Analysis of p27 responsive gene as a novel molecular therapeutic target

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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.