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系統識別號 U0026-0812200915310023
論文名稱(中文) Autocrine IL-6在腫瘤細胞發生的機制和生物學上扮演的角色:側重於與腫瘤抗藥性相關之研究
論文名稱(英文) The mechanism and biological role of autocrine IL-6 in cancer cells: focusing on tumor drug resistance
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 97
學期 2
出版年 98
研究生(中文) 黃偉倫
研究生(英文) WEI-LUN HUANG
電子信箱 s5891142@mail.ncku.edu.tw
學號 s5891142
學位類別 博士
語文別 英文
論文頁數 91頁
口試委員 召集委員-劉校生
指導教授-蘇五洲
口試委員-賴明德
口試委員-沈孟儒
口試委員-蔣輯武
口試委員-陳立宗
口試委員-施能耀
口試委員-戴明泓
中文關鍵字 癌症  抗藥性 
英文關鍵字 tumor  drug resistance  Stat3  IL-6 
學科別分類
中文摘要 自發性的IL-6產生已在多種癌症中被發現,並且被報導和癌症的病發、病程和抗藥性有關。大部分的相關報告強調NF-κB和AP-1在IL-6 調控上的重要性。其他的報告則顯示HIF-1α和p53可能也在其中扮演一定的角色。然而,腫瘤中IL-6 autocrine 的分子機制並未被充分地被了解,對於IL-6如何導致癌症之抗藥性的領域也未完全明朗。我們實驗室先前的研究即指出,在肺腺癌病人惡性肋膜積水中IL-6的含量高於一般非惡性腫瘤引發之肋膜積水。此外,在肺癌的系統中我們也發現經由IL-6下游的Stat3所傳遞的訊息在癌細胞的轉移及化學治療藥物之感受性上扮演重要的角色。在本研究中,我們針對腫瘤中IL-6 autocrine 的機制和IL-6如何導致癌症之抗藥性進行研究。首先,我們證實了autocrine IL-6能在癌細胞中有效地活化下游訊息傳遞路徑,並引發癌症之抗藥性。我們發現在肺腺癌細胞、抗藥性癌細胞及病人的肺癌細胞中,Jak2/Stat3 pathway如同先前已被報導過的MEK/Erk, PI3-K/Akt and NF-κB pathway參與了IL-6 autocrine secretion的調控。Stat3不但能調控內源性的IL-6 autocrine,它也能影響外源性刺激所引發的IL-6表現。除此之外,Stat3可能在調控IL-6表現的同時也調整endosome associated secretion pathway,藉此調控IL-6 autocrine secretion。雖然IL-6 autocrine在癌症抗藥性上扮演重要的角色,我們使用single cell phospho-specific flow cytometry analysis的結果卻發現IFN-γ所引發的Stat1活化而非IL-6所引發的Stat3活化可作為判斷肺癌病人是否產生癌症抗藥性的指標。
英文摘要 Spontaneous IL-6 production has been observed in various tumors and has been implicated in cancer pathogenesis, progression, and drug resistance. Most studies emphasized the importance of NF-κB and AP-1 on IL-6 regulation. Others pointed out the potential roles of HIF-1α and p53. However, the molecular mechanism of IL-6 autocrine in tumor cells and the impact of IL-6 on drug resistance are not well defined yet. The previous study in our laboratory has demonstrated high IL-6 levels in malignant pleural effusions of patients with lung adenocarcinoma than those of non-malignant patients. In addition, in Stat3 downstream of IL-6 also plays an important role in the metastatic property and drug sensitivity of lung cancer cells. In this study, we planed to uncover the mechanism of IL-6 autocrine in cancer cells and the impact of IL-6 on cancer drug resistance. First of all, we demonstrated that autocrine IL-6 was able to activate downstream signals and result in drug resistance in cancer cells. We showed that Jak2/Stat3 pathway as well as previously reported MEK/Erk, PI3-K/Akt and NF-κB pathways contribute to IL-6 autocrine secretion in an aggressive lung cancer cell line, various drug resistant cancer cell lines, and patients' primary lung cancer cells. We showed that Stat3 not only contributed to the regulation of endogenous IL-6 autocrine but also to the exogenous-stimulation induced IL-6 expression. In addition, Stat3 may regulate IL-6 autocrine by modulating endosome associated secretion pathway in parallel with controlling IL-6 expression. In spite of the importance of autocrine IL-6 in cancer drug resistance, the Stat1 activation responding to IFN-γ stimulation instead of the Stat3 activation responding to IL-6 stimulation was shown to be an ideal indicator of the development of drug resistance in human lung cancers using single cell phospho-specific flow cytometry analysis.
論文目次 摘要………………………………………………………………………I
Abstract………………………………………………………………II
誌謝……………………………………………………………………III
Figure contents………………………………………………………VI
Abbreviation list……………………………………………………IX
Chapter 1: Introduction……………………………………………1
Cancer treatment………………………………………………………2
Chemotherapy……………………………………………………………3
Drug resistance………………………………………………………4
IL-6………………………………………………………………………7
Jak/Stat pathway………………………………………………………8
IL-6 and cancer………………………………………………………10
Rationales……………………………………………………………11
Specific aims…………………………………………………………12
Chapter 2: Materials and Methods………………………………13
Materials………………………………………………………………14
Cell culture…………………………………………………………14
Patients and sample processing…………………………………15
Cell lysis and Western blotting…………………………………15
Enzyme-linked immunosorbent assay for IL-6…………………16
MTT assay………………………………………………………………16
RNA extraction and semiquantitative RT-PCR…………………16
siRNAs, shRNAs, and transfections………………………………17
Flow cytometry analysis……………………………………………17
Animals and ascites models………………………………………18
Statistical analysis………………………………………………19
Chapter 3: Results…………………………………………………20
Stat3 activation up-regulates IL-6 autocrine secretion in lung cancer and drug resistant cancer cells…………………21
Stat3 play important role not only in endogenous IL-6 autocrine production but also in cytokines induced IL-6 expression in cancer cells………………………………………27
Stat3 may regulate IL-6 autocrine by modulating endosome associated secretion pathway……………………………………28
Analysis of pStat1 in lung cancer cells from cell lines, in vivo tumor cells and human malignant pleural effusions at the single cell level…………………………………………30
Chapter 4: Conclusion and Discussion…………………………36
References……………………………………………………………47
Figures…………………………………………………………………63
作者簡歷………………………………………………………………91
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