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研究生： 沈雨璇
Shen, Yu-Shiuan
論文名稱： 建立高侵襲性之消化系統癌細胞株並分析其細胞特異性
Establishment and characterization of highly invasive digestive system carcinoma cell lines
指導教授： 王群超
Wang, Chun-Chao
口試委員: 邱慶豐
Chiu, Ching-Feng
廖柏翔
Liao, Po-Hsiang
學位類別： 碩士
Master
系所名稱： 生命科學暨醫學院 - 分子醫學研究所
Institute of Molecular Medicine
論文出版年： 2020
畢業學年度： 108
語文別： 英文
論文頁數： 60
中文關鍵詞： 消化系統癌 、轉移 、肝癌 、胰臟癌 、高轉移 、高侵襲
外文關鍵詞： Digestive system cancers, liver cancer, pancreatic cancer, cancer metastasis, migration, invasion
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    • 關鍵字: 消化系統癌(Digestive system cancers, DSC)、轉移、肝癌、胰臟癌、高轉移、高侵襲
    消化系統癌症（DSC）是全球常見的惡性癌症類型。消化系統包括食道、胃、肝臟、胰臟，和大小腸。大多數DSC的病患初期通常因為沒有症狀或其他疾病掩蓋而造成延遲診斷，往往確診時已是晚期甚至出現轉移到其他器官的情況。而晚期的癌症診斷非常困難，治療後容易發生復發，導致在治療上出現棘手的問題。癌症死亡中，有高達90%的原因是因為癌症轉移。其中肝細胞癌（HCC）患者因為不易早期確診，通常確診時已為晚期並且可能出現轉移，造成傳統化療的效果不佳。儘管肝癌治療方式不斷突破，預後仍然很差，因此目前肝癌仍然是難以治療的癌症之一。另外，胰腺癌患者治療效果很差，亦是因為前期不易診斷，診斷後都已是晚期，腫瘤已造成局部浸潤和轉移，這也是造成胰腺癌為死亡率最高的癌症之一的主要原因。然而，肝癌和胰腺癌的轉移機制仍不清楚。因此在本論文中，我們使用人類肝癌Huh-7細胞和胰腺癌AsPC-1細胞透過transwell實驗的方式，建立高遷徙/侵襲的細胞模式。將癌細胞接種在不含基質的transwell chamber上，培養24小時後，收集移至chamber底部的細胞，將這些細胞繼續培養，反覆篩選三次後得到高遷徙細胞Huh-7/M3和AsPC-1/M3 細胞。接著我們進一步利用高遷徙細胞接種到含有基質的transwell上，培養72小時後，收集通過chamber底部的細胞，將這些細胞繼續培養，反覆二次後建立高侵襲細胞Huh-7/M3-I2和AsPC-1/M3-I2細胞。我們也利用了transwell遷移及侵襲實驗證實我們所建立之細胞株具有高遷移及高侵襲能力。我們也進一步比較了親代、高遷移及高侵襲細胞株型態、生長、遷移/侵襲及細胞週期之間差異。在未來，我們可以利用所建立的高轉移及高侵襲的肝癌以及胰臟癌細胞模型，篩選新的診斷標誌並作為發展有效的治療方法的參考依據。

    Digestive system cancers (DSC) are the most common malignancy worldwide. The digestive system contained several organs, such as esophagus, stomach, intestine, colorectum, pancreas, gallbladder and liver. In clinical, the outcome of DSC remains unfavorable and the survival rate is poor, mainly because of late diagnosis, recurrence and tumor metastasis. Among 90% of cancer-associated deaths are due to cancer metastasis, which means the original tumor cells from initial or primary tumor to the distant sites. Metastasis is also the major wherefore for poor prognosis of liver cancer and pancreatic cancer. The metastatic process of liver cancer and pancreatic cancer including several steps, cancer cells via a peripheral blood vessel or lymphatic vessel move to liver, lung, peritoneum, brain and other parts of tissues and organs, then the tumor cells conduct division and growth. Nevertheless, the mechanisms of metastasis in liver cancer and pancreatic cancer are still not fully revealed. Therefore, understanding the mechanism of metastasis is important. In this study, we use human liver cancer (Huh-7) and pancreatic cancer (AsPC1) cell lines to establish high migration/invasion cell models by transwell assays. First, parental liver cancer and pancreatic cancer cells were seeded onto the noncoated membrane. After 24 hr. incubation, cells migrated to the bottom-well were collected. These cells were regrown and repeatedly passed through the migratory selection three times and resulted in the cells with high migratory ability, Huh-7/M3 and AsPC1/M3. Next, Huh-7/M3 and AsPC1/M3 cells were further seeded onto matrigel-coated membrane in the chamber. After 72 hr, the cells invade to the bottom of the chamber and cells were collected as invasive populations which grown in the culture medium. These steps were repeated for two times, the obtain cells have high invasive ability, we call the Huh-7/ M3-I2 and AsPC1/M3-I2 cells. Utilizing these valuable cell models, we can screen novel diagnostic biomarkers and develop effective therapeutic agents for liver cancer and pancreatic cancer patients.

    Keywords: Digestive system cancers (DSC), liver cancer, pancreatic cancer, cancer metastasis, migration, invasion.  

    目錄 (TABLE OF CONTENTS) 目錄 (TABLE OF CONTENTS) I 中文摘要 III 英文摘要(Abstract) IV 1. 前言(Introduction) 1 1.1 Digestive system cancer (DSC) 1 1.2 Metastasis and Cancers 3 1.3 Liver cancer 5 1.4 Pancreatic cancer 7 1.5 Hypothesis and Specific Aim 10 2. 材料與方法 (Materials and methods) 11 2.1 Cell lines 11 2.2 Cell proliferation assay 11 2.3 Colony formation 11 2.4 Migration assay 12 2.5 Invasion assay 12 2.6 Wound healing assay 13 2.7 Cell cycle analysis 13 2.8 Statistical analysis 13 3. 結果 (Results) 14 3.1 Establishment of HCC cell lines with difference migratory ability. 14 3.1-1 Cell growth and colony formation analyses of parental and migratory HCC cell lines. 14 3.1-2 Cell cycle analysis of parental and migratory HCC migration cell lines. 15 3.1-3 Migration ability of parental and migratory HCC migration cell lines. 15 3.2 Establishment of PDAC cell lines with difference migratory ability. 16 3.2-1 Cell growth and colony formation analyses of parental and migratory PDAC cell lines. 16 3.2-2 Cell cycle analysis of parental and migratory PDAC cell lines. 17 3.2-3 Migration ability of parental and migratory PDAC cell lines. 17 3.3 Establishment of HCC cell lines with difference invasionary ability. 18 3.3-1 Cell growth and colony formation analysis of parental and invasionary HCC invasion cell lines. 18 3.3-3 Cell cycle analysis of parental and invasionary HCC cell lines. 19 3.3-2 Invasion ability of parental and invasionary HCC cell lines. 19 3.4 Establishment of PDAC cell lines with difference invasionary ability. 20 3.4-1 Cell growth and colony formation analysis of parental and invasionary PDAC invasion cell lines. 21 3.4-2 Cell cycle analysis of parental and invasionary PDAC invasion cell lines. 21 3.4-3 Invasion ability of parental and invasionary PDAC cell lines. 21 4. 討論 (Discussion) 23 5. 參考文獻 (Reference) 26 6. 圖片 (Figures) 37

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