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研究生:羅勻瑄
研究生(外文):Yun-Shiuan Luo
論文名稱:MnSOD藉由減少氧化壓力以維持癌幹細胞族群
論文名稱(外文):MnSOD reduces ROS stress to maintain cancer stem cell
指導教授:陳彥榮
指導教授(外文):Yen-Rong Chern
口試委員:黃楓婷張玉芳華國泰
口試委員(外文):Feng-Ting Huang,Yu-Fang ChangKuo-Tai Hua
口試日期:2015-07-23
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:生化科技學系
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2015
畢業學年度:103
語文別:英文
論文頁數:51
中文關鍵詞:大腸癌癌幹細胞活性氧化物錳型超氧化物歧化酶休眠狀態
外文關鍵詞:colon cancercancer stem cellreactive oxygen speciesmanganese superoxide dismutasequiescence
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近年來大腸癌罹病率因飲食習慣及年齡結構的改變而有逐漸攀升的現象。目前對大腸癌主要以外科手術、化療、放射線治療以及標靶治療作為治療手法。然而,癌症的復發降低了病患術後的生存率。近年研究指出,在大腸癌細胞中存在一群擁有似幹細胞特性的少數族群。此族群因具有自我更新及無限制細胞分裂的能力而取名為癌幹細胞 (cancer stem cell)。癌幹細胞被指出能在化療及放射線治療中存活,並能夠產生新的腫瘤而造成癌症的復發。因此,大腸癌幹細胞成為有效治療癌症的新標的。許多研究認為癌幹細胞與幹細胞具有一定程度的相似性。而在幹細胞的眾多特性中,活性氧化物被認為參與了幹細胞與癌幹細胞調節。錳型超氧化物歧化酶 (Manganese superoxide dismutase, MnSOD)為超氧化物歧化酶的其中一型,其特別之處在於專一性地座落於細胞的粒線體中。而此特性增加了MnSOD對細胞內活性氧化物調節的重要性。過去研究曾發現MnSOD對於幹細胞的細胞命運及維持十分重要。然而,MnSOD在癌幹細胞中的角色目前尚未釐清。因此本研利用大腸癌細胞株,DLD-1,作為研究對象並同時使用懸浮培養的方式篩選大腸癌幹細胞。首先,偵測大腸癌幹細胞中的粒線體超氧化物含量,比較後發現其含量高於未經篩選之大腸癌細胞。此外,更進一步的發現調節粒線體超氧化物的MnSOD在大腸癌幹細胞含量較高。接著,我使用RNAi的方式降低MnSOD表現量後偵測其粒線體超氧化物含量,發現粒線體超氧化物含量只有在大腸癌幹細胞中上升,而非在未經篩選之大腸癌細胞裡。此外,我對大腸癌幹細胞的數量及其相關基因的表現做檢測,結果發現降低MnSOD表現量後始大腸癌幹細胞的數量降低且相關的基因表現下降。因MnSOD在過去曾被認為調節細胞週期及休眠狀態,因此我偵測MnSOD表現量降低的細胞株中休眠時期的細胞數量,結果發現MnSOD表現量會降低使休眠時期的細胞數量減少。而透過偵測不同天數培養的細胞中休眠狀態的細胞數量後,我發現癌細胞中休眠狀態的細胞比例會隨著培養時間而增加;然而,降低MnSOD表現可能會影響癌幹細胞重新回到休眠狀態。此發現可能為癌症治療提供了新的標的

Colon cancer incidence has been rising due to changes of diet habits and age composition. Surgery, chemotherapy, irradiation, and target therapy are common strategies to treat patients with different stages of colon cancer. However, tumor regrowth, which is called relapse, reduces patients’ survival rate. It was found that a subpopulation exists in colon cancer which is named colon cancer stem cell and endows stem cell-like properties including, self-renewal and limitless division. Colon cancer stem cells could survive in chemotherapy and radiation therapy and reestablish a tumor, which results in relapse. Therefore, colon cancer stem cell is considered as an efficient target for cancer therapy. Several studies reported that colon cancer stem cell may share characteristics with normal stem cells. Among natures of stem cells, reactive oxygen species (ROS) are known to involve in the regulation of cancer cells and stem cells. MnSOD is a superoxide dismutase which locates exclusively in mitochondrial matrix and is believed to be important for controlling the level of cellular ROS. It was found to be important for the fate of stem cell and cancer cell maintenance. However, the role of MnSOD in cancer stem cells is not clear. Therefore, in this study, I used the colon cancer cell line, DLD-1, under the suspension culture as colon cancer stem cells and detected the level of mitochondrial superoxide. The data showed that level of mitochondrial superoxide is higher in cancer stem cells than that in cancer cell pool. I also found that MnSOD expression level is higher in cancer stem cells. Next, we knockdown MnSOD in DLD-1 cell line and examined the population and expression of genes related to cancer stem cells, including CD24, p21, Bmi1, and ABCG2. The result showed that the amount and gene expression of cancer stem cells reduced in the knockdown cell line. Since MnSOD is known to involve in cell cycle regulation, I assumed that changes in MnSOD may disturb the quiescent cancer stem cells. By analyzing proliferation marker and DNA content, I found that the percentage of quiescent population is lower in knockdown cell line. Furthermore, I also found that knowckdown MnSOD impaired cancer cell to re-enter quiescent state by analyzing quiescent population in cells with different culture time. The results suggested that the regulation of mitochondrial superoxide by MnSOD may help in cancer stem cell pool maintenance and re-entry of quiescence. These finding might provide a novel therapeutic target for cancer treatment.

口試委員審定書 i
中文摘要 ii
Abstract iv
Table of contents vi
Introduction 1
Colon cancer 1
Concept of cancer stem cell 2
Identification of colon cancer stem cells 4
Common characteristics between stem cell and cancer stem cell 5
Reactive oxygen species (ROS) 6
Regulation of ROS 7
Manganese superoxide dismutase (MnSOD) 9
Function of superoxide dismutase family 9
Importance of MnSOD in stem cell and cancer cell 10
Materials and methods 12
Cell culture and knockdown cell line generation 12
Western blot 13
Quantitative reverse transcription PCR 13
Flow cytometry 14
Colony formation assay 15
Measurement of mitochondrial superoxide level 15
Sphere formation assay 15
Results 17
Suspension culture system enriched colon cancer stem cells 17
Colon cancer stem cells may need MnSOD to maintain the lower level of mitochondrial superoxide 17
Knockdown MnSOD increase mitochondrial superoxide in colon cancer stem cells but not in cancer cell pool 18
Knockdown of MnSOD results in the reduction of colon cancer stem cells 19
Elevated mitochondrial superoxide in colon cancer stem cell may disturb the entry of quiescent state 21
Figures 22
Discussion 34
References 40
Appendix 51



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