系統識別號 U0026-1901201119405300
論文名稱(中文) 惡性肋膜積液中肺腺癌細胞顯示糖代謝調控基因的異常表現且該癌細胞之Stat1磷酸化狀態與腫瘤抗藥性相關
論文名稱(英文) Malignant pleural effusion cells show aberrant glucose metabolism gene expression and the level of cellular Stat1 phosphorylation reflects the chemoresistance
校院名稱 成功大學
系所名稱(中) 臨床醫學研究所
系所名稱(英) Institute of Clinical Medicine
學年度 99
學期 1
出版年 100
研究生(中文) 林建中
研究生(英文) Chien-Chung Lin
學號 s9893101
學位類別 博士
語文別 英文
論文頁數 108頁
口試委員 指導教授-蘇五洲
中文關鍵字 惡性肋膜積水  肺腺癌  醣解作用  流式細胞儀  Stat1磷酸化 
英文關鍵字 Malignant pleural effusion  lung adenocarcinoma  glycolysis  flow cytomety  Stat1 phosphorylation 
中文摘要 肺癌為癌症死因第一位。而其中15%病人一開始以惡性肋膜積水表現,50%肺癌病人晚期會有惡性肋膜積水產生。不同於其它固體腫瘤有周圍血管提供營養,惡性肋膜積水的癌細胞可自主地增殖並具有高轉移能力和抗藥性。而這些肺腺癌的病人最近更被證實其預後應視同對側肺轉移。我們利用惡性肋膜積水的癌細胞去探討這些肺腺癌的基因表現與訊息傳導以了解這些癌細胞如何維持生長及了解訊息傳導的變化是否可預估其化學治療反應。我們針對三個組群(7位健康女性、13位惡性肋膜積水及18位I至III期肺癌病人)將其正常肺組織或腫瘤細胞及相鄰正常組織作微陣列分析晶片分析;首先比較7位健康女性肺組織及13位惡性肋膜積水中腫瘤細胞表現差異最多前500基因,這500基因再與18位I至III期肺癌病人做相關基因比較並做相關限制的標準;最後總共有20個基因符合標準,利用生物資訊平台進一步發現大部分基因與代謝有關尤其是醣類代謝-這包括了 aldolase A (ALDOA), sorbitol dehydrogenase (SORD), transketolase (TKT), and tuberous sclerosis 1 (TSC1)。我們利用定量real time PCR、免疫螢光染色分析、免疫組織化學染色作定性及定量分析病人的肺癌組織,確認這些基因的表現在病人的肺癌組織與正常組織有所差異。在細胞實驗中,我們一方面確認肺癌細胞較正常肺組織及支氣管上皮細胞株有不同的表現,另一方面TKT 的抑制劑(oxythiamine)及TSC1-AMPK的促進劑(metformin)抑制癌細胞的增生能力及VEGF的分泌。利用siRNA系統去剔除TKT的表現亦抑制癌細胞的增生能力及VEGF的分泌。證實有氧醣解作用在惡性肋膜積水癌細胞的自主地增生能力增加及而且與VEGF增加惡性肋膜積水相關。我們進一步利用Ingenuity Pathway Analysis找尋可能調控這些在惡性肋膜積水表現異常基因之上游可能之轉錄因子,發現HNF4A (hepatocyte nuclear factor 4A)不但在肺癌細胞較正常肺組織有不同的表現,而且利用HNF4A抑制劑(MEDICA16)抑制了肺癌細胞生長。
其次,我們亦探討惡性肋膜積水的癌細胞訊息傳導的變化是否可預估其化學治療反應,之前在白血病的研究發現,單一細胞磷酸化流式細胞儀(Single cell phospho-specific flow cytometry, SCPFC)對於細胞內訊息磷酸化變化,可以預估白血病對化學治療的反應,而Stat1 (Signal transducer and activator of transcription 1)已被證實與化學治療如紫杉醇及順鉑之抗藥性相關,因此,我們進一步用惡性肋膜積水的癌細胞去探討Stat1磷酸化高低變化是否可以決定順鉑治療效果好壞。我們首先確認單一細胞磷酸化流式細胞儀可以在肺癌細胞、動物轉移腹水及皮下腫瘤模式和人類惡性肋膜積水樣本,測試給予干擾素-γ刺激後Stat1磷酸化的反應。我們進一步發現這些惡性肋膜積水中的肺癌細胞經順鉑處理後細胞凋亡情形與pStat1螢光強度變化之相關性。最後再利用對順鉑抗藥性細胞株轉染siRNA- Stat1去抑制Stat1表現,確認了Stat1表現與否決定對順鉑的感受性。而最近的研究,而醣解作用的異常表現影響化學治療之抗藥性,而metformin可加強乳癌化學治療之療效。因此,惡性肋膜積水的癌細胞有氧醣解作用異常表現及Stat1磷酸化的反應,將可作為判斷肺癌病人是否產生癌症抗藥性的指標,而針對這些醣解作用相關基因及上游調節因子之促進劑或抑制劑可用以加強化學治療之療效。
英文摘要 Lung cancer is the leading cause of cancer deaths worldwide. Approximately 15% of lung cancer patients have complications with malignant pleural effusion (MPE) at their initial diagnosis, and 50% of patients develop MPE later in the course of the disease. Unlike other solid cancers with surrounding vascular structures to provide conduits for travel and nutrient delivery, malignant cells within MPE are uniquely capable of surviving and proliferating without a solid-phase scaffolding. These characteristics contribute their potential of metastasis and chemoresistance. The prognosis of patients with MPE is comparable to M1 cases with metastases to the contralateral lung. Our study aimed at disclosing the genes involved in MPE formation and associated signal pathway which may account for high chemoresistance and become the predictor of chemotherapy. We first identified the genes contributing to the formation of MPE. Three cohorts were included in the study of whole genome expression using an Affymetrix Human U133 oligonucleotide microarray. By restricting to genes that were at least a two-fold change between MPE and normal tissue and expressed differentially from early to late stage, 20 genes were identified. Bioinformatics platform analysis demonstrated that most of the identified genes are related to glucose metabolism, including aldolase A (ALDOA), sorbitol dehydrogenase (SORD), transketolase (TKT), and tuberous sclerosis 1 (TSC1). Then we used quantitative RTPCR to confirm the aberrant expression of these genes in the patient's lung cancer compared to normal tissue. Using the specimens from different stages of lung cancer and pleural metastasis in lung cancer tissues, we verified the dysregulation of these genes by immunohistochemistry and immunofluorescence staining. And the TKT inhibitor (oxythiamine) and TSC1/AMPK activator (metformin) were proved to inhibit the proliferation of lung cancer cell. We further used siRNA expression system to knockdown TKT and demonstrated the inhibition of cell proliferation, VEGF secretion cell line in vitro, vascular permeability in vivo. Using Ingenuity Pathway Analysis (IPA) to examine the relation between the dysregulated genes in MPE and the biological networks involved, hepatocyte nuclear factor-4α (HNF4A) was identified as the central molecules of these pathways. We further proved that the HNF4A was upregulated in cancer tissue and HNF4A inhibitor interfered lung cancer cell proliferation. Secondly, we investigated the signal pathway which may involve the chemoresistance in lung cancer. Most human neoplasms have aberrant signal transduction elements. Understanding the structure and the regulation of these signal transductions offers the progress in treatment of lung cancer. Single cell phospho-specific flow cytometry (SCPFC) has been used to monitor phosphorylation change of intracellular signal after certain stimuli treatment and predict response to chemotherapy in leukemia patients. And Stat1 has been proved to determine the sensitivity to cisplatin in ovarian cancer. We first demonstrated SCPFC is applicable in monitoring pStat1 after IFN-γ stimulation in lung cancer cell lines, cancer cells from animal models of subcutaneous tumor metastasis and ascites and MPEs of lung cancer patients. Furthermore, cancer cells from different patient MPEs have different sensitivities to IFN-γ stimulation. The activation of Stat1 by lower doses of IFN-γ predicts cancer cell vulnerability to cisplatin. The reverse of cisplatin sensitivity of cancer cell after transfection with Stat1 siRNA further confirmed the role of Stat1 in cisplatin sensitivity. It has been report that glycolytic inhibition also potently induced apoptosis in multidrug-resistant cells. Metformin increased the pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer Taken together, malignant pleural effusion cells show aberrant glucose metabolism gene expression and Stat1 phosphoryaltion predict the cisplatin sensitivity of MPE cancer cells. The predictor role of pStat1 is promising and the activator or inhibitor targeting these glucose metabolism genes and upstream transcription factor may become new treatment strategies for MPE-associated lung adenocarcinoma.
論文目次 Contents
Abstract in Chinese-I
Abstract in English-III

