探討新建立子宮頸神經內分泌腫瘤細胞株之特徵與藥物反應分析

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研究生：	賴姿吟 Lai, Zih-Yin
論文名稱：	探討新建立子宮頸神經內分泌腫瘤細胞株之特徵與藥物反應分析 Characterization and Drug Response Analysis of a Newly Established Neuroendocrine Cervical Carcinoma Cell Line
指導教授：	莊永仁 Chuang, Yung-Jen
口試委員:	張幸治 Chang, Shing-Jyh 詹鴻霖 Chan, Hong-Lin 郭靜娟 Kuo, Ching-Chuan 陳冠宇 Chen, Guan-Yu
學位類別：	博士 Doctor
系所名稱：	生命科學暨醫學院 - 生物資訊與結構生物研究所 Institute of Bioinformatics and Structural Biology
論文出版年：	2017
畢業學年度：	105
語文別：	英文
論文頁數：	64
中文關鍵詞：	子宮頸神經內分泌腫瘤、合併療法、基因毒性藥物、磷脂醯醇3激酶抑制劑、BEZ235
外文關鍵詞：	Neuroendocrine cervical carcinoma, Combination therapy, Genotoxic drug, PI3K inhibitor, BEZ235
相關次數：	點閱：3 下載：0
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子宮頸神經內分泌腫瘤是子宮頸癌中相當罕見且具有高侵犯性的類型。至今，並沒有相關體外細胞株可供建立細胞研究模式，這也阻礙了臨床上發展治療子宮頸神經內分泌腫瘤的相關研究。本篇研究因此規劃從活體組織樣本分離出原代培養細胞，希望藉此細胞株，研究治療子宮頸神經內分泌腫瘤的合併藥物療法。
透過檢體細胞分離選殖的方式，子宮頸神經內分泌腫瘤的原代細胞成功的從一位75歲女性患者檢體中被分離出來，此細胞株被命名為HM-1。我們首先探討關於HM-1細胞株的特徵型態：包含生長曲線、生物標記以及人類乳突病毒感染等情形。研究結果顯示，HM-1細胞株高度表現神經內分泌細胞的生物標記synaptophysin。在HM-1細胞株中也發現了感染第16型人類乳突病毒; 此外，將HM-1細胞株異種移植至裸鼠上，證實HM-1細胞株確實可以形成腫瘤。
我們接著使用磷脂醯醇3激酶抑制劑：BKM120、BEZ235，或者BEZ235搭配兩種現行治療子宮頸神經內分泌腫瘤的化療藥物：etoposide和cisplatin，進行不同藥物排列組合的抗癌功效分析。利用HM-1細胞株檢測細胞存活率、細胞凋亡以及目標蛋白表現等各種數據，希望藉此找出其中最有抑癌效果的藥物組合。一如預期，研究結果顯示，etoposide和cisplatin的藥物組合，可以有效地抑制HM-1細胞株的增生。而當磷脂醯醇3激酶抑制劑BEZ235搭配etoposide和cisplatin，HM-1的生長會被更顯著抑制。另一方面，我們發現HM-1受磷脂醯醇3激酶抑制劑BEZ235處理後，會下調pAKT 及 p4E-BP1的蛋白表現量。綜合來說，這些實驗結果顯示，當磷脂醯醇3激酶抑制劑BEZ235搭配etoposide和cisplatin作為處理HM-1細胞株的藥物組合時，不僅能有效抑制HM-1細胞增生更能增加HM-1細胞凋亡。
這個新建立的子宮頸神經內分泌腫瘤細胞株HM-1，不僅是實用的細胞研究工具，使用HM-1找出的協同藥物合併療法：磷脂醯醇3激酶抑制劑搭配現行使用的基因毒性藥物，也許能成為子宮頸神經內分泌腫瘤臨床治療上的新治療方針。

