1R03CA223893-01 (R03) ApplID: 9443442 | |||
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Title | Characterization of Ras/Akt/CFIm25/APA signaling in Glioblastoma Development and Progression | ||
Institution | UNIVERSITY OF TEXAS MED BR GALVESTON, GALVESTON, TX | ||
Principal Investigator | JI, PING | NCI Program Director | Strasburger |
Cancer Activity | Cancer Cell Biology | Division | DCB |
Funded Amount | $78,875 | Project Dates | 06/01/2018 - 05/31/2020 |
Fiscal Year | 2018 | Project Type | Grant |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) | Brain (100.0%) | ||
Research Type | |||
Cancer Initiation: Alterations in Chromosomes Cancer Progression & Metastasis |
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Abstract | |||
PROJECT SUMMARY Glioblastoma multiforme (GBM; World Health Organization grade IV glioma) is the most common and most aggressive brain tumor. Despite aggressive treatment with surgery, radiation, and the alkylating agents like temozolomide (TMZ), GBM inevitably recurs, and the median survival of GBM patients is only 15 months [3]. It is well documented that disruption of receptor tyrosine kinase (RTK)/Ras and phosphoinositide 3-kinase (PI3K)/Akt signaling is a key driving event in GBM. However, accumulating evidence has emerged implicating the importance of alternative polyadenylation (APA) in GBM, which is manifested through downregulation of the APA regulator called Cleavage Factor I of 25 kDa (CFIm25). Over 50% of human genes have multiple polyadenylation sites in their 3'UTR and its shortening is observed in response to proliferation or transformation or tumorigenesis. The Cleavage Factor I 25kDa subunit (CFIm25) is a master regulator of 3'UTR APA, and reduce of CFIm25 expression was associated with worse survival in TCGA GBM patients. Our previous study demonstrated that reduction of CFIm25 enhanced cell proliferation through 3'UTRs shortening of several oncogenes, including Cyclin D1. In addition, we observed that shortened 3?UTRs in breast cancers are strongly associated with repression of tumor suppressors in trans via competing endogenous RNAs (ceRNAs) crosstalk. At the heart of this proposal, we are going to test the relationship between CFIm25 inactivation, Ras/Akt activation, and 3'UTR APA events in cell proliferation. We are also going to test the critical role of Ras/Akt/CFIm25/APA axis in GBM development and progression in vivo. We will be testing two Specific Aims: Specific Aim 1. What are the key 3'UTR APA genes in response to CFIm25 inactivation and/or Ras/Akt activation in cell proliferation? Specific Aim 2. What is a critical role of CFIm25 inactivation in cooperation with Ras/Akt activation to promote GBM?" |