Analysis of p27 responsive gene as a novel molecular therapeutic target

在不同类型的癌症患者中，细胞周期蛋白依赖性激酶抑制物p27(Kip1)的表达水平降低与肿瘤恶性程度增加和预后不良有关。为了研究这种关系的基础，我们应用微阵列分析来筛选p27(+/-)和亲本(p27(+/+))人结肠癌细胞之间差异表达的基因。孤儿G蛋白偶联受体(PPAG4)基因在p27(+/-)细胞中表达增加。强制表达GPR48可增强HCT116细胞的体外侵袭活性和肺转移潜能。相反，通过RNA干扰去除内源性PPAG4不仅降低了HeLa和Lewis肺癌细胞的体外侵袭能力，也降低了体内的侵袭能力。PPAG4的表达与结肠癌的淋巴结转移显著相关，与p27的表达呈负相关。因此，PPAG4可能在肿瘤的侵袭和转移中发挥重要作用，因此可能是一个潜在的预后标志物或治疗靶点。

A reduced expression level of the cyclin-dependent kinase inhibitor p27 (Kip1) is associated with increased tumor malignancy and poor prognosis in individuals with various types of cancer. To investigate the basis for this relation, we applied microarray analysis to screen for genes differentially expressed between p27(+/-)and parental (p27(+/+)) HCT116 human colon carcinoma cells. Expression of the gene for orphan G protein-coupled receptor (PPAG4) was increased in the p27(+/-)cells. Forced expression of GPR48 increased both in vitro invasive activity and lung metastasis potency of HCT116 cells. In contrast, depletion of endogenous PPAG4 by RNA interference reduced the invasive potential of HeLa and Lewis lung carcinoma cells not only in vitro but also in vivo. Moreover, PPAG4 expression was significantly associated with lymph node metastasis and inversely correlated with p27 expression in human colon carcinomas. PPAG4 may thus play an important role in invasiveness and metastasis of carcinoma and might therefore represent a potential prognostic marker or therapeutic target.