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研究生:王化邦
研究生(外文):Hua-Bang Wang
論文名稱:探討Ddx3x在小鼠腸道上皮中所扮演的角色
論文名稱(外文):Functional Role of Ddx3x in mouse colorectal epithelium
指導教授:陳俊銘陳俊銘引用關係
指導教授(外文):Chun-Ming Chen
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:生命科學系暨基因體科學研究所
學門:生命科學學門
學類:生物訊息學類
論文種類:學術論文
論文出版年:2017
畢業學年度:105
語文別:中文
論文頁數:58
中文關鍵詞:大腸癌結腸炎腸道上皮
外文關鍵詞:DDX3Xcolorectal cancercolitisDNA damage
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Ddx3x為一種具有多功能性的DEAD-box RNA解螺旋酶,其幾乎參與所有細胞內RNA的代謝過程,包含轉錄、RNA剪接、mRNA的出核以及轉譯等作用。過去研究也表明Ddx3x也參與在細胞週期的調控、腫瘤形成過程以及HIV感染宿主的過程中。然而近年來在in vitro探討Ddx3x的功能的相關研究指出,Ddx3x在腫瘤形成過程中可能扮演著抑癌基因或是致癌基因的兩種截然不同的角色。本篇研究利用能夠在腸道上皮細胞中表現的Villin-Cre基因轉殖小鼠,專一性的在小鼠的腸道上皮中進行Ddx3x的剔除,配合給予AOM烷化致變劑以及DSS誘發小鼠結腸炎產生,進而探討Ddx3x在腸道腫瘤形成過程、發炎反應以及DNA損傷反應中所扮演的角色。我們的結果顯示,在AOM/DSS處理之下,18周齡的Vil-Ddx3xflox/flox基因剔除小鼠相較於control有明顯數量較多且較大的腸道腫瘤生成,表明Ddx3x在腸道上皮的缺失可促進AOM/DSS誘導的大腸直腸腫瘤進程。而以DSS探討Ddx3x在小鼠結腸炎模式扮演的角色中,我們發現在DSS處理一周的過程中,Vil-Ddx3x公母基因剔除小鼠相較於control表現出體重顯著下降的情形;組織學以及腸道通透性分析結果也表明經過DSS處理後的Vil-Ddx3xflox/flox基因剔除小鼠有較嚴重的腸道上皮損傷。另外,在DSS長期處理後,H&E組織染色分析顯示Vil-Ddx3xflox/flox小鼠中相較於control小鼠呈現出腸道上皮排列較不緊密的現象,表明Ddx3x的缺失同樣影響腸道上皮的再生過程。
另外,由於近年來多項研究證據顯示,Ddx3x可能參與在DNA損傷修復的過程之中。因此我們藉由單獨給予小鼠AOM處理的方式,探討Ddx3x在AOM誘導之DNA損傷反應中所扮演的角色。我們的結果顯示,經AOM處理後的Ddx3xflox/flox與Ddx3xflox/Y小鼠相較於untreated組別,其腸道上皮中Ddx3x皆表現出大量進核的現象;AOM處理後的Ddx3xflox/Y公鼠腸道上皮內Ddx3x表現量更呈現顯著上升的情形。在進一步分析Vil- Ddx3x基因剔除小鼠腸道上皮細胞內DNA損傷反應相關蛋白質的表現量,我們發現在AOM處理下,Vil-Ddx3x公母基因剔除小鼠相較於control表現出DNA損傷標記RPA磷酸化程度顯著上升的現象,其中Vil-Ddx3xflox/Y小鼠更表現出Mre11顯著上升的情形,顯示Vil-Ddx3x基因剔除小鼠於AOM處理下其DNA損傷程度較高。綜合以上所述,我們的結果表明,Ddx3x在腸道上皮的缺失可促進小鼠中AOM/DSS誘導的大腸直腸腫瘤形成、對於DSS處理有較低的耐受性並對腸道上皮的再生過程產生影響。並且在AOM處理之下,Ddx3x的缺失可引發腸道上皮細胞更高程度的DNA損傷。
Ddx3x, a member of DEAD box RNA helicase family, has multiple functions involved in all aspects of RNA metabolism, including transcription, RNA splicing, mRNA nuclear export and translation. Ddx3x is also reported to participate in the cell cycle regulation, tumorigenesis and viral infection. Recently, several studies contradictorily reported that Ddx3x has oncogenic and tumor suppressive roles in colorectal cancer cell lines. In my study, I propose to conduct tissue-specific ablation of Ddx3x in mice and address the role of Ddx3x in colorectal epithelial homeostasis and tumorigenesis. Firstly, I used AOM/DSS approach, which induces inflammation-associated colorectal cancer development in mice, to address the role of Ddx3x in colorectal cancer development. I found more tumors developed in 18-week-old Villin-Cre/+;Ddx3xflox/flox mice than that in controls under AOM/DSS treatment. These preliminary results indicate that Ddx3x loss promotes AOM/DSS-induced colorectal cancer progression. Secondly, I used DSS to induce colitis for investigating colorectal epithelial regeneration in Ddx3x knockout mice. Compared with Ddx3xflox/flox control mice, the body weights of Villin-Cre/+; Ddx3x flox/flox mice show a significant decrease after DSS treatment. The permeability assay and histology of colorectal epithelium also indicate severe damages in DSS-treated Villin-Cre/+;Ddx3xflox/flox mice compared to controls.