Chapter 1. Introduction-1
Lung cancer-2
Malignant pleural effusion cancer cell-3
Single cell phospho-specific flow cytometry-4
Signal transducer and activator of transcription 1 (Stat1) and chemoresistance-4

Chapter 2. Materials and Methods-6
MPE cancer cells, healthy normal lung tissue, and stage I-III lung cancer for microarray analysis-7
Blood and pleural effusion collection and cancer cell purification from malignant pleural effusions for SCPFC-8
Statistical analysis of micro-array data-9
RNA extraction and quantitative RT-PCR-10
Immunohistochemistry and immunofluorescent images-10
Immuno-fluorescent images and quantitative analyses-11
Cell lines, cell lysates, and Western blot-12
TKT inhibitor-oxythiamine, TSC1-AMPK activator-metformin, HNF4A inhibitor-MEDICA 16 and MTT test-13
Transfection with Small Interfering RNA (siRNA) against Stat1 using lipofectamine-15
Antibodies for flow cytometry-16
Collection of cancer cells from animal, aubcutaneous and ascites tumor models for SCPFC-16
E-cadherin staining-17
Single Cell Phospho-specific Flow Cytometry (SCPFC)-17
Apoptosis analysis after cisplatin treatment-18
Statistical analysis-18

Chapter 3. Malignant Pleural Effusion Cells Show Aberrant Glucose Metabolism Gene Expression-20

Chapter 4. Single Cell Phospho-Specific Flow Cytometry Can Detect Dynamic Changes of Phospho-Stat1 Level in Lung Cancer Cells-37

Chapter 5. Discussion-51

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