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This dissertation, Roles of Twist in Prostate Cancer Progression by 阮曉峰, Hiu-fung, Yuen, 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 Roles of TWIST in prostate cancer progression Submitted by YUEN, Hiu-Fung For the Degree of Doctor of Philosophy at The University of Hong Kong in October 2007 Prostate cancer ranks first in cancer incidence and is the second leading cause of cancer-related death among American men. In Hong Kong, the incidence rate of prostate cancer is increasing sharply probably due to the adoption of Westernized living style. The 5-year survival rate of a patient with localized prostate cancer approaches 100%. However, the median survival decreases sharply to 12-15 months when metastatic disease is clinically detected. Around 90% of metastatic prostate cancer develops metastasis in bone. Therefore, there are urgent needs in identification of prognostic biomarkers that can reliably predict metastasis in prostate cancer patients and also in understanding the mechanisms of bone metastasis for the development of novel therapeutic targets. Treatment of prostate cancer to bone metastasis relies largely on chemotherapy, and an understanding of how Taxol resistance develops could shed light on proper management of patients with advanced prostate cancer. TWIST, a basic helix-loop-helix transcription factor, has recently been shown to enhance metastatic ability of cancer cells through promoting epithelial to mesenchymal transition. Up-regulation of TWIST in prostate cancer confers Taxol resistance. In addition, TWIST is an important transcription factor governing bone development and differentiation of osteoblasts. I hypothesized that TWIST might play an important role in prostate cancer progression through enhancing the ability of prostate cancer cells to metastasize to bone. In this study, I aimed to investigate, firstly, the prognostic significance of TWIST in prostate cancer, secondly, the functional role of TWIST in prostate cancer to bone metastasis and thirdly, the downstream mechanisms of TWIST- induced Taxol resistance in prostate cancer cells. I found that high level of TWIST expression was correlated with an increased risk of developing metastatic disease in the prostate cancer cohort. High levels of TWIST were associated with aberrant expression pattern of E-cadherin, suggesting that TWIST might promote prostate cancer metastasis through epithelial-mesenchymal transition. Moreover, a high level of TWIST expression in prostate cancer cells increased their ability to induce differentiation of osteoclasts and these effects were partly mediated by a TWIST downstream target, DKK-1. On the other hand, TWIST also promoted osteomimicry of prostate cancer cells. These results suggest that TWIST might promote the initial phase of prostate cancer to bone metastasis through activating the early phase osteolytic event of bone metastasis and promoting prostate cancer to acquire bone cell- like characteristics, thereby, increasing their ability to survive and thrive in the bone environment. In addition, I found that although TWIST positively regulated DKK-1, TWIST- mediated Taxol resistance in prostate cancer cells was not attributed to DKK-1. On the contrary, DKK-1 over-expression sensitized prostate cancer cells towards Taxol while up-regulation of DKK-1 in TWIST-suppressed prostate cancer cells resulted in further sensitization towards Taxol. These results show that, unlike in the case of prostate cancer to bone metastasis, TWIST and DKK-1 might work separately on development of Taxol resistance in prostate cancer.

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