Functional Analysis of IGFBP-3 Gene Expression in Ovarian Endometrioid Carcinoma

• Main Authors: Jia-Hung Ye, 葉家宏
• Other Authors: Chin-Tarng Lin
• Format: Others
• Language: en_US
• Published: 2005
• Online Access: http://ndltd.ncl.edu.tw/handle/19747984461982945737

碩士 === 國立臺灣大學 === 病理學研究所 === 93 === To identify the signaling pathway responsible for the establishment of a metastatic phenotype in carcinoma cells is of crucial importance for the understanding of the pathogenesis of cancer metastasis. The process of metastasis usually involves several steps, including increase the cell motility to invade, degradation of extracellular matrix and basement membranes and cell proliferation. In our study, we used an ovarian cancer invasion model to define five OVTW59 sublines P0 to P4, with progressive increase in invasion capabilities for investigation of genes involved in invasion and metastasis. By cDNA microarray and quantitative real-time PCR analysis, we performed global gene screening and found 39 genes related with invasion and metastasis. Thirteen genes of them were down-regulated and twenty-six genes were up-regulated with the increase of ovarian cancer invasion. One of the down-regulated invasion-related genes, insulin-like growth factor-binding protein 3 (IGFBP-3), showed surprisingly differential expression in the ovarian cancer invasion model. For investigation of the role of the differentially expressed IGFBP-3 gene in the tumor progression, especially in the invasion and metastasis of ovarian cancer, we transfected a plasmid containing IGFBP-3 cDNA into the P0 and P4 cells. It was found that IGFBP-3 could inhibit cell migration in the scratch analysis and cell invasion in the invasion chamber assay. In addition, it could also inhibit tumor growth and metastasis and induce apoptosis in the animal model. These functions could be reversed when shRNA was transfected. We further studied the inhibitory mechanism of IGFBP-3 in cancer migration, invasion and metastasis, especially focusing in the signaling pathways and the interacting genes related to IGFBP-3. Our result revealed that IGFBP-3 could inhibit the activation of extracellular signal-regulated kinase (ERK)1/2 - mitogen-activated protein kinase (MAPK) signaling pathways. It is concluded that the IGFBP-3 gene, selected from the progressive increase in invasion capability sublines of ovarian cancer cell line, plays a role as a tumor suppressor to inhibit tumor cell migration, invasion and metastasis and to induce apoptosis in ovarian cancer pathogenesis.