Neuroendocrine cervical carcinoma (NECC) is a rare and aggressive subtype of cervical cancer. To date, no NECC cell-based model is available, which hinders the development of new therapeutic strategies for NECC. In this study, we derived a new NECC cell line from an ex vivo biopsy and used it to explore novel drug combination approach for NECC therapy.
A NECC tissue sample from a 75-year-old female patient was processed to derive a primary cell line annotated as HM-1. The features of HM-1 in growth kinetics, biomarker profiles, and HPV exposure were analyzed to establish its characteristic profile. Next, HM-1 was treated with phosphatidylinositol-3 kinase (PI3K) inhibitors, BKM120 or BEZ235, or BEZ235 in combination with the two known genotoxic drugs, etoposide and/or cisplatin, that have been used in current NECC therapy, to evaluate which drug combination could serve as a more effective treatment approach. The inhibiting effects on HM-1 were evaluated by cell viability, apoptosis, and target kinase expression.
The stable NECC cell line HM-1 displayed high expression levels of the neuroendocrine marker, synaptophysin. Human papillomavirus-16 was also found in HM-1 and HM-1 cell transplantation could induce tumor growth in nude mice. As expected, the combination of etoposide and cisplatin could synergistically inhibit HM-1 cell proliferation. Strikingly, when etoposide and cisplatin were combined with PI3K inhibitor BEZ235, the growth of HM-1 cells was significantly reduced. Kinase profiling revealed the expression levels of pAKT and p4E-BP1 were affected by BEZ235 treatment. Taken together, the data implied the combination of genotoxic drugs (etoposide and cisplatin) with BEZ235 not only inhibited HM-1 cell proliferation but also increased cell apoptosis.
The newly established NECC cell line HM-1 could serve as a cell-based model for NECC research. The synergistic drug combination of PI3K inhibitor with genotoxic drugs might become a new treatment strategy against NECC.

中文摘要    I
Abstract    III
Abbreviations    V
Table of contents    VII
   Introduction    1
1 Cervical cancer    2
2 Neuroendocrine cervical carcinoma (NECC) and its treatment strategies    3
3 Genotoxic agents for neuroendocrine cervical carcinoma (NECC)    4
4 Target therapy and phosphatidylinositol-3 kinase (PI3K) signaling pathway    5
5 Synergistic anti-cancer activity of drug combinations    7
6 Objectives and significant finding of this study    7
   Materials and methods    9
1 Ethics approval and consent to participate    10
2 Cancer cell isolation and cell culture    10
3 SH-SY5Y and H9C2 cell culture    11
4 Doubling time assay    12
5 Short tandem repeat (STR) analysis    12
6 HPV detection    12
7 Western blot analysis    13
8 Immunocytochemistry (ICC)    13
9 Xenotransplantation    14
10 Genotoxic agents and PI3K inhibitors    14
11 Cell proliferation assay    15
12 Cell viability assay    15
13 DNA fragmentation ELISA    15
14 Cell Caspase-3 apoptosis    16
15 Statistics    17
   Results    18
1 Establishment of a new neuroendocrine cervical carcinoma cell line in vitro    19
2 HM-1 is a novel neuroendocrine cervical carcinoma cell line    19
3 General characteristics of HM-1 cells derive from human NECC:          morphology, growth rate and HPV infection    20
4 HM-1 cells express the neuroendocrine marker synaptophysin (SYP)    21
5 In vivo xenotransplantation of HM-1    22
6 Combination of etoposide and cisplatin effectively inhibits the growth of NECC    22
7 PI3K inhibition decreases HM-1 cell proliferation    24
8 PI3K inhibition results in an increase in HM-1 apoptosis and DNA damage    25
9 The triple-drug combination of etoposide, cisplatin and BEZ235 is the most effective in suppressing HM-1 viability and increasing HM-1 apoptosis in vitro    25
   Discussion    27
1 HM-1 is a cell-based NECC research model    28
2 HPV infection might correlate to the tumorigenesis of NECC    28
3 Epithelial-to-mesenchymal transition (EMT) might play a critical role in high metastatic rate of NECC    29
4 PI3K/Akt/mTOR signaling pathway might be involved in driving NECC progression    31
5 BEZ235 is a potential drug for treating NECC    32
6 Other potential drugs for treating NECC    33
7 More clinical samples are required for studying NECC    34
8 Perspective of this study    35
   References    36
   Tables    45
Table 1. Antibodies list    46
Table 2. Allele table for the HM-1 cells    47
Table 3. Comparison the STR profile between HM-1 cells and other neuroendocrine tumor cell lines    48
Table 4. Comparison the STR profile between HM-1 cells and ATCC database    49
   Figures    50
Figure 1. Characterization of HM-1 cells.    51
Figure 2. HM-1 cells expressed the neuroendocrine marker neuroendocrine synaptophysin (SYP).    52
Figure 3. In vivo xenotransplantation of HM-1.    54
Figure 4. Dose response curves of HM-1 cells to etoposide and cisplatin treatment.    55
Figure 5. PI3K inhibitors decreased cell proliferation rate and cell viability of HM-1 cells.    57
Figure 6. PI3K inhibitors enhanced cell apoptosis of HM-1 cells.    59
Figure 7. Triple-drug combination of etoposide, cisplatin and BEZ235 resulted in more effective cell inhibition and DNA damage in HM-1.    61
Figure 8. Schematic model for a novel therapeutic strategy for treating NECC.    62
   Appendix figure    63
Figure A1. HM-1 cells expressed the EMT mesenchymal marker, vimentin.    64


                                

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