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This dissertation, Role of Id-1 in Proliferation and Survival of Esophageal Carcinoma Cells by Cheuk-man, Hui, 許卓文, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract of thesis entitled Role of Id-1 in proliferation and survival of esophageal carcinoma cells Submitted by HUI Cheuk Man for the degree of Master of Philosophy at The University of Hong Kong in October 2004 Id proteins (inhibitor of differentiation or DNA binding) are a group of helix-loop-helix (HLH) transcription factors that mainly act as dominant inhibitors of basic HLH proteins, resulting in inhibition of the expression of differentiation- related genes. Ectopic Id-1 expression has been shown to increase cell proliferation, survival, aggressiveness and metastasis in cancer cells. Although it has been reported that Id-1 is over-expressed in esophageal squamous cell carcinoma (ESCC), little is known about its function and signaling pathways in esophageal cancer. In this study, the effect of Id-1 expression on esophageal cancer and the molecular events involved were investigated using a human esophageal squamous cell carcinoma cell line HKESC-3 which showed serum-dependent expression of Id-1. HKESC-3 was transfected with Id-1 expression vector and clones were isolated. The ectopic Id-1 expression resulted in an increased growth rate and promoted G1-S phase transition in the transfectant clones cultured in serum-free medium. The effects were associated Waf1/Cip1 with up-regulation of MDM2 and down-regulation of p21 protein expressions in a p53-independent manner. Stable transfection of Id-1 antisense expression vector to inhibit the expression of endogenous Id-1 in another ESCC cell line with serum- independent Id-1 expression (HKESC-1) reversed the effects on MDM2 and Waf1/Cip1 p21 . My results suggest for the first time that enforced Id-1 expression may increase cellular proliferation rate in ESCC cells through the regulation of MDM2- Waf1/Cip1 p21 pathway in the absence of p53 expression. INK4a The p16 /Rb pathway is implicated to play a role in Id-1 induced cell proliferation in other types of cancer. I found that the HKESC-3 and its Id-1 INK4a transfectant clones did not express p16 and Rb proteins, and they did not show any significant difference in CDK4 expression. These findings suggest that Id-1 induced ESCC cell proliferation may be independent of this pathway and that the downstream signaling pathways of Id-1 may differ between cancer types. Interestingly, the transcription factor E2F-1, which is a final effector of the p16/Rb pathway controlling G1-S phase transition, was up-regulated in Id-1 expressing clones. This could be mediated by MDM2 over-expression. In addition to increasing cell proliferation and promoting cell cycle progression, ectopic Id-1 expression also protected esophageal carcinoma cells from TNF-α induced apoptosis. This could be associated with up-regulation and activation of anti- apoptotic protein Bcl-2. Although the expression levels of Bax, a pro-apoptotic protein, in the Id-1 transfectant clones were similar to that of the vector control, increased relative ratio of pro- to anti-apoptotic proteins may help protect ESCC cells from drug-induced apoptosis. Moreover, a significant increase in NF-κB transcriptional activity was found in most of the Id-1 transfectants, activation of NF- κB signaling pathway may also be involved in Id-1 promoted cell survival in ESCC. The expressions of members of the extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) pathway, associated with I

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