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研究生:賴俊凱
研究生(外文):Jun-Kai Lai
論文名稱:探討HepG2肝癌細胞受到肝臟生長因子誘發KLF4表現的現象
論文名稱(外文):Studies on HGF-induced increase of KLF4 in HepG2 cell line
指導教授:張嘉哲張嘉哲引用關係
指導教授(外文):Chia-Che Chang
學位類別:碩士
校院名稱:國立中興大學
系所名稱:生命科學系所
學門:生命科學學門
學類:生物學類
論文種類:學術論文
畢業學年度:96
語文別:中文
論文頁數:57
中文關鍵詞:肝臟生長因子
外文關鍵詞:HGFKLF4p21
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中文摘要

肝臟生長因子(Hepatocyte growth factor, HGF)又叫做分散因子(Scattering factor),因為它在細胞中扮演調控細胞生長的角色,也具有引起細胞型態改變和加強其移動能力的功能。HGF透過高專一性的接受體MET,經由不同的訊息傳遞路徑和方式,影響正常細胞或癌症細胞的特性;包括細胞增生、細胞存活、細胞移動力以及侵襲能力。Kruppel factor蛋白最早是在果蠅當中被發現,之後在人類中也發現結構類似的蛋白並命名為Kruppel-like factor (KLF)。KLF家族蛋白是和細胞分化有關的轉錄因子,目前已有超過十六個家族成員已經被發現,其中KLF4是在結腸直腸細胞中被發現的,所以又稱為Gut kruppel-like factor (GKLF)。目前的研究指出,KLF4蛋白表現在某些正常的組織當中以維持該組織細胞生理的正常,然而在癌細胞的研究中,發現KLF4蛋白在不同的癌症細胞株中扮演著不同角色。
在本論文當中發現當HepG2細胞處理HGF之後,KLF4的表現量會有上升的趨勢,此現象不管在轉譯層次或是轉錄層次都有發現,所以KLF4可能在HGF引起的眾多生理現象中扮演著某種角色。為了更確定HGF會促進KLF4表現量上升,將KLF4的啟動子轉殖出來並進行冷光測定實驗,發現HGF的確會調控KLF4啟動子增加其產物的表現量,並且調控活化的區域介於轉譯起始點前819到1374個核甘酸之間。接著將MAPK信號通路抑制劑PD98059或SP600125,中文摘要

肝臟生長因子(Hepatocyte growth factor, HGF)又叫做分散因子(Scattering factor),因為它在細胞中扮演調控細胞生長的角色,也具有引起細胞型態改變和加強其移動能力的功能。HGF透過高專一性的接受體MET,經由不同的訊息傳遞路徑和方式,影響正常細胞或癌症細胞的特性;包括細胞增生、細胞存活、細胞移動力以及侵襲能力。Kruppel factor蛋白最早是在果蠅當中被發現,之後在人類中也發現結構類似的蛋白並命名為Kruppel-like factor (KLF)。KLF家族蛋白是和細胞分化有關的轉錄因子,目前已有超過十六個家族成員已經被發現,其中KLF4是在結腸直腸細胞中被發現的,所以又稱為Gut kruppel-like factor (GKLF)。目前的研究指出,KLF4蛋白表現在某些正常的組織當中以維持該組織細胞生理的正常,然而在癌細胞的研究中,發現KLF4蛋白在不同的癌症細胞株中扮演著不同角色。
在本論文當中發現當HepG2細胞處理HGF之後,KLF4的表現量會有上升的趨勢,此現象不管在轉譯層次或是轉錄層次都有發現,所以KLF4可能在HGF引起的眾多生理現象中扮演著某種角色。為了更確定HGF會促進KLF4表現量上升,將KLF4的啟動子轉殖出來並進行冷光測定實驗,發現HGF的確會調控KLF4啟動子增加其產物的表現量,並且調控活化的區域介於轉譯起始點前819到1374個核甘酸之間。接著將MAPK信號通路抑制劑PD98059或SP600125,結果發現KLF4蛋白的表現量會因為MAPK信號通路被抑制之後下降,由此可見KLF4蛋白可能是經由MAPK信號通路調控。由於HGF透過MAPK信號通路調控細胞移動能力以及增生能力,所以推論KLF4可能是影響HGF所引起的細胞移動和細胞增生的因子之ㄧ。另外觀察KLF4下游的蛋白p21的表現量,結果發現p21的表現量和KLF4有相同的變化趨勢,推測p21可能是KLF4調控細胞增生重要的下游因子。以上的發現將有助於HGF生理功能分子機制的了解。
Abstract

