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Up-regulation of GPR48 Induced by Down-regulation of p27^Kip1 Enhances Carcinoma Cell Invasiveness and Metastasis

Departments of ¹ Biochemistry 1 and ² Endoscopic and Photodynamic Medicine, ³ Second Department of Surgery, and ⁴ Oral and Maxillofacial Surgery, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan; ⁵ Division of Developmental Genetics, Center for Translational and Advanced Animal Research on Human Diseases, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan; and ⁶ Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Higashi-ku, Fukuoka, Japan

Requests for reprints: Masatoshi Kitagawa, Department of Biochemistry 1, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Japan. Phone: 81-53-435-2322; Fax: 81-53-435-2322; E-mail: kitamasa{at}hama-med.ac.jp.

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. (Cancer Res 2006; 66(24): 11623-31)

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