Up-regulation of GPR48 induced by down-regulation of p27Kip1 enhances carcinoma cell invasiveness and metastasis.
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.
Gao
Yun
Y
Department of Biochemistry 1, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.
Kitagawa
Kyoko
K
Hiramatsu
Yoshihiro
Y
Kikuchi
Hirotoshi
H
Isobe
Tomoyasu
T
Shimada
Mai
M
Uchida
Chiharu
C
Hattori
Takayuki
T
Oda
Toshiaki
T
Nakayama
Keiko
K
Nakayama
Keiichi I
KI
Tanaka
Tatsuo
T
Konno
Hiroyuki
H
Kitagawa
Masatoshi
M
D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms; D050760:Cyclin-Dependent Kinase Inhibitor p27; D017931:DNA Primers; D005347:Fibroblasts / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008156:Luciferases / Q000235:genetics; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics*; D009362:Neoplasm Metastasis / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics; D034622:RNA Interference; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
C436291:CDKN1B protein, human; D017931:DNA Primers; D047908:Intracellular Signaling Peptides and Proteins; C411562:LGR4 protein, human; D018809:Proliferating Cell Nuclear Antigen; D043562:Receptors, G-Protein-Coupled; C413374:p27 antigen; D050760:Cyclin-Dependent Kinase Inhibitor p27; D008156:Luciferases