title: Severe suppression of Frzb/sFRP3 transcription in osteogenic sarcoma.
abstract: Deciphering the molecular basis of cancer is critical for developing novel diagnostic and therapeutic strategies. To better understand the early molecular events involving osteogenic sarcoma (OGS), we have initiated a program to identify potential tumor suppressor genes. Expression profiling of total RNA from ten normal bone cell lines and eleven OGS-derived cell lines by microarray showed 135-fold lower expression of FRZB/sFRP3 mRNA in OGS cells compared to bone cells; this down-regulation of Frzb/sFRP3 mRNA expression was found to be serum-independent. Subsequently, fourteen OGS biopsy specimens showed nine-fold down-regulation of Frzb/sFRP3 mRNA expression compared to expression in eight normal bone specimens as determined by microarray. FRZB /sFRP3 protein level was also found to be at a very low level in 4/4 OGS cell lines examined. Quantitation by RT-PCR indicated approximately 70% and approximately 90% loss of Frzb/sFRP3 mRNA expression in OGS biopsy specimens and OGS-derived cell lines respectively, compared to expression in bone (p<0.0001). Hybridization experiments of a cDNA microarray containing paired normal and tumor specimens from nineteen different organs did not show any significant difference in the level of Frzb/sFRP3 mRNA expression between the normal and the corresponding tumor tissues. Exogenous expression of FRZB/sFRP3 mRNA in two OGS-derived cell lines lacking endogenous expression of the mRNA produced abundant mRNA from the exogenous gene, eliminating degradation as a possibility for very low level of FRZB/sFRP3 mRNA in OGS specimens. Results from PCR-based experiments suggest that the FRZB/sFRP3 gene is not deleted in OGS cell lines, however, karyotyping shows gross abnormalities involving chromosome 2 (location of the FRZB gene) in five of twelve OGS-derived cell lines. Together, these data suggest a tumor-suppressive potential for FRZB/sFRP3 in OGS.
authors.affiliation: Department of Orthopedic Research, Mayo Clinic and Foundation, 200 1st St. SW, Rochester, MN 55905, USA.
authors.forename: Deendayal
authors.initials: D
authors.lastname: Mandal
authors.forename: Alok
authors.initials: A
authors.lastname: Srivastava
authors.forename: Eric
authors.initials: E
authors.lastname: Mahlum
authors.forename: Dinakar
authors.initials: D
authors.lastname: Desai
authors.forename: Avudaiappan
authors.initials: A
authors.lastname: Maran
authors.forename: Michael
authors.initials: M
authors.lastname: Yaszemski
authors.forename: Syed M
authors.initials: SM
authors.lastname: Jalal
authors.forename: Steven
authors.initials: S
authors.lastname: Gitelis
authors.forename: Franco
authors.initials: F
authors.lastname: Bertoni
authors.forename: Tim
authors.initials: T
authors.lastname: Damron
authors.forename: Ronald
authors.initials: R
authors.lastname: Irwin
authors.forename: Mary
authors.initials: M
authors.lastname: O'connor
authors.forename: Herbert
authors.initials: H
authors.lastname: Schwartz
authors.forename: Mark E
authors.initials: ME
authors.lastname: Bolander
authors.forename: Gobinda
authors.initials: G
authors.lastname: Sarkar
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D001859:Bone Neoplasms / Q000235:genetics* / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006023:Glycoproteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D012516:Osteosarcoma / Q000235:genetics* / Q000378:metabolism; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology*; D000099274:Frizzled-Related Proteins; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D006023:Glycoproteins; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D011506:Proteins; D000099274:Frizzled-Related Proteins; D000094742:Secreted Frizzled-Related Proteins; C455624:MYOZ3 protein, human