Malignant gliomas are the most common brain tumors and are associated with extremely high rates of morbidity and mortality. The long-term goal of our research is to reveal the molecular mechanisms underlying glioma development and progression, of which very little is currently known. Recent studies using oligonucleotide microarray analysis have shown that alteration to the Forkhead box M1 (FoxM1) transcription factor is one of the most frequent molecular alterations in malignant gliomas. Our preliminary results indicate a direct correlation between FoxM1 expression level and the grade of gliomas. Enforced FoxM1 expression in immortalized normal human astrocytes (NHAs) was sufficient to transform the cells into glioma cells. Enforced FoxM1 expression in anaplastic astrocytoma cells promoted their progression into glioblastomas in nude mouse models, and suppressed FoxM1 expression inhibited the anchorage-independent growth of glioblastoma cells. Moreover, gliomas arisen from FoxM1-transfected cells were highly proliferative, invasive, and angiogenic. FoxM1-transfected glioma cells had increased expression of activated Akt, VEGF and MMP-2, whereas FoxM1-siRNA-transfected glioma cells had decreased expression of activated Akt. Here, we propose to determine the causal effects and mechanisms of aberrant FoxM1 expression on glioma development and progression. We hypothesize that aberrant expression of FoxM1 contributes to glioma development and progression by promoting uncontrolled cell proliferation, invasion, and angiogenesis.
Our Specific Aims are 1) To determine the effect of altered FoxM1 expression on glioma biology. We will determine the critical contribution of FoxM1 to glioma cell proliferation, invasion, and angiogenesis in vitro and in vivo by using the FoxM1-siRNA inhibition system, FoxM1-overexpressing cell lines, and in vivo mouse models. 2) To determine the cooperation between FoxM1 overexpression and Rb loss in glioma development and progression. We will investigate whether FoxM1 transgene expression accelerates glioma formation and promotes glioma progression in a genetic mouse glioma model with an inactivated pRb pathway. 3) To determine whether FoxM1 overexpression contributes to glioma development and progression via activation of Akt pathway. 4) To identify the molecular mechanisms by which FoxM1 regulates glioma invasion and angiogenesis. The mechanisms of FoxM1 regulating invasion and angiogenesis will be investigated with a particular focusing on how it regulates the expression of the MMP-2, and VEGF genes. The findings from our proposed studies will contribute to a better understanding of the molecular mechanisms of glioma development and progression and will identify potential targets for novel therapeutic strategies against malignant glioma. ? ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA116528-01A1
Application #
7148378
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Jhappan, Chamelli
Project Start
2006-09-15
Project End
2010-07-31
Budget Start
2006-09-15
Budget End
2007-07-31
Support Year
1
Fiscal Year
2006
Total Cost
$218,680
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Neurosurgery
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Li, Zhiwei; Jia, Zhiliang; Gao, Yong et al. (2015) Activation of vitamin D receptor signaling downregulates the expression of nuclear FOXM1 protein and suppresses pancreatic cancer cell stemness. Clin Cancer Res 21:844-53
Cui, Jiujie; Shi, Min; Xie, Dacheng et al. (2014) FOXM1 promotes the warburg effect and pancreatic cancer progression via transactivation of LDHA expression. Clin Cancer Res 20:2595-606
Li, Lei; Li, Zhaoshen; Kong, Xiangyu et al. (2014) Down-regulation of microRNA-494 via loss of SMAD4 increases FOXM1 and ?-catenin signaling in pancreatic ductal adenocarcinoma cells. Gastroenterology 147:485-97.e18
Kong, Xiangyu; Li, Lei; Li, Zhaoshen et al. (2013) Dysregulated expression of FOXM1 isoforms drives progression of pancreatic cancer. Cancer Res 73:3987-96
Huang, Chen; Qiu, Zhengjun; Wang, Liwei et al. (2012) A novel FoxM1-caveolin signaling pathway promotes pancreatic cancer invasion and metastasis. Cancer Res 72:655-65
Chiu, Wen-Tai; Lee, Hsueh-Te; Huang, Feng-Ju et al. (2011) Caveolin-1 upregulation mediates suppression of primary breast tumor growth and brain metastases by stat3 inhibition. Cancer Res 71:4932-43
Dai, Bingbing; Pieper, Russell O; Li, Dawei et al. (2010) FoxM1B regulates NEDD4-1 expression, leading to cellular transformation and full malignant phenotype in immortalized human astrocytes. Cancer Res 70:2951-61
Zhang, Yujian; Zhang, Nu; Dai, Bingbing et al. (2008) FoxM1B transcriptionally regulates vascular endothelial growth factor expression and promotes the angiogenesis and growth of glioma cells. Cancer Res 68:8733-42
Dai, B; Kang, S-H; Gong, W et al. (2007) Aberrant FoxM1B expression increases matrix metalloproteinase-2 transcription and enhances the invasion of glioma cells. Oncogene 26:6212-9