The Role of Pdcd4 in Colorectal Tumor Progression

Grants and Contracts Details


Colorectal cancer is the second leading cause of cancer-related deaths in the United States, largely due to Inv~slon. and metast~sl~ to the liver and lymph nodes. Thus, there is an urgent need for a better understanding of Invas.'on/metastasls In colon cancer to facilitate the development of new therapeutic approaches. Overexpression of programmed cell death 4 (Pdcd4), a novel tumor suppressor, in colon tumor cells inhibits their Matrigel invasion abilities. Pdcd4 expression is frequently down-regulated in cancerous colon tissues as compared to adjacent normal tissues. However, the biological impacts of Pdcd4 down-regulation and the underlying mechanisms remain unknown. The overall objective of the proposed study is to define the function of Pdcd4 in tumor invasion/metastasis and elucidate the molecular mechanisms involved in these processes. To study the role of Pdcd4 in colon tumor cell invasion/metastasis, we knocked down Pdcd4 expression in colon tumor GEO and HT29 cells and found that Pdcd4 knock-down triggered fibroblast-like morphological changes and induced invasion. This observation led us to the finding that E-cadherin expression decreased in Pdcd4 knock-down cells, correlating with an increase in the protein level of Slug, a transcription repressor for E-cadherin expression. Meanwhile, l3-catenin, the key effector in the Wnt pathway, accumulated in the nuclei of Pdcd4 knock-down cells. We, therefore, hypothesize that Pdcd4 knock-down promotes colon tumor cell invasion/metastasis through down-regulation of E-cadherin and activation of l3-catenin dependent transcription. To test our hypothesis, three Specific Aims are proposed. In Specific Aim 1, we will determine whether Pdcd4 knock-down is sufficient to promote metastasis in colon tumor cells. Extracellular matrix (ECM) proteinase activity, cell-to-ECM adhesion, and liver metastasis in nude mice will be assayed. For Specific Aim 2, we will assess whether knock-down of Pdcd4 promotes invasion/metastasis via activation of l3-catenin/Tcf dependent transcription. To do so, we will take four steps; determining the activation of ~-catenin/Tcf dependent transcription in Pdcd4 knock-down cells, establishing Tcf4 as the functional partner of ~-catenin in Pdcd4 knock-down cells, over-expressing E-cadherin in Pdcd4 knock-down cells to inhibit ~-catenin/Tcf dependent transcription and uPAR expression, and reversing the invasive/metastatic ability of Pdcd4 knock-down cells by inhibiting j3-catenin/Tcf dependent transcription. In Specific Aim 3, we will determine whether Pdcd4 translationally inhibits transcription repressor Slug expression resulting in up-regulation of E-cadherin and suppression of invasion/metastasis. Translation inhibition and the inhibitory mechanism will be analyzed using in vitro and in vivo translation assays followed by an examination of E-cadherin expression level and the capacity for invasion/metastasis in Slug knock-down cells. The data generated from these studies will enable us to modulate the expression of key molecules implicated in colon cancer progression, which eventually will be beneficial for cancer prevention and/or therapeutics.
Effective start/end date1/1/0911/30/14


  • National Cancer Institute: $1,474,888.00


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