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Investigation of the roles of Cdk5 protein in bladder cancer and prostate cancer
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Androgen receptor is a potential therapeutic target for bladder cancer. Urology 75, 820-827. Xie, Z., and Tsai, L. H. (2004). Cdk5 phosphorylation of FAK regulates centrosome-associated miocrotubules and neuronal migration. Cell cycle 3, 108-110. Yeh, J. Y., Huang, W. J., Kan, S. F., and Wang, P. S. (2001). Inhibitory effects of digitalis on the proliferation of androgen dependent and independent prostate cancer cells. J Urol 166, 1937-1942.||摘要:||
Prostate cancer is the most common malignancy among men and bladder cancer is the fourth most common malignancy among men in the United States. In Taiwan, prostate cancer and bladder cancer also play an important role in male urinary tract malignancies. Recent studies have explored the roles of cyclin-dependent kinase 5 (Cdk5) and its activator p35 in cancer research. We previously suggested that Cdk5 regulates the proliferation of prostate and thyroid cancer cells; thus, the aim of this thesis is to investigate the relation between Cdk5/p35 protein expression and the biophysical function in prostate and bladder cancer cells.
Part I: The overexpression of cyclin-dependent kinase 5 and p35 in urinary bladder urothelial carcinoma and associated with bladder cancer cells migration activity
We collected bladder cancer specimens from 27 patients (admitted by Institutional Review Board of Chang Bing Show Chwen Memorial Hospital). The levels of Cdk5 and p35 protein were analyzed using immunohistochemical staining or western blotting and compared between tumors and adjacent non-cancerous bladder tissues from individual patient. Migration array was conducted using bladder cancer cell line T24 in while Cdk5 was overexpressed or inhibited by inhibitor. The data indicated that the levels of Cdk5 and p35 protein expression were higher in tumors compared with the adjacent normal bladder tissues in 18 out of 27 patients. In addition, Cdk5 overexpression increased the migration activity of bladder cancer cell line T24 and the migration can be inhibited by treating with the Cdk5 inhibitor, roscovitine (p < 0.05). We first report the overexpression of Cdk5 and p35 proteins in bladder cancer specimens. These findings suggest that Cdk5 might be a tumor marker of bladder cancer and respond to regulate cell migration. Thus, these findings should help future bladder cancer diagnosis and treatment.
Part II: Cyclin-dependent kinase 5 and p35 protein expressions were associated with prostate cancer grade and stage
Prostate cancer is the most frequently diagnosed cancer and second leading cause of cancer-related deaths in men. The roles of cyclin-dependent kinase 5 (Cdk5) and its activator p35 in cancer biology have been extensively studied. We previously demonstrated that Cdk5 may regulate proliferation of prostate and thyroid cancer cells. The aim of this study was to investigate the relationship between Cdk5 and p35 protein expressions and prostate cancer cell grade and stage. We collected 212 patient specimens of prostate cancer from commercial tissue array. Cdk5 and p35 protein levels were evaluated by immunohistochemical staining. The images were double-blind evaluated by two experts in accordance with a scoring system based on the intensity and distribution of staining signals. The correlations between Cdk5 and p35 protein levels and tumor grade or stages were analyzed using Fisher's exact test. The overexpression of Cdk5/p35 was significantly correlated with prostate cancer grade (p = 0.0277) as well as stage (p = 0.0150). A higher grade and stage of prostate cancer was associated with higher expressions of Cdk5 and p35 proteins. This study first identified overexpression of Cdk5 and p35 in prostate cancer using tissue array specimens, which implies that Cdk5 is a potential tumor marker of prostate cancer. These findings may help making early diagnosis of prostate cancer and in the development of new treatments in the future.
To sum up the conclusions of part I and part II, we indicate the role of Cdk5 and p35 in bladder cancer and prostate cancer. By investigating on the expression of Cdk5 and p35 proteins, we explored the potential roles of Cdk5 and p35 proteins in prostate cancer and bladder cancer. We look forward to the further cell biology evidence to demonstrate the mechanism of Cdk5 and p35 proteins in tumors of prostate and bladder.
前列腺癌是美國男性最常見的癌症和第二大癌症相關死亡的原因。Cdk5蛋白及活化子p35的作用於癌症生物學已被廣泛研究；根據我們之前發表之文獻指出，Cdk5基因可調節前列腺癌和甲狀腺癌細胞的增生。本研究的目的是觀察Cdk5和p35蛋白表現與前列腺癌的細胞惡性度和分期之間的關係。我們利用市售的組織微陣列切片觀察了212個前列腺癌組織標本。Cdk5和p35蛋白表現以組織免疫染色評估。這些影像由兩位專家以雙盲之模式，依據染色信號強度和分佈的評分系統加以評估。Cdk5和p35蛋白表現與腫瘤的細胞惡性度和分期之間的相關性採用Fisher精確檢驗統計。結果顯示，Cdk5和P35蛋白的表現與前列腺癌細胞惡性度（p = 0.0277）或分期（p = 0.0150）呈現顯著地相關性，亦即較高細胞惡性度和分期的前列腺癌有較高的Cdk5和P35蛋白之表現。由此推論， Cdk5可能是前列腺癌的一個潛在腫瘤標記物，配合本團隊已發表的文獻可知，抑制Cdk5蛋白表現或活性可抑制前列腺癌的生長。希望這些發現未來有助於使前列腺癌的早期診斷和發展新的治療方法。
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