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Please use this identifier to cite or link to this item: http://ntour.ntou.edu.tw:8080/ir/handle/987654321/34613

Title: 探討CCL2促進膀胱癌細胞轉移機制
Studies on the mechanism of CCL2 in the migration of bladder cancer cells
Authors: Hsiao-Ying Chiu
Contributors: NTOU:Institute of Bioscience and Biotechnology
Keywords: 膀胱癌;趨化素
bladder cancer;CCL2;chemokine;paxillin;PKC
Date: 2012
Issue Date: 2013-10-07T02:44:26Z
Abstract: 膀胱癌乃是台灣泌尿道腫瘤中發生率最高者,以尿路上皮細胞癌 (urothelial cell carcinoma,UCC)為主,臨床上20-30%非肌肉型侵犯UCC病人 (non-muscle-invasive disease)最後會轉型為肌肉侵犯型,且UCC癌症轉移者其存活率很差。因此探討膀胱癌之轉移機制,將有助於發展膀胱癌診斷與新療法。 Monocyte chemoattractant protein-1 (MCP-1/CCL2)大量表現於臨床上高復發率與預後差之膀胱癌中,CCL2對腫瘤遷移機制之影響仍不是很明確。本實驗首先以蛋白質陣列 (protein array)分析具高度細胞遷移能力之老鼠膀胱癌細胞株MBT2,發現CCL2在MBT2細胞株表現量高,推測CCL2與膀胱癌細胞遷移 (cell migration)有相關聯性。為了進一步探討CCL2在UCC膀胱癌之重要性,分析不同程度 (UCC Grading)之人類UCC膀胱癌細胞株,觀察CCL2對癌細胞遷移之影響,本實驗發現Grading G3膀胱癌細胞株,其CCL2表現與遷移能力皆高於Grading G0-G2膀胱癌細胞株。 探討CCL2是否調節細胞遷移與侵犯(invasion),本實驗以small hairpin RNA (shCCL2)、CCR2拮抗劑(antagonist, RS)或專一性抑制劑等策略,發現減少CCL2 (shCCL2)或抑制CCR2 (CCR2拮抗劑)可降低細胞遷移與侵犯;且減少PKC活性與paxillin之磷酸化 (Y118)。經動物實驗,餵食RS之MBT2細胞腫瘤發生與knock-down CCL2之MBT2細胞的tumorigenicity皆顯著被抑制。另外,以組織微陣 (tissue array)分析臨床上99個患者檢體(UCC grading, G1-G3 core)也發現,隨著UCC膀胱癌程度增加,其CCL2與Y118顯著上升。故本研究結論顯示,autocrine CCL2透過CCR2-PKC-Y118途徑,促進UCC癌細胞遷移與侵犯。
Bladder cancer is the tenth most common malignancy in Taiwan and its incidence continues to rise each year. Most bladder cancers are urothelial cell carcinomas (UCC), and on average 20-30% of patients with non-muscle invasive bladder cancer will subsequently develop muscle-invasive UCC. It has been reported that the correlation of urinary monocyte chemoattractant protein-1 (MCP-1/CCL2) levels with tumor stage, grade and distant metastasis is highly significant. Since CCL2 has been shown to correlate with poor survival in the bladder cancer patients, this chemokine may play a particularly important role in tumor progression. The amount of CCL2 produced by an UCC is directly correlated with high recurrence and poor prognosis in bladder cancer. However, the mechanisms underlying the effects of CCL2 on tumor progression remain unexplored. In view of the important roles played by CCL2 in cancer progression, we strive to provide insights into the regulation of CCL2-induced cell migration as well as invasion and to investigate molecular mechanisms involving migration in response to the chemokine. To investigate the role played by CCL2, we examined cell migration in various bladder cancer (UCC Grading G0-G3) cell lines. We found that high-grade UCC G3 cancer cells expressing high levels of CCL2 showed more migration activity than low-grade UCC (G0-G2) cells expressing low levels of the chemokine. Although the activation of CCL2/CCR2 signals did not appreciably affect cell growth, it mediated cell migration and invasion via the activation of protein kinase C and phosphorylation of tyrosine in paxillin. Blocking CCL2 and CCR2 with small hairpin RNA (shCCL2) or a specific inhibitor reduced CCL2/CCR2-mediated cell migration. The antagonist of CCR2 promoted the survival of mice bearing MBT2 bladder cancer cells, and CCL2-depleted cells showed low tumorigenicity compared with shGFP cells. In addition, the over-expression of CCL2 and tyrosine phosphorylation of paxillin (Y118) were found in human UCC (G3) cancer cells and UCC (G3) patients. In conclusion, we showed that the CCL2/CCR2 signaling pathway mediated migratory and invasive activity, whereas blocking the pathway decreased migration and invasion. In this study, we further address the regulation of CCL2-mediated cell migration by focusing on PKC activation and phosphorylation of tyrosine in paxillin (Y118).
URI: http://ethesys.lib.ntou.edu.tw/cdrfb3/record/#G0D95360003
Appears in Collections:[生命科學暨生物科技學系] 博碩士論文

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