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研究生:吳泰昇
研究生(外文):Tai-Sheng Wu
論文名稱:MLL1經由c-MYC增加癌細胞放射線抗性及幹細胞特性
論文名稱(外文):Methyltransferase MLL1 Increased Radioresistance andStemness Properties in Cancer Cells through c-MYC
指導教授:郭彥彬郭彥彬引用關係章浩宏章浩宏引用關係
口試委員:江俊斌魏耀揮林芸薇
口試日期:2017-06-14
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:臨床牙醫學研究所
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:2017
畢業學年度:105
語文別:英文
論文頁數:103
中文關鍵詞:BCL10癌症轉移放射線抗性表基因修飾癌症幹細胞口腔鱗狀上皮細胞癌
外文關鍵詞:BCL10MetastasisRadioresistanceEpigenetic modificationCancer stem cellOSCC
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惡性度較高的癌細胞通常表現出較高的侵入能力以及生長力,而這些能力與促使口腔鱗狀上皮細胞癌轉移有所關聯,也似乎會去影響到癌細胞對於治療的反應。基因的轉錄、分子的表基因調控、以及細胞的訊息傳遞皆是促成口腔鱗狀上皮細胞癌生成的基礎,並且更會造成細胞顯型的改變。本論文在探討促使口腔癌進程的可能致癌基因以及研究表基因修飾調控所造成的口腔癌放射線抗性機轉。
在第二章中,我們著重在細胞凋零調控蛋白BCL10,其已經被發現與口腔癌惡性程度以及再復發有所關聯。抑制內生性BCL10 的表現量能夠顯著的降低細胞移動以及侵襲能力,並且阻礙細胞生長以及抑制腫瘤生成。在分子層面上,我們發現S100P 是BCL10 誘導細胞進程的重要下游調控因子。S100P 的mRNA 以及蛋白質表現皆在抑制BCL10 轉殖株中顯著降低,且轉染S100P 表現質體後可以明顯的恢復細胞移動、侵入、生長以及腫瘤生長的能力。我們也提供證據證實BCL10 調控S100 的表現量是經由轉錄因子STAT1 以及ATF4,在抑制BCL10表現量後會明顯降低S100P 啟動子活性,但是將其SAT1/ATF4 的結合位置截斷的啟動子則
不會受到影響。除此之外,BCL10 促進的口腔癌進程有P50/P65 訊息傳遞參與,在抑制BCL10轉植株中回復S100P 表現量可以明顯重建P65 的活性。
由於現今口腔癌的再復發一直是臨床上遇到的重大難題,其中一部分是因為口腔癌的惡性以及侵入能力,而另一方面則是放射線治療上無法成功的移除殘餘癌細胞。在第三章中,我們分析了組蛋白甲基化轉移酶的表現量在癌症幹細胞、脂肪幹細胞以及放射線處理之癌細胞中,發現了H3K4 組蛋白甲基化轉移酶在幹細胞特性以及放射線抗性上實為重要。除此之外,我們更進一步找出其中一個H3K4 組蛋白甲基化轉移酶MLL1 在癌症幹細胞以及具有放射線抗性的口腔癌細胞和大腸癌細胞皆有高度表現。抑制MLL1 的表現會明顯增加原本具有抗性之口腔癌及大腸癌細胞的放射線敏感度、降低癌細胞聚球以及腫瘤生成能力。更進一步的我們分析出具有放射線抗性的細胞以及口腔癌臨床檢體中c-MYC 下游基因皆有顯著上升的情形,並且發現MLL1 會經由直接結合到c-MYC 啟動子的區域,促進其表現量後使其下游
基因表現量增加進而造成細胞具有幹細胞特性以及放射線抗性。
總結來說,我們發現了一個經由BCL10 調控STAT1/ATF4/S100P/P65 訊息傳遞鏈促使口腔癌進成的新路徑,可作為口腔癌的預後因子以及有潛力發展為口腔癌治療的新策略。除此之外,我們還證實了組蛋白甲基化轉移酶MLL1 可以經由表基因修飾機轉調控幹細胞特性以及放射線抗性,提供了一個新的移除癌症幹細胞的治療目標。
Advanced cancer cells show higher invasion and proliferation abilities, and such capacities have implications in progression of oral squamous cell carcinoma (OSCC) to metastasis, and will likely influence response to therapy. The transcriptional and epigenetic regulation of molecular and cell signaling that underlie OSCC and result in characteristic change in cell phenotype. We investigated the potential oncogene in cancer progression and elucidated the crucial epigenetic regulator in radioresistance of OSCC.
