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研究生：	鄧洧婷 Deng, Wei-Ting
論文名稱：	探討RPA2蛋白在人類乳癌中的功能性角色 The functional studies of RPA2 in human breast cancer
指導教授：	張敏政 Chang, Ming-Chung
學位類別：	碩士 Master
系所名稱：	醫學院 - 生物化學暨分子生物學研究所 Department of Biochemistry and Molecular Biology
論文出版年：	2013
畢業學年度：	101
語文別：	中文
論文頁數：	93
中文關鍵詞：	細胞老化、單股結合蛋白
外文關鍵詞：	RPA2, senescence
相關次數：	點閱：79 下載：0
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Replication protein A (RPA)是真核生物中最主要的單股DNA結合蛋白，會參與在大部分DNA代謝的生理功能，例如複製、修復、重組及細胞週期等調控。整個RPA複合體是由三個次單元體所組成，分別是70KDa的RPA1、34KDa的RPA2以及14KDa的RPA3。其中，RPA2在DNA損傷及細胞週期的時候會被磷酸化，進而影響RPA複合體的構型並且改變其對DNA的結合能力。關於RPA複合體在癌症的研究顯示，RPA1以及RPA2可作為惡性大腸癌的預後指標，並且和病人低存活率、高轉移性有正相關性。近來的研究也都推論RPA複合體可能為未來癌症治療的新標的，因此，在我們的研究中想要清楚了解RPA蛋白在癌症中所扮演的角色為何，並且以乳癌作為研究的主要癌症類別。首先，我們利用西方墨點法去分析25個乳癌病人檢體中RPA1以及RPA2兩個次單體的表現量，結果顯示，25位病人中有23位病人檢體內的RPA2表現量是腫瘤細胞多於正常周邊細胞，然而我們同時去分析RPA1次單體的表現量發現，25個病人裡僅有9位病人在腫瘤細胞中表現較高，顯示RPA2在乳癌細胞裡的大量表現可能暗示著調控重要的功能。接著，我們在乳癌細胞株MDAMB231以及MCF7中建立了RPA2穩定抑制的細胞株，想要藉由抑制RPA2表現釐清其在乳癌細胞中所扮演的角色。根據實驗結果顯示，在乳癌細胞株中抑制RPA2的表現會減緩細胞生長的速度以及降低細胞形成聚落的能力，並且，細胞會呈現攤平肥大的型態且有少許死亡的細胞漂浮在培養液之中。我們也由SA-β-gal活性、肌動蛋白壓力性纖維累積以及老化指標基因等發現，抑制RPA2基因會誘發細胞產生老化的現象。另一方面，由PI/Annexin-V雙染色法發現RPA2抑制同時也會誘發細胞凋亡。最後，為了去檢視RPA2抑制所誘發的細胞老化現象是否會影響癌細胞移動能力，我們去比較兩株不同處理的細胞株，在RPA2表現量少且沒有轉移能力的MCF7中去超表現RPA2，另外，在RPA2表現量多且具轉移能力的MDAMB-231中去抑制RPA2表現，結果顯示，RPA2抑制的MDAMB-231細胞株移動能力會下降，相反的，RPA2超表現的MCF7細胞株移動能力會上升並且有型態上的改變。另外一方面，我們檢測了兩組細胞內EMT相關分子的變化，實驗顯示在RPA2抑制的MDAMB-231細胞株中vimentin表現大幅的下降，而e-cadherin有明顯上升的情況，也就是抑制RPA2之後細胞EMT分子有反轉的情形。綜合以上實驗結論，我們認為RPA2在乳癌中應該扮演致癌基因的角色且可做為日後癌症治療的新標的。

Replication protein A (RPA), the major eukaryotic single strand DNA (ssDNA)-binding protein, is essential for replication, repair, recombination and checkpoint activation. It is a heterotrimer complex composed of three tightly associated subunit of RPA1 (70KDa), RPA2 (34KDa) and RPA3 (14KDa). RPA complex conformation is regulated by RPA2 phosphorylation and phosphorylated RPA2 results in a decreased affinity for ssDNA and duplex substrates. Previous investigations have identified that RPA complex act as an autoantigene in breast cancer and squamous cell carcinoma of lung. In addition, a recently study suggests that both RPA1 and RPA2 act as indicator of adverse prognosis in patient with colon cancer. These studies suggest that RPA2 may be a therapeutic target for cancer treatment. However, the role of RPA2 in tumor progression remains unknown. Here, we analyzed the expressions of RPA1 and RPA2 protein in 25 breast cancer specimens by western blot. We found that RPA2 protein was upregulated in 23 of 25 pairs of breast cancer/normal breast specimens, whereas RPA1 upregulation was found in 9 of 25 breast cancer specimens, suggesting that RPA2 may play an important role in tumor progression. To elucidate the role of RPA2 in tumor, we established the RPA2 down-regulation stable cell lines in MDA-MB-231 and MCF7. The results showed that MDA-MB-231 and MCF7-RPA2-knockdown cells exhibited a significant decrease in cell growth and colony formation, had an enlarged cell morphology and induced senescence. On the other hand, we also found that RPA2 knockdown induced cell apoptosis by PI/Annexin-V assay. At the end, in order to examine whether RPA induced senescence affected breast cancer progression, we established RPA2 overexpression stable cell line in MCF that is non-metastasis breast cancer cell line and compared to RPA2 knockdown stable cell line. Notably, down-regulation RPA2 in MDMMB-231 reduced cell migration. Contrarily, up-regulation RPA2 in MCF7 induced fibroblast-like morphology and gain higher migratory ability. Besides, we examined the EMT correlated marker vimentin and E-cadherin. The data showed that EMT correlated marker dramatically reversed in RPA2 knockdown stable cell lines. Collectively, our finding suggested that RPA2 serves as an oncoprotein in breast cancer and could be a therapeutic target for cancer treatment.

