降低致癌基因MCT-1表現抑制異種移植腫瘤發生與Shc-Ras-ERK訊息傳遞路徑

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研究生：	施宏儒 Shih, Hung-Ju
論文名稱：	降低致癌基因MCT-1表現抑制異種移植腫瘤發生與Shc-Ras-ERK訊息傳遞路徑 Reduction of MCT-1 oncogene suppresses xenograft tumorigenicity and Shc-Ras-ERK pathway
指導教授：	徐欣伶 Hsu, Hsin-Ling 劉銀樟 Liu, Yin-Chang
口試委員:	王陸海 Wang, Lu-Hai 陳振陽 Chen, Jen-Yang 林素芳 Lin, Su-Fang
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：	2011
畢業學年度：	100
語文別：	英文
論文頁數：	71
中文關鍵詞：	MCT-1 、Shc 、致癌蛋白
外文關鍵詞：	MCT-1, Shc, tumorigenicity
相關次數：	點閱：85 下載：0
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Oncoprotein MCT-1 (Multiple Copies in T-cell malignancies) is a regulator of cell proliferation and survival. However, the MCT-1-mediated oncogenic mechanism, which confers to tumor development, remains unclear. In this study, the knockdown of MCT-1 is demonstrated that suppressed Shc expression followed by reduction of Ras-ERK1/2-cyclin D1 pathway is observed both in vitro and in vivo. MCT-1 knockdown is also found to lead to p53 accumulation accompanying with proteolysis of the caspase substrates, integrin β4 and vimentin. Furthermore, we discover that the loss of MCT-1 confers cellular susceptibility to apoptosis in undernourished condition and concomitantly enhances the activation of caspases 3 and 7, but caspase 6. Interfering MCT-1 oncogenicity with shRNA in non-small cell lung cancer cell lines (H1299 and A549) is found to effectively suppress cancer cell growth (proliferation and survival). The reduction of MCT-1 also significantly suppresses xenograft tumor growth associated with the inhibition of Shc pathway. Our clinical evidence further demonstrates that both MCT-1 and Shc genes are evidently stimulated during malignant progression of human breast cancer. Accordingly, MCT-1 activation may be recognized as a prognostic tumor marker and it is prospective to be a promising therapeutic target for cancer treatment.

致癌蛋白MCT-1 (Multiple copies in T-cell malignancies) 是細胞增生與細胞存活的調節者。然而，MCT-1調控腫瘤生成的致癌機制仍不清楚。在本篇論文中我們證明，在人類乳腺細胞株或是非小細胞肺癌細胞株降低MCT-1蛋白質量，會減少Shc的表現量，同時降低Ras-ERK1/2-cyclin D1訊息傳遞路逕。此外，降低MCT-1表現將導致p53抗癌蛋白質的累積，進而引起caspase受質integrin β4和vimentin的蛋白質水解。再者，減少MCT-1蛋白質量將提高細胞對養分不足環境的敏感性，進一步增加caspase 3和caspase 7之活化與養分不足造成之細胞凋亡，但不影響caspase 6之功能活性。藉由MCT-1 shRNA (抑制MCT-1表現量) 可降低MCT-1在非小細胞肺癌細胞株 (H1299和A549) 的腫瘤生長能力，且有效地抑制癌細胞的生長 (增生與存活)，並顯著抑制Shc訊息傳遞路逕與異種移植腫瘤發生。分析臨床乳癌病患的mRNA表現量，進一步證明了MCT-1和Shc的基因表現之相關性，顯然在人類乳腺癌的惡性腫瘤發展過程中呈現高量表現。我們推測，MCT-1蛋白質可能做為預期偵測的腫瘤標誌，且MCT-1是一相當有前瞻性的癌症治療的治療標的。

