Expression profiling of cellular process in uterine leiomyoma omic approaches and its correlation with molecular cytogenic analysis of the uterine leiomyosarcoma by array based-CGH

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This study utilized cDNA microarray, 2D protein gel electrophoresis and array-based comparative genomic hybridization (A-CGH) technology to investigate the multiple interactions of genes and proteins involved in uterine leiomyoma pathophysiology and carcinogenesis. The Gene Ontology (GO) analysis was also used to systematically characterize the global expression profiles and correlate with leiomyosarcoma. Uterine leiomyosarcoma biopsies were obtained from patient in the Oepartment of Obstetrics and Gynecology, The Catholic University of Korea. cDNA microarray was applied to multiple samples obtained from 6 uterine leiomyosarcomas. Screening by cDNA microarray up to 17,000 genes identified 71 genes (21 up-regulated and 50 down-regulated). The gene expression profiles were classified into mutually dependent 420 functional sets, resulting in 611 cellular processes according to the gene ontology. Also, protein analysis using 2D gel electrophoresis identified 33 differentially expressed proteins (17 up-regulated and 16 down-regulated) of more than 500 total spots, which was classified into 302 cellular processes. Of these functional profiling, down-regulations of genes and proteins were shown in cell adhesion, cell motility, organogenesis, enzyme regulator, structural molecule activity, and response to external stimulus functional activities, which are supposed to play important roles in leiomyoma pathophysiology. In contrast, the up-regulation was only shown in nucleic acid binding activity. And A-CGH was applied to multiple samples obtained from 10 uterine leiomyosarcomas. By A-CGH, all uterine leiomyosarcomas specimens demonstrated chromosomal aberrations. Chromosome 15q13.1 and 15q14 imbalances were very prominent. The most frequent losses were detected on 1p32.2, 2p23-25.2, 7q32.1, 10p11.2, 11p12-15, 13q32, 14q21-32, 15q13.1-14 and 21q21.3-22.12 in uterine leiomyosarcomas. Losses on 14q21-32 are rarely seen in other types of leiomyosarcoma and may be a distinctive feature of uterine leiomyosarcomas. Gains on chromosomes 7q33-35, 8q24.21, 11q12.3 and 22q13.1 in uterine leiomyosarcomas were observed in half the cases and were accompanied by high-level amplification. The nine overexpressed genes (ATAD3A, KIAA1669 and HSMDPKIN etc) and 62 suppressed genes (MCOLN2, PGM1 and USP48 etc.) located in these regions. Potentially significant pathogenetic cellular processes were identified and showed that the down-regulated functional profiling has an important impact on discovery of disease-specific pathogenetic pathway of leiomyoma. Also, A-CGH is a reliable approach for identifying candidate oncogenes that are associated with uterine leiomyoma carcinogenesis.