Abstract
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 G protein-coupled receptor 48 (GPR48) 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 GPR48 by RNA interference reduced the invasive potential of HeLa and Lewis lung carcinoma cells not only in vitro but also in vivo. Moreover, GPR48 expression was significantly associated with lymph node metastasis and inversely correlated with p27 expression in human colon carcinomas. GPR48 may thus play an important role in invasiveness and metastasis of carcinoma and might therefore represent a potential prognostic marker or therapeutic target.
Highlights
Metastasis is a major clinical determinant of the poor prognosis of various human cancers
The amount of Skp2 mRNA was directly correlated with that of G protein–coupled receptor 48 (GPR48) mRNA in the tumor samples (Fig. 6D, bottom). These results indicated that GPR48 expression was significantly associated with lymph node metastasis and inversely correlated with p27 expression in human colon carcinomas
Pathologic studies have revealed that the abundance of p27 in tumors is inversely correlated with malignancy and is associated with clinical prognosis of human cancers [9]
Summary
Metastasis is a major clinical determinant of the poor prognosis of various human cancers. The expression of a cyclin-dependent kinase (CDK) inhibitor p27Kip (hereafter p27) is reduced in many types of human cancer, including breast [1, 2] and colorectal [3] carcinomas, and it is inversely related to tumor aggressiveness and directly associated with prognosis in individuals with such cancers [4]. Degradation of p27 results in the activation of G1 cyclin-CDK complexes and consequent promotion of cell cycle progression from G1 to S phase. Expression of Skp is increased in certain transformed cell lines and various types of human cancer [10]. Such increased expression of Skp may enhance the degradation of p27 and thereby promote cell cycle progression. We found that expression of the gene for G protein–coupled receptor 48 (GPR48) was increased in the p27+/À cells
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