿瘤抑制作用。