誌謝   iii
Abstract   iv
中文摘要   v
Chapter 1. Introduction   1
Chapter 2. Materials and methods   7
2.1 Antibodies   7
2.2 Cell culture and transfections   7
2.3 Western blotting analysis   8
2.4 MTT cell proliferation and cell viability assay   9
2.5 Immunofluorescence microscopy   10
2.6 Cell cycle and call death assays   11
2.7 Caspase 3 activity assay   12
2.8 Ras activity assay   12
2.9 Trypan blue exclusion assay of cell viability   13
2.10 Clonogenic growth assays   13
2.11 RNA isolation and quantitative real-time polymerase chain reaction (Q-RT-PCR)   14
2.12 Xenograft tumorigenicity in nude mice   15
2.13 Immunohistochemistry study of the xenograft tumor tissues from mice xenografts   15
2.14 Analysis of MCT-1 and Shc mRNA levels in human breast cancers   16
2.15 Statistics   17
Chapter 3. Results   18
3.1 MCT-1 controls Shc-Ras-Raf-MEK-ERK signaling cascade   18
3.2 Knockdown of MCT-1 suppresses cell growth of NSCLC, H1299   20
3.3 Removal of MCT-1 suppresses A549 cell growth   21
3.4 Loss of MCT-1 enhances cell death and cleavage of caspase substrates   22
3.5 Stimulated cleavage of PARP, caspase 3 and 7 by MCT-1 knockdown   24
3.6 Reduction of MCT-1 confers cellular sensitivity to the therapeutic agent   25
3.7 Silencing MCT-1 prominently suppresses H1299 xenograft tumorigenicity   27
3.8 MCT-1 knockdown attenuates tumor growth of A549 xenografts   29
3.9 MCT-1 and Shc genes are highly expressed in human breast cancers   31
Chapter 4. Discussion   33
4.1 Knockdown of MCT-1 suppresses Shc signaling pathway and cell proliferation   33
4.2 High frequencies of apoptosis induced by starvation stress and chemo-agent treatment in the absence of MCT-1   35
4.3 Concurrent induction of MCT-1 and Shc expression in cancers   36
Chapter 5. References   39
Figures   52
Figure 1.  Endogenous MCT-1 protein is knocked down in MCF-10, H1299 and A549 cells   52
Figure 2.  Shc protein and mRNA levels are decreased when MCT-1 is knocked down in MCF-10A cells   53
Figure 3.  Knockdown of MCT-1 reduces Ras-ERK1/2 signaling transduction and decreases cell proliferation   54
Figure 4.  Removal of MCT-1 in H1299 cells reduces Shc-ERK1/2-cyclin D1 pathway and cell proliferation   55
Figure 5.  Shc-ERK1/2-cyclin D1 pathway and cell growth rate are repressed by knockdown of MCT-1 in A549 cells   56
Figure 6.  Knockdown of MCT-1 in MCF-10A cells increase spontaneous apoptosis   57
Figure 7.  MCT-1 deficiency in MCF-10A cells cause accumulation of p53 and activation of caspase 3   58
Figure 8.  Knockdown of MCT-1 suppresses cell growth but stimulates cleavage of PARP, caspases 3 and 7   59
Figure 9.  Cells silenced MCT-1 are more responsive to the cancer therapeutic drug     60
Figure 10.  Loss of MCT-1 pronouncedly suppresses  H1299 xenograft tumorigenicity   61
Figure 11.  Knockdown of MCT-1 decreases Shc mRNA and protein levels in H1299 xenograft tumors   62
Figure 12.  MCT-1 knockdown significantly attenuates tumor growth of A549 xenografts   63
Figure 13.  MCT-1 deficiency reduces Shc protein and mRNA levels in A549 xenograft tumors   64
Figure 14.  Predominant expression of MCT-1 mRNA in human breast cancer patients (BCPs)   65
Figure 15.  MCT-1 and Shc mRNA highly express in BCPs   66
Figure S1.  Cellular MCT-1 protein amount is decreased by MCT-1 shRNA treatment   67
Figure S2.  Silencing of MCT-1 in MCF-10A and H1299 do not affect the cell cycle profiles   68
Figure S3.  Knockdown of MCT-1 reduces cell growth as assessed by clonogenic growth assay   69
Tables   70
Table 1.  Elevated MCT-1 gene expression in BCPs   70
Table 2.  Correlation of MCT-1 and Shc gene expressions in BCPs   71

                                

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