Colorectal cancer is the second leading cause of cancer-related deaths in the United States, largely due to invasion and metastasis to the liver and lymph nodes. Thus, a thorough understanding of invasion/metastasis is necessary for prevention and treatment of colon cancer. Over- expression of programmed cell death 4 (Pdcd4), a novel tumor suppressor, inhibits invasion and AP-1 dependent transcription in colon tumor cells. Pdcd4 expression is frequently down-regulated in colon tumor tissues as compared to adjacent normal tissues. The 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. We knocked down Pdcd4 expression in colon tumor GEO and HT29 cells and found that Pdcd4 knock-down triggers morphological changes, induces invasion, and activates 2-catenin/Tcf and AP-1 dependent transcription. Our preliminary results further demonstrated that a decrease in E-cadherin expression correlates with an increase in the protein level of Slug, a transcription repressor for E-cadherin expression. We, therefore, hypothesize that Pdcd4 knock-down promotes colon tumor cell invasion/metastasis through down-regulation of E-cadherin and activation of 2-catenin/Tcf and AP-1 dependent transcription. To test our hypothesis, four Specific Aims are proposed.
Aim 1 : determine whether Pdcd4 functions as a metastasis inhibitor in colon tumor cells. Epithelial-to-mesenchymal transition and metastasis in mice will be assayed using Pdcd4 knock- down and over-expressed cells.
Aim 2 : examine whether activation of 2-catenin/Tcf dependent transcription led by E-cadherin down-regulation in Pdcd4 knock-down cells promotes invasion/metastasis. We will test activation of 2-catenin/Tcf dependent transcription by knocking down E-cadherin, reversion of the invasive/metastatic ability by inhibiting 2-catenin/Tcf dependent transcription, verification of uPAR and c-Myc as the target genes of 2-catenin/Tcf dependent transcription, and inhibition of 2-catenin/Tcf4 dependent transcription and its target gene expression by over-expressing Pdcd4.
Aim 3 : determine whether activation of 2-catenin/Tcf4 dependent transcription in Pdcd4 knock-down cells up-regulates MAP4K1 expression and AP-1 activity through c-Myc. We will establish the c-Myc as a regulator of MAP4K1 expression, and activation of 2- catenin/Tcf dependent transcription causing up-regulation of MAP4K1 expression, JNK activation, and AP-1 dependent transcription.
Aim 4 : 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 ability of invasion/metastasis in Slug knock-down and Pdcd4 expressing cells. This work will provide a comprehensive understanding of how Pdcd4 modulates colon tumor progression and holds great promise for novel interventions for preventing and treating colon cancer.

Public Health Relevance

Colorectal cancer is the second most fatal cancer in the United States, largely due to invasion and metastasis to the liver and lymph nodes. In this proposal, we intend to understand the effects of a novel tumor suppressor, Pdcd4, on colon tumor metastasis and the molecular mechanism involved in this process. This work will provide a comprehensive understanding of how Pdcd4 modulates colon tumor progression and holds great promise for novel interventions for preventing and treating colon cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Tumor Progression and Metastasis Study Section (TPM)
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Jhappan, Chamelli
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University of Kentucky
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