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研究生:鞏馬克
研究生(外文):Marco Antonio Gonzalez Sander
論文名稱:研究c-KIT-ETV1路徑對胃腸道基質瘤的癌化與進程之影響
論文名稱(外文):Investigation of the c-KIT-ETV1 Axis in Tumorigenesis and Progression of Gastrointestinal Stromal Tumors
指導教授:李財坤
指導教授(外文):Tsai-Kun Li
口試委員:董馨蓮賴逸儒
口試委員(外文):Shin-Lian DoongI-Rue Lai
口試日期:2014-07-24
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:微生物學研究所
學門:生命科學學門
學類:微生物學類
論文種類:學術論文
論文出版年:2014
畢業學年度:102
語文別:英文
論文頁數:67
中文關鍵詞:胃腸道基質瘤間葉細胞Cajal氏間質細胞受體酪氨酸激&;#37238;近膜區MiRNA
外文關鍵詞:Gastrointestinal stromal tumorsMesenchymeInterstitial cells of CajalReceptor tyrosine kinaseJuxtamembraneMicroRNA
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胃腸道基質瘤(gastrointestinal stromal tumors, 簡稱GISTs)是腸胃道中最常見的間葉細胞 (mesenchyme) 瘤, 它可能發生在腸胃道中的任何一處。這些腫瘤並非源自於上皮細胞,可能由Cajal氏間質細胞 (interstitial cells of Cajal, ICCs)造成。
世界各地的研究顯著地顯示出一致的結果,每年每百萬人口中有11到20例,胃與小腸是最常出現的地方。在外科切除後,這些腫瘤通常局部復發,擴散分佈於腹部的漿膜表面,而且經常轉移到肝臟。GIST晚期會轉移到遠處器官,包括肺臟與骨頭。
約95%利用免疫組織化學法檢測細胞表面受體KIT(CD117)為陽性,是GIST非常重要的診斷標記。c-kit 基因可以編譯出 145-kDa細胞表面糖蛋白。它是Ⅲ型受體酪氨酸激&;#37238;的家族 [type III receptor tyrosine kinase (RTK) family]成員之一,此家族其中包括platelet-derived growth factor receptor-α and -β (PDGFRA與PDGFRB)。
大部分的GISTs (約75%) 在KIT近膜區 (juxtamembrane region) 的發生突變。而導致受體本質的活化。因此突變的KIT仍然是這些腫瘤非常重要的治療標的。
這些KIT的突變與GIST的發展高度相關而且突變率的提高也被視為GIST的診斷標記。而SCF-KIT 的交互作用在許多人類細胞中包含ICCs的發展是非常重要。
雖然多數GISTs的發生是具偶發性,但有少數發生在罕見家族型 (familial forms) c-kit遺傳疾病基因特定的遺傳突變有關。家族型GISTs是體染色體顯性遺傳。
此外,由於在自然生物體中存在(GNNK+, GNNK-) 之c-KIT的兩種異構體(isoforms)。相較於轉染c-KIT-GNNK+ 之293T細胞,含有c-KIT-GNNK- isoform 之293T細胞不論在形成細胞聚落或是在soft agar中生長的能力都比較具有優勢。
另外,也有大量的文獻報導GIST的發生與ETS家族成員的ETV1的高度表現相關,被視為在這類型癌症的腫瘤生成中扮演重要的角色。另一方面,當使用KIT或MEK抑制劑治療GISTs cell lines,透過蛋白&;#37238;体降解,ETV1蛋白質含量降低。 這些報告,證明了KIT signal transduction pathway是透過MAPK路徑,穩定了ETV1。
在本篇研究,我們利用microarray技術分析了不同惡化能力的GISTs 極低 (VL)、低(L)、中(I)、高(H) 並抽取其RNA去釐清miRNA在GIST癌化的進程所扮演的角色。我們發現在GIST癌化進程中有一些miRNA表現有變化(包括miR-296, miR-627, miR-1237),而且會使ETV1的蛋白表現減少。因此我們預測這些miRNA有潛力成為 target c-KIT 3’UTR。


Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. They can occur anywhere along the gastrointestinal tract. These tumors are of non-epithelial origin potentially arising from the interstitial cells of Cajal (ICC).
Worldwide studies show strikingly consistent annual incidences of 11 to 20 per million populations with the stomach and small intestine being the most common sites. After surgical resection, these tumors usually recur locally, spread diffusely throughout the serosal surfaces of the abdomen and usually the most common site of metastases is the liver. Advanced disease is associated with metastases to more distant sites, including the lungs and bones.
Most GISTs (~95%) are immunohistochemically positive for the cell surface receptor KIT (also known as CD117), which remains as a very important diagnostic marker for these tumors. The c-kit gene encodes for a receptor tyrosine kinase (RTK), the cell surface receptor for a growth factor termed stem cell factor (SCF). KIT is a 145-kDa cell surface glycoprotein. It is a member of the type III receptor tyrosine kinase family that includes platelet-derived growth factor receptor-α and -β (PDGFRA, and PDGFRB) among others.
The majority of GISTs (~75%) contain activating mutations within the KIT juxtamembrane region. These mutations lead to the constitutive activation of the receptor and mutant KIT remains a very important therapeutic target for these tumors. These gain-of-function mutants of the c-kit proto-oncogene have been tightly associated with the development of GISTs and their elevated expression in these tumors has also been regarded as a diagnostic marker for GISTs. SCF-KIT interaction is crucial for the development of various cell types such as melanocytes, erythrocytes, germ cells, mast cells and ICCs.