In addition, previous study has reported that loss of Ddx3x leads to higher levels of DNA damage during embryogenesis. In order to investigate the functional role of Ddx3x in DNA damage response during intestinal carcinogenesis, I treated control mice with 3 doses of alkylating agent AOM and then examined the expression and localization of Ddx3x in colorectal epithelium using immunofluorescence and western blotting analysis. I found higher levels of Ddx3x in colorectal epithelium of AOM-treated Ddx3xflox/Y mice than that in the untreated group. Also, the nuclear Ddx3x was clearly observed in colorectal epithelial cells of AOM-treated control mice. Also, I examined the expression levels of proteins involved in DNA damage response pathways in the AOM-treated colorectal epithelium. I found higher levels of phosphorylated RPA32, which served as a marker for sites of DNA damage, in the colorectal epithelium of AOM-treated Villin-Cre/+;Ddx3xflox/flox and Villin-Cre/+;
Ddx3xflox/Y compare to controls. The higher levels of Mre11 were also observed in AOM-treated Villin-Cre/+;Ddx3xflox/Y colorectal epithelium compare to controls. These findings show that loss of Ddx3x appears to have increased DNA damages during AOM-induced DNA damage response and impaired epithelial healing during DSS-damaged intestinal epithelial regeneration.
目錄……i
中文摘要…… iii
Abstract……iv
I. 緒論……1
I-1消化系統與腸道疾病……1
I-2 Ddx3x的多功能性角色……6
I-3 DNA損傷反應(DNA damage response, DDR)……9
I-4 研究動機……10
II. 材料與方法……11
II-1 實驗小鼠……11
II-2 聚合酶連鎖反應小鼠基因型鑑定……11
II-3小鼠組織脫水與石蠟包埋切片……13
II-4 H&E組織染色(Hematoxylin &Eosin staining) ……13
II-5免疫組織染色……13
II-6 AOM (Azoxymethane)與DSS (Dextran sulfate sodium)處理……16
II-7 腸道通透性分析(permeability assay)……16
II-8 小鼠腸道上皮組織蛋白分析……17
III. 實驗結果……19
III-1 以AOM/DSS模式探討Ddx3x在大腸癌形成過程扮演的角色……19
III-2 DSS誘導小鼠結腸炎模式中Ddx3x的功能性探討……20
III-3 探討Ddx3x在AOM誘導之DNA損傷過程中所扮演的角色……22
IV. 討論……26
IV-1 DSS處理下Ddx3x對腸道再生能力與腫瘤形成的影響……26
IV-2 結腸炎相關性腸癌與 p53 腫瘤抑制蛋白……26
IV-3 AOM 處理後的 Ddx3x 上調作用與進核現象……27
IV-4 AOM 誘導之 DNA 損傷與 MGMT 修復作用……28
IV-5 Ddx3x缺失下AOM誘導的DNA損傷反應與修復作用……29
IV-6來自於Ddx3x同源基因Ddx3y的影響……30
IV-7 腸道幹細胞中 Ddx3x 的功能性探討……31
V. 參考文獻……33
VI. Figure and legends……44
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