Hepatocyte growth factor (HGF)/scatter factor (SF) is so named because it was identified independently as both a growth factor for hepatocytes and as a fibroblast-derived cell motility factor, or scatter factor. The receptor for HGF/SF, c-Met, controls a program of invasive epithelial growth through the coordination of cell activities. It is known that the HGF- c-MET signaling pathway can enhance tumor cell proliferation, survival, motility, and invasion. Kruppel like factors (KLFs) are transcriptional regulators that regulate several cellular functions, including proliferation. The role of one family member, KLF4, in tumorigenesis is somehow controversial; it has been reported that both RNA and protein levels of KLF4 were significantly decreased in the dysplastic epithelium of the colon while up-regulated in the breast cancer cell line.
Here, we report that KLF4 expression arises when HepG2 cells are treated with HGF, suggesting that KLF4 may be an effecter of HGF-induced cellular reaction. To study the mechanims underlying HGF-induced increase of KLF4, we cloned KLF4 promoter region and showed that HGF can activate KLF4 promoter to increase the level of KLF4 mRNA. In addition, to study the singnaling pathways that medicate HGF-induced of KLF4, we found that ERK and JNK pathway are involved. On the other hand, we found that the level of KLF4 downstream gene p21CIP1/WAF1 is also upregulated by HGF. Presumably, p21 CIP1/WAF1 upregulateion is mediated by KLF4 and may play an important role in HGF-reduced cell cycle arrest in HepG2 cell. Overall, these finding demonstrate a new machanism by which HGF regulates cellular behavior.
目次
縮寫字對照表 i
中文摘要 iii
英文摘要 v
序論 1
ㄧ、肝癌介紹 1
二、HGF文獻回顧 5
三、KLF蛋白家族文獻回顧 10
四、KLF4蛋白文獻回顧 11
五、KLF4與癌症的關係 12
研究動機與目的 14
實驗材料 15
實驗方法 17
一、 細胞株之培養與繼代 17
二、 細胞株之冷凍保存與解凍 17
三、 細胞計數 18
四、 細胞分散實驗分析 18
五、 細胞總量RNA之萃取 18
六、 反轉錄聚合酵素反應 19
七、 Realtime-PCR 20
八、 KLF4 啟動子與ORF 的選殖 23
九、 PCR 產物存化與雙限制酵素切割選殖載體與PCR 產物 23
十、 膠體DNA萃取 23
十一、 選殖載體與PCR 產物的結合作用與定序分析 24
十二、 總蛋白之萃取 24
十三、 蛋白濃度定量分析 25
十四、 西方點墨法 25
十五、 轉型作用 27
十六、 報導基因冷光測定 27
試劑配方 28
實驗結果 31
一、 HepG2細胞處理HGF產生細胞分散的現象31
二、 HGF 提升KLF4蛋白表現量伴隨著其他細胞附著及細胞增生蛋白 的改變 31
三、 HGF由轉錄層次 (transcription level) 調控KLF4表現量32
四、 HepG2細胞處裡HGF之後對MAPK訊息傳遞蛋白的影響 33
五、 利用MAPK信號通路的抑制劑探討MAPK通路相關蛋白在HGF 引起之細胞行為的影響33
六、 HGF調控KLF4蛋白表現量可能利用MAPK蛋白訊息傳遞路徑 34
討論 35
結語 38
實驗結果圖表 39
參考文獻 49
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