Colorectal cancer is a leading cause of cancer mortality among adults. Commonly observed in colon cancer cells and tumors is overexpression of many growth- and inflammation-associated immediate-early response genes. A critical point in controlling the expression of these factors in normal intestinal epithelium occurs through post-transcriptional mechanisms that regulate mRNA decay. The two primary RNA-binding proteins associated with post-transcriptional regulation are the mRNA stability factor Hu antigen R (HuR) and the mRNA decay factor tristetraprolin (TTP). Both of these factors bind AU-rich mRNA elements (ARE) present in a majority of cancer-associated immediate-early response gene transcripts and target the mRNA for stabilization or rapid decay. However, a characteristic feature observed in colon cancer cells and tumors is overexpression of the stability factor HuR and loss of expression of the decay factor TTP. These combined defects allow for stabilization and overexpression of cancer-associated growth factors. Based on these observations we hypothesize that loss of post-transcriptional regulation promotes intestinal epithelial cell tumorigenesis by selectively stabilizing AU-rich element containing-mRNA transcripts. The following specific aims are proposed to test this hypothesis.
Specific Aim 1 : Determine whether altered expression of the mRNA stability factor HuR and the mRNA decay factor TTP can promote intestinal cell transformation and tumorigenesis.
Under Aim 1 we will determine whether HuR overexpression and TTP loss play a causal role in promoting epithelial cell transformation and tumorigenesis through a mechanism of defective rapid mRNA decay and cancer-associated gene overexpression.
Specific Aim 2 : Determine the ability of low-molecular- weight inhibitors of HuR and viral-mediated delivery of TTP to impact colon cancer cell growth and gene expression. The emphasis of this aim is to investigate the therapeutic potential of targeting HuR-mediated mRNA stabilization.
Specific Aim 3 : Determine if HuR overexpression and TTP loss in the murine gastrointestinal tract promotes cancer-associated gene expression and tumorigenesis in vivo. In this Specific Aim we will determine the in vivo significance of HuR overexpression and TTP loss in promoting intestinal tumorigenesis.
Specific Aim 4 : Determine the molecular events in colon cancer cells and tumors that promote HuR overexpression and silencing of TTP expression. Under this aim, we will determine the mechanisms promoting HuR expression and TTP gene silencing in colon cancer. This study will enhance our understanding of colorectal cancer biology and lead to the identification of novel molecular targets, which will improve current treatment and prevention strategies.
Colorectal cancers are a leading cause of cancer incidence and death among adult Americans. In colorectal cancer cells and tumors, uncontrolled expression of many growth- and inflammation-associated genes occurs. By better understanding the cellular mechanisms involved in controlling the expression of these factors, we aim to identify and define new molecular targets for controlling gene expression in colorectal cancer and improve current treatment and prevention strategies.
|Aguado, Andrea; Fischer, Thierry; RodrÃguez, Cristina et al. (2016) Hu antigen R is required for NOX-1 but not NOX-4 regulation by inflammatory stimuli in vascular smooth muscle cells. J Hypertens 34:253-65|
|Wu, Xiaoqing; Lan, Lan; Wilson, David Michael et al. (2015) Identification and validation of novel small molecule disruptors of HuR-mRNA interaction. ACS Chem Biol 10:1476-84|
|Sobolewski, Cyril; Sanduja, Sandhya; Blanco, Fernando F et al. (2015) Histone Deacetylase Inhibitors Activate Tristetraprolin Expression through Induction of Early Growth Response Protein 1 (EGR1) in Colorectal Cancer Cells. Biomolecules 5:2035-55|
|Aguado, A; RodrÃguez, C; MartÃnez-Revelles, S et al. (2015) HuR mediates the synergistic effects of angiotensin II and IL-1Î² on vascular COX-2 expression and cell migration. Br J Pharmacol 172:3028-42|
|Blanco, Fernando F; Sanduja, Sandhya; Deane, Natasha G et al. (2014) Transforming growth factor * regulates P-body formation through induction of the mRNA decay factor tristetraprolin. Mol Cell Biol 34:180-95|
|Upadhyay, Rohit; Sanduja, Sandhya; Kaza, Vimala et al. (2013) Genetic polymorphisms in RNA binding proteins contribute to breast cancer survival. Int J Cancer 132:E128-38|
|Dixon, Dan A; Blanco, Fernando F; Bruno, Annalisa et al. (2013) Mechanistic aspects of COX-2 expression in colorectal neoplasia. Recent Results Cancer Res 191:7-37|
|Young, Lisa E; Moore, Ashleigh E; Sokol, Lena et al. (2012) The mRNA stability factor HuR inhibits microRNA-16 targeting of COX-2. Mol Cancer Res 10:167-80|
|Sanduja, Sandhya; Blanco, Fernando F; Young, Lisa E et al. (2012) The role of tristetraprolin in cancer and inflammation. Front Biosci (Landmark Ed) 17:174-88|
|Rounbehler, Robert J; Fallahi, Mohammad; Yang, Chunying et al. (2012) Tristetraprolin impairs myc-induced lymphoma and abolishes the malignant state. Cell 150:563-74|
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