Insulin-Like Growth Factor Binding Protein 3 (Igfbp3) as a Grade-Related Prognostic Factor and a Therapeutic Target of Gliomas and the Molecular Mechanism of Igfbp3-Regulated Cell Behavior

Gliomas are solid tumors that originate from glial cells in the brain or spine. Gliomas account for 81% of malignant brain tumor and the five-year survival rates post diagnosis of the most common and aggressive glioma, glioblastoma (GBM) is only 5%. The patient survival and tumor recurrent rates are closely correlated with tumor grades. However, it’s hard to accurately classify gliomas just based on several molecular markers or tissue histology. While the progression processes of some popular cancers are well-defined, the causes of gliomas are still unrevealed. Searching for new grading and prognostic factors and development of new therapies and therapeutic targets are imperative in glioma treatments. IGFBP3 belongs to the IGFBP family and was first recognized as a binding partner of insulin-like growth factors (IGFs), stabilized circulating IGFs, and prevented IGF binding with insulin-like growth factor receptors. Recently, more studies have shown that IGFBP3 can bind to not only IGFs but extracellular matrixes, cell surface receptors, and transcription factors. The roles of IGFBP3 in cancers are ambiguous, it may function as a tumor suppressor or an enhancer depended on the cancer types. In gliomas, the protein and mRNA expression of IGFBP3 is elevated and associated with increased tumor grade and poor survival of glioma patients. However, the real functions of IGFBP3 in glioma cells and the underlying molecular mechanisms of IGFBP3-regulated tumor progression are unclear. In the first year, we will focus on the IGFBP3 protein and RNA expression in glioma patient tissues from the Chang-Gung Memorial Hospital, also its correlation with clinicopathological characteristics and patient survival. Next, we will investigate the IGFBP3 expression in blood vessels and its expression correlation with angiogenic factors. Because we found that IGFBP3 knockdown suppressed cell growth, caused cell cycle arrest at G1 phase, and inhibited Rb phosphorylation in U-87 MG cells, we will focus on the effect of IGFBP3 expression on cell proliferation and cell cycle progression in at least 4 different glioma cells. Also, we will try to investigate the underlying molecular mechanism that caused cell cycle arrest at G1 phase and prepare the IGFBP3 stable overexpression and knockdown cells for in vivo mouse xenograft models. In the final year, we will search the alterations of RNA expression associated with IGFBP3 expression using Affymetrix GeneChip® Human Genome U133 Plus 2.0 Array and check the effect of IGFBP3 on in vivo cell growth using mouse xenograft models. In this project, we will find the correlation between IGFBP3 expression and clinicopathological factors also the angiogenic factors in gliomas patients in Taiwan. Furthermore, we will examine the effect of IGFBP3 on cell growth in vivo and in vitro and try to reveal its underlying molecular mechanisms using RNA microarrays screening and experiments focused on cell cycle progression. IGFBP3 may be a good prognostic factor that predicts poor outcome of glioma patients in Taiwan and a strong tumor enhancer as a potential therapeutic target in the future glioma treatment.

Project ID:PC10507-0237
External Project ID:MOST105-2314-B182-019-MY3