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研究生:陳玉屏
研究生(外文):Yu-Ping Chen
論文名稱:STK15之異常在口腔鱗狀上皮細胞癌之功能性研究
論文名稱(外文):A functional study of the STK15 alteration in oral squamous cell carcinoma
指導教授:張國威
指導教授(外文):Kuo-Wei Chang
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:口腔生物研究所
學門:醫藥衛生學門
學類:牙醫學類
論文種類:學術論文
論文出版年:2008
畢業學年度:96
語文別:中文
論文頁數:90
中文關鍵詞:絲胺酸/酥胺酸激酶15口腔鱗狀上皮細胞癌細胞自噬刪減
外文關鍵詞:STK15OSCCautophagyknockdown
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  • 被引用被引用:0
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  • 收藏至我的研究室書目清單書目收藏:0
口腔癌為世界普見的癌症,在台灣,自1991年起,也是前十大癌症死亡原因之一,近年來口腔癌的發生率及死亡率有逐漸增加的趨勢,雖然診斷及治療技術不斷的進步,但口腔癌之五年存活率在過去十幾年來並沒有明顯改善。本實驗室曾發現20q在口腔癌細胞及組織有增幅的現象,而STK15(Aurora A)為一種絲胺酸/酥胺酸激酶,主要與調控有絲分裂相關,其基因坐落在20q13.2-13.3,在許多癌症中都有增幅及過度表現的現象,但在口腔癌中研究極少,本研究探討STK15在口腔癌扮演之角色,以期找到新的治療目標,增加病患存活率。以即時定量PCR及免疫組織染色法、西方墨點法偵測口腔鱗狀上皮細胞癌細胞株、口腔癌原發及復發組織、淋巴轉移組織及高危險群口腔上皮,發現口腔鱗狀上皮細胞癌之STK15基因套數異常增幅的為11.6%,且由高危險群至原發乃至復發癌之病程基因套數有漸進式的增加。至於在蛋白質表現方面,大多數之口腔鳞狀上皮細胞癌組織細胞質都有表現STK15,有一些則是核及質都有,細胞核內表現的STK15在癌旁組織至口腔鱗狀上皮細胞癌組織及至淋巴轉移腫瘤組織亦有逐步漸增之趨勢,與增幅之結果可以互相証驗,另外細胞核內表現STK15比例愈高者,病人之存活率愈差。以shRNA刪減OECM-1口腔癌細胞株STK15之表現,可降低STK15所引發的生長、移行及非依附性生長導致癌相關表型,並增加細胞之自噬。目前正在從事動物研究,看是否shRNA之注射可以減少裸鼠腫瘤生成力,以推估其應用於臨床治療之潛力。
Oral squamous cell carcinoma (OSCC) is one of commonly diagnosed cancers all over the world. It has been one of the 10 leading causes of death from cancer in Taiwan since 1991. In the past decades, incidence and mortality rate of OSCC increased remarkably. Although the technologies of diagnosis and therapy have been remarkably developed, the 5-year survival rate of OSCC has not been improved significantly. Our laboratory has found that chromosome 20q was a hotspot for gene amplification in OSCC. STK15 (Aurora A) is a serine/threonine kinase which has been identified as a regulator of the mitosis and it localizes on 20q13.2-13.3. The amplification and overexpression of STK15 was found in many cancers; however, the alterations of STK15 was rarely reported in OSCC. In this study, we attempted to identify the role of STK15 in OSCC, which may provide us the insight to develop a potential therapeutic regimen for increasing survival rate of human. We used real-time PCR, immunohistochemistry and Western blot to analyze OSCC cell lines, buccal brushes from high risk individuals, primary tumors, recurrent tumors, and nodal metastasis. We found that the copy number of STK15 increased following the disease progression from high risk non-tumor tissue to primary tumors, then to recurrent tumors, although the incidence of copy number amplification was only 11.6%. Cytosolic STK15 was detected in most tissues examined and some cases had both cytosol and nuclear STK15 expression. Interestingly, the percentage of nuclear STK15 expression increased following the progression from non-cancerous tissue to primary tumor, then to metastatic tumor. Furthermore, higher nuclear STK15 expression was significantly associated with the worse survival rate of OSCC patients. We further elucidated the functions of STK15 in OSCC by using shRNA to knockdown STK15 in OECM-1 cells. The results showed that the proliferation, migration and anchorage-independent growth were decreased and autophagy was induced after STK15 knockdown in OECM-1 cells. This study provides clinicopathological and functional evidences suggesting that STK15 is oncogenic for OSCC. Preclinical therapeutic trials is underway to clarify if the knockdown of STK15 bestows potential therapeutic efficacy for controlling OSCC.
目錄
中文摘要 1
Abstract 2
緒論 4
一、口腔癌 4
二、口腔癌之基因變異 5
三、STK15(絲胺酸/酥胺酸激酶15)的功能簡介 6
四、STK15與癌症 7
五、細胞凋亡與自噬 8
研究目標 14
研究材料與方法 15
壹、細胞培養 15
貳、細胞及組織DNA萃取 17
叁、同步定量聚合酶連鎖反應(Quantitative Real-time PCR) 18
肆、西方墨點法(Western Blot) 19
伍、組織切片與免疫組織染色 21
陸、Lentivirus製備 23
柒、病毒感染 25
捌、致癌能力分析(Tumorigenesis Assay) 25
玖、螢光染色(Fluorescence Staining) 27
拾、統計分析 27
研究結果 29
一、STK15的基因套數在口腔鱗狀上皮細胞癌細胞株之基因變化 29
二、STK15的基因套數在口腔鱗狀上皮細胞癌組織之基因變化及其臨床病理意義 29
三、STK15的基因套數在嚼食檳榔之健康者及原發和復發之口腔鱗狀上皮細胞癌組織之基因變化 30
四、STK15蛋白在口腔鱗狀上皮細胞癌細胞株及腫瘤組織之表現 31
五、STK15刪減對細胞表型之影響 32
六、STK15刪減後細胞死亡現象之探討 34
討論 36
研究結論 41
圖 42
表 58
附圖 65
附表 74
參考文獻 75
附錄 82

