Roles of luteinizing hormone/chorionic gonadotropin receptor in anchorage-dependent and -independent growth in human ovarian surface epithelial cell lines.
Epithelial ovarian carcinomas are thought to arise from cells of ovarian surface epithelium (OSE) covering the free surface of the human ovary. Two immortalized human cell lines, OSE2a (non-tumorigenic) and OSE2b-2 (tumorigenic), were previously established from normal OSE cells of a reproductive-age patient. In the present study, we found that expression of luteinizing hormone (LH)/chorionic gonadotropin (CG) receptor (LH/CGR) is present in OSE2a cells and absent in OSE2b-2 cells. In OSE2a cells, a low concentration (10(3) mIU/ml) of CG enhanced anchorage-dependent growth via up-regulation of insulin-like growth factor-1 (IGF1), whereas a high concentration (10(5) mIU/ml) of CG induced anchorage-independent growth and down-regulation of IGF1 expression. To investigate involvement of other genes in LH/CGR-related tumorigenicity, we compared cDNA expression arrays of OSE2a and OSE2b-2 cells, and found that the following genes had lower expression in OSE2b-2 than in OSE2a: integrin beta 1, intercellular adhesion molecule-1 (ICAM1), and Waf1/Cip1. Subsequent semiquantitative reverse transcription polymerase chain reaction using OSE2a cells showed that expression of integrin beta 1 was down-regulated by a high concentration (10(5) mIU/ml) of CG. These results suggest that LH/CGR affects anchorage-dependent and -independent growth by mediating up- and down-regulation of IGF1 and integrin beta 1. Repetitive and excessive activation of LH/CGR may cause genetic alteration of its signal transduction pathway, resulting in stimulation of growth of OSE cells, initiation of ovarian carcinogenesis, and cancer progression.
Tashiro
Hironori
H
Department of Obstetrics and Gynecology, Kumamoto University School of Medicine, Kumumoto City, Kumamoto 860-8556.
Katabuchi
Hidetaka
H
Begum
Monjura
M
Li
Xiaoguang
X
Nitta
Makoto
M
Ohtake
Hideyuki
H
Okamura
Hitoshi
H
D002448:Cell Adhesion; D002455:Cell Division; D002478:Cells, Cultured / Q000187:drug effects; D006063:Chorionic Gonadotropin / Q000494:pharmacology*; D003114:Colony-Forming Units Assay; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D007986:Luteinizing Hormone / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D010053:Ovary / Q000187:drug effects*; D011974:Receptors, LH / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
C493956:CDKN1A protein, human; D006063:Chorionic Gonadotropin; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D019012:Integrin beta1; D011974:Receptors, LH; D018799:Intercellular Adhesion Molecule-1; D007334:Insulin-Like Growth Factor I; D007986:Luteinizing Hormone