Although the vast majority of GISTs incidences are sporadic, rare familial forms exist that are associated with the characteristic heritable mutations in the KIT gene. The familial form of GIST is autosomal dominant.
Knowing the existence of several naturally occurring isoforms of c-KIT (GNNK+ and GNNK-) protein we decided to investigate their effect on tumorigenesis of HEK-293T cells. We have found that, c-KIT-GNNK- is better at supporting the growth of HEK-293T cell colonies than its counterpart, c-KIT-GNNK+. Besides, c-KIT GNNK- was also stronger at promoting the anchorage-independent growth of these cells in soft agar.
Besides the very important role of c-KIT in GISTs, the ETS family member ETV1 has also been shown to be universally highly expressed in all GISTs and suggested to play an crucial role in the tumorigenesis of this type of cancer. On the other hand, when GIST cell lines are treated with either a KIT or a MEK inhibitor ETV1 protein levels can be reduced through proteasomal degradation. These reports support the current belief that KIT signaling through the MAPK pathway stabilizes ETV1 thus maintaining its activity.
In the second part of this study, we performed microRNA (miRNA)-expression profiling analyses on the isolated RNA samples of GISTs with different clinical risk schemes [very low (VL), low (L), intermediate (I) and high (H)] to gain insight of the potential role(s) of miRNAs in GIST tumorigenesis and progression. We have found that the expression of several miRNAs change during GIST tumor progression. Furthermore, a few of these miRNAs are able to down-regulate the expression of ETV1 at a protein level. These results suggest that our candidate miRNAs could be targeting ETV1 3’UTR leading to its degradation.


ACKNOWLEDGEMENTS i
摘要 ii
ABSTRACT iv
CHAPTER ONE INTRODUCTION 1
Gastrointestinal Stromal Tumors 1
History 1
Clinical Presentation and Epidemiology 2
The Origin of GISTs 4
Interstitial Cells of Cajal 4
Molecular Oncology 6
KIT 6
Alternative Splicing of c-KIT 8
Stem Cell Factor 9
ETS Translocation Variant 1 (ETV1) and GISTs 9
MicroRNAs and Cancer 10
CHAPTER TWO SPECIFIC AIMS 14
CHAPTER THREE MATERIALS AND METHODS 16
Cell Culture 16
Plasmids 16
Transfection 17
Western Blot 17
Cell Proliferation and Tumorigenic Growth Assays 18
Efficiency of Plating 18
Anchorage-independent Growth of Soft Agar 19
RNA Samples 19
cDNA Synthesis 20
PCR Amplification 20
Quantitative Measurements and Statistical Analyses 21
CHAPTER FOUR 22
RESULTS 22
ETV1 is Universally Highly Expressed in All GISTs 22
The c-Kit mRNA Contains a Predominant Splicing Isoform of GNNK- in Clinical GIST Samples 23
MicroRNAs and ETV1 Expression 24
The miRNA Expression Profiling Shows a Myriad of 25
Over- and Under-expressed miRNAs 25
Several Underexpressed TS-miRs in High-risk GISTs were 26
Predicted to Target ETV1 3’-UTR 26
Candidate miRNAs Reduce ETV1 Protein Expression 27
Western Results show a lower ETV1 Protein Level in the Presence of Either Isoform of c-KIT 28
c-KIT GNNK- in Combination with ETV1 Promotes the Growth of the Highest Number of Colonies 29
c-KIT GNNK- and c-KIT GNNK+ in Combination with ETV1 Support the Anchorage-independent Growth of HEK-293T Cells in Soft Agar 30
CHAPTER FIVE DISCUSSION AND CONCLUSIONS 32
The ETV1 Protein Level Increases as the 32
Aggressiveness of GIST Increases 32
Down-regulation of ETV1 protein may be an indirect 32
indicator of a miRNA/mRNA target pair 32
ETV1 Increases Dramatically the Number of HEK-293T Colonies 33
ETV1 needs one of the c-KIT Isoforms to Support 34
Colony Growth on Soft Agar Assay 34
ETV1 Protein Level Appears Reduced Compared to ETV1 Only Control 35
When Co-transfected With Either c-KIT Isoform 35
CHAPTER SIX TABLES AND FIGURES 36
Table 1 36
Table 2 37
Table 3 38
Figure 1 c-KIT and ETV1 protein expression in different GIST samples 39
Figure 2 Expression of c-KIT isoforms GNNK+ and GNNK- in several patients’ samples 40
Figure 3 A schematic diagram illustrating the predicted expression patterns of oncogenic and tumor-suppressive miRNA during GIST tumorigenic progression. 41
Figure 4 miRNA expression profile of GISTs during progression 42
Figure 5 Microarray expression date showing those miRNAs predicted to bind ETV1 3'' UTR 43
Figure 6 Candidate miRNAs downregulate ETV1 protein levels 44
Figure 7 Western results showing ETV1 protein expression levels in combination with the different c-KIT isoforms 45
Figure 8 Colony formation assay showing cell growth of human embryonic kidney 293T cells after different transfection treatments 46
Figure 9 Anchorage-independent growth showing focus formation by human embryonic kidney 293T cells expressing the different isoforms of c-KIT co-transfected with empty vector or ETV1, as indicated. 47
Figure 10 Therapeutic potential of our candidate miRNAs in GISTs 49
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