In chapter II, we focus on an apoptotic regulatory protein named BCL10, which related to advanced TNM stage and disease recurrence in OSCC. Knockdown of endogenous BCL10 significantly reduce cell migration and invasion abilities, retard cell proliferation and inhibit tumorigenicity in vivo. In molecular level, we identified S100P as a crucial downstream effeter of BCL10-mediated OSCC progression. S100P mRNA and protein expression levels significantly diminished in silenced BCL10 clones, and transfected S100P expression plasmids restored migration, invasion, proliferation abilities and tumorigenicity in shBCL10 transfectants. We provided evidence that BCL10 regulated S100P expression through STAT1 and ATF4, and knockdown of BCL10 decreased S100P promoter activity, but showed no effect in truncated STAT1/ATF4 S100P promoter. In addition, P50/P65 signaling pathway was involved in BCL10-enhanced OSCC progression. Restored S100P in silenced-BCL10 clones could markedly reverse P65 activation via outside-in signaling.
Because relapsed of OSCC represents a major clinical challenge in part due to their aggressive and invasive behaviors, and the fact that the radiotherapy has not succeeded eliminate the residual cancer. In chapter III, we analyzed histone methyltranferases (HMT) expression profile of stem-like cancer cells, adipose-derived stem cells, and IR-treated cancer cells, and identified histone H3-lysine 4 (H3K4) as a crucial residue for epigenetic modification in stem cell phenotype and radio-resistance contribution. Moreover, we have determined that one of H3K4 HMT, mixed-lineage leukemia 1 (MLL1), which is highly expressed in stem-like cells and IR-resistant OSCC and colorectal cancer cells (CRC). Knockdown of MLL1 in IR-resistant OSCC and CRC cells significantly induced radiosensitivity, disrupted cancer spheroid formation, and decreased tumorigenicity in vivo. Furthermore, IR-resistant subpopulation in both cancer cell lines and OSCC patients were highly expressed c-MYC downstream target genes, and we founded that MLL1 directly bound to HOXC8 and c-MYC promoter region, and further induced downstream effecter expression that contribute stemness properties and IR resistance.
In summary, we discover a novel axis of BCL10-regulated OSCC progression via STAT1/ATF4/S100P/P65 signaling, which could predict the prognosis of OSCC and will be beneficial for developing therapeutic strategy against advanced OSCC. In addition, we also demonstrate and characterize an epigenetic mechanism that underlines MLL1 in the regulation of stem cell feature and IR resistance, suggesting a potential therapeutic target for eradicating stem-like cancer cells.
目錄 (Index)
口試委員審定書.............................................. i
中文摘要.................................................. ii
英文摘要.................................................. iv
目錄 (Index) ............................................ vi
第一章 序論 (Introduction) ................................ 1
第一節 人類口腔鱗狀細胞癌 (Human oral squamous cell carcinoma) ............................................... 2
第二節 B 細胞淋巴癌10 號(B cell lymphoma/leukemia 10) ....... 4
第三節 組蛋白甲基化酶 (Histone methyltransferase) ........... 5
第四節本論文的研究動機與方向 (Motivation and purpose in this thesis)....................................................6
第二章 (B-Cell Lymphoma/Leukemia 10 Promotes Oral Cancer Progression through STAT1/ATF4/S100P Signaling Pathway) ................................................. 7
第一節 摘要 (Abstract) .................................... 8
第二節 前言 (Introduction)............................................ 9
第三節 材料與方法 (Materials and methods) ................. 11
第四節 實驗結果 (Results) ................................. 16
第五節 討論 (Discussion) ................................. 20
第六節 表格 (Tables) ..................................... 22
第六節 附圖及說明 (Figures and figure legends)............. 25
第三章(Methyltransferase MLL1 Increased Radioresistance and Stemness Properties in Cancer Cells through c-MYC) ...... 39
第一節 摘要 (Abstract) ................................... 40
第二節 前言 (Introduction) ............................... 41
第三節 材料與方法 (Materials and methods) ................. 43
第四節 實驗結果 (Results) ................................. 47
第五節 討論 (Discussion) ................................. 54
第六節 附圖及說明 (Figures and figure legends)............. 58
第四章 結論 (Conclusion) ................................. 86
參考文獻 (Reference)...................................... 89
附錄:已發表之論文(Publication list) ...................... 103
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