中文摘要	I
Abstract	III
誌謝	V
目錄	VII
圖表目錄	XI
附錄目錄	XIII
縮寫表	XIV
第一章、緒論	1
1-1  RPA複合體簡介	1
1-2  RPA複合體的功能	2
1-3  RPA次單元介紹	3
1-4  RPA磷酸化	5
1-5  RPA與癌症的關連性	6
1-6  細胞老化	8
1-7  研究動機	10
第二章、材料與方法	12
2-1 實驗菌株培養	12
2-1-1 實驗菌株	12
2-1-2 培養基配方	12
2-2 質體建構	13
2-2-1 聚合酶連鎖反應(polymerase chain reaction)	13
2-2-2 建構PCR片段於載體中	14
2-2-3 大腸桿菌(E. coli)形質轉型	15
2-2-4 小量質體製備	16
2-3 細胞培養	17
2-3-1 實驗細胞株	18
2-3-2 細胞解凍	18
2-3-3 細胞繼代培養	19
2-3-4 細胞計數	20
2-3-5 細胞保存	21
2-3-6 細胞轉染	22
2-4 蛋白質分析	23
2-4-1 蛋白質萃取	23
2-4-2 蛋白質定量	23
2-4-3 蛋白質電泳(SDS-PAGE)	24
2-4-4 西方墨點法	26
2-5在MDA MB-231及MCF7中建立RPA2表現抑制穩定細胞株	28
2-5-1 RPA2 shRNA來源	28
2-5-2病毒製備	28
2-5-3 病毒感染	29
2-5-4 利用抗生素篩選穩定細胞株	30
2-6 RPA2表現穩定抑制細胞株對於腫瘤生長能力的分析	31
2-6-1 利用細胞計數法檢測穩定細胞株生長速率	31
2-6-2 利用Colony Formation Assay觀察穩定細胞株形成細胞聚落的能力	32
2-7  利用Propldium(PI)-Annexin V雙染色實驗分析穩定細胞株細胞凋亡現象。	33
2-8  RPA2抑制的穩定細胞株對於細胞老化的影響分析	34
2-8-1利用senescence-associated β-galatosidase的活性去檢測RPA2抑制穩定細胞株	34
2-8-2利用Rhodamine phalloiidn螢光染色觀察RPA2抑制穩定細胞株內肌動蛋白應力纖維分布	35
2-9 觀察RPA2抑制的穩定細胞株與RPA2過度表現穩定細胞株細胞爬行能力	36
2-9-1利用傷痕癒合(wound healing)實驗分析穩定細胞株爬行能力	36
2-9-2利用transwell實驗分析穩定細胞株爬行能力	37
第三章、實驗結果	39
3-1 檢測25位乳癌病人檢體中RPA1以及RPA2蛋白質的表現量	39
3-1-1乳癌檢體中RPA2蛋白質表現量在腫瘤組織中大量表現，RPA1蛋白質則無此現象	39
3-1-2乳癌檢體中RPA2蛋白質表現量與RPA1蛋白質表現量沒有正相關性	40
3-1-3 25位乳癌病人病史整理表格	40
3-2不同人類乳癌細胞株中RPA2蛋白質的表現量	40
3-3 在MDAMB-231人類乳癌細胞株中建立RPA2表現抑制的穩定細胞株	41
3-4 在MDAMB-231細胞株中抑制RPA2蛋白質表現量會降低細胞生長速度及形成聚落能力	41
3-4-1 利用細胞計數法檢測細胞生長速度	41
3-4-2利用colony formation assay檢測細胞群聚能力	42
3-5在MDAMB-231細胞株中抑制RPA2蛋白質表現量會誘發細胞凋亡及細胞老化產生	42
3-5-1利用Propldium(PI)和Annexin V雙染色方法檢測細胞凋亡程度	42
3-5-2分析RPA2抑制穩定細胞株中抗細胞凋亡及細胞凋亡相關基因的蛋白質表現	43
3-5-3 利用相位差顯微鏡觀察穩定細胞株之細胞型態	44
3-5-4檢測穩定細胞株內senescence-associated β-galatosidase(SA-β-gal)活性	44
3-5-5利用Rhodamine Phalloidin螢光染色觀察肌動蛋白應力性纖維堆積情況	45
3-5-6分析RPA2抑制穩定細胞株中細胞老化相關基因的蛋白質表現	45
3-6 分析RPA2抑制穩定細胞株及RPA2過度表現穩定細胞株對癌細胞發展進程及細胞移動能力的影響	46
3-6-1 分析RPA2抑制對轉移性乳癌細胞株MDAMB-231細胞移動能力的影響	48
3-6-2 分析RPA2過度表現對非轉移性乳癌細胞株MCF7細胞移動能力的影響	48
3-7檢測不同穩定細胞株細胞內EMT相關分子變化情形。	49
第四章、實驗討論	51
4-1 RPA2在癌症中扮演的角色	51
4-2 抑制RPA2同時誘發細胞老化與細胞凋亡	53
4-3 在RPA2抑制之中p53以及p21扮演的角色	54
4-4 RPA2抑制在癌症治療上的應用	55
4-5 RPA2抑制誘發老化及細胞凋亡的機制	56
參考文獻	58
實驗結果圖表	66
附錄	88
自述	93

                                    

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