圖次目錄
圖一、口腔鱗狀上皮細胞癌細胞株之STK15基因套數高於正常口腔上皮細胞之STK15基因套數 42
圖二、STK15基因套數在口腔鱗狀上皮細胞癌高危險群、原發性口腔鱗狀上皮細胞癌及復發性口腔鱗狀上皮細胞癌組織有漸進式增高 43
圖三、復發性口腔鱗狀上皮細胞癌組織之STK15基因套數增幅較原發性口腔鱗狀上皮細胞癌組織之STK15基因套數增幅顯著增加 44
圖四、口腔鱗狀上皮細胞癌細胞株SAS及OECM-1之STK15蛋白表現較正常口腔上皮細胞NHOK高 45
圖五、免疫組織染色法偵測STK15在癌旁組織、口腔鱗狀上皮細胞癌組織及淋巴轉移腫瘤組織之分布情形 46
圖六、細胞核之STK15蛋白表現在癌旁組織(NCMT)、口腔鱗狀上皮細胞癌(OSCC)與淋巴轉移腫瘤組織(LNM)有漸進式增高,且口腔鱗狀上皮細胞癌STK15在細胞核表現高低與病人存活度有關 47
圖七、利用西方墨點法分析病毒感染OECM-1後所篩選穩定細胞株之STK15刪減效果 48
圖八、STK15 shRNA viral vector經由限制酶切割確認所純化之質體之正確性 49
圖九、利用西方墨點法分析病毒感染OECM-1後24、48、72小時STK15刪減效率,以感染後24小時STK15刪減效率最好 50
圖十、刪減STK15後, OECM-1之生長能力下降 51
圖十一、刪減STK15後, OECM-1之移行能力下降 52
圖十二、刪減STK15後, OECM-1之非貼附性生長能力下降 53
圖十三、OECM-1之STK15被刪減後5天之細胞型態 54
圖十四、OECM-1之STK15被刪減後4天及5天,半胱胺酸蛋白酶第三型之Pro-form的表現下降,但亦有少部分細胞之半胱胺酸蛋白酶第三型活性上升 55
圖十五、OECM-1-pEGFP-C1-LC3之STK15被刪減後4天及5天細胞自噬比例增加 56
圖十六、OECM-1之STK15被刪減後4天或5天膜型之LC3B-II量上升 57

表次目錄
表一、 分析STK15基因套數在口腔鱗狀上皮細胞癌細胞株、口腔鱗狀上皮細胞癌原發組織、口腔鱗狀上皮細胞癌復發組織及高危險群之變化 58
表二、 口腔鱗狀上皮細胞癌組織STK15基因套數增幅及蛋白質表現與臨床病理關係分析 59
表三、癌旁組織(NCMT)與口腔鱗狀上皮細胞癌(OSCC)組織之細胞核STK15免疫組織染色分析 60
表四、口腔鱗狀上皮細胞癌之STK15套數變化及核STK15蛋白表現之分析 61
表五、 同步定量PCR引子序列 62
表六、 抗體 63
表七、STK15 shRNA序列 64

附圖、附表目錄
附圖一、口腔癌化之基因變化模式 65
附圖二、比較基因雜交法分析出口腔鱗狀上皮細胞癌細胞株SAS及OECM-1在染色體20q有基因增幅的現象,OC3則是整個第20對染色體基因都有增幅 66
附圖三、細胞死亡之分類 67
附圖四、攜帶STK15 shRNA的Viral vector,STK15 shRNA位置在Age I及Eco RI之間 68
附圖五、Lentivirus製備與感染流程 69
附圖六、pCMVΔR8.91質體簡介 70
附圖七、pMD.G質體簡介 71
附圖八、pLKO.1-shLuc質體簡介 72
附圖九、pEGFP-C1-LC3質體,LC3 cDNA接在Pvu II及Nar I之間 73
附表一、行政院衛生署公佈台灣地區主要癌症死亡原因(2007年) 74
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