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| 研究生： |
鐘麗蘭 Chung, Li-Lan |
|---|---|
| 論文名稱： |
BMP7在肺癌細胞異質性和腫瘤進展中的作用 Role of BMP-7 in lung cancer cellular heterogeneity and tumor progression |
| 指導教授： |
黎耀基
Lai, Yiu-Kay 周裕珽 Chou, Yu-Ting |
| 口試委員: |
柯政昌
Ko, Jen-Chung 周裕珽 Chou, Yu-Ting |
| 學位類別： |
碩士 Master |
| 系所名稱： |
生命科學暨醫學院 - 生物科技研究所 Biotechnology |
| 論文出版年： | 2017 |
| 畢業學年度： | 105 |
| 語文別： | 英文 |
| 論文頁數： | 38 |
| 中文關鍵詞： | 肺癌 、腫瘤異質性 、BMP7 |
| 外文關鍵詞： | Lung cancer, cancer cellular heterogeneity, BMP7 |
| 相關次數： | 點閱：2 下載：0 |
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已知腫瘤中的癌細胞異質性與腫瘤發展具有相關性，如轉移、抗藥性及復發。然而，腫瘤中異質性的癌細胞之間的訊息傳遞如何影響腫瘤發展尚未被了解。我們發現BMP-7在肺腫瘤細胞CL1-0中高度表達，其中BMP7表現量與淋巴結轉移呈負相關。在生長速度快的肺癌細胞CL1-0中，BMP7表現量降低會促進其細胞侵襲能力。降低CL1-0細胞的BMP7表現量並將其培養基加入CL1-5細胞中，發現CL1-5細胞生長會被抑制。細胞週期分析顯示CL1-0培養基加入CL1-5細胞會抑制CL1-5細胞進入S期。Q-PCR分析顯示CL1-0培養基在CL1-5中誘導p21CIP1表達。透過Q-PCR基因表達分析，我們確認BMP7在CL1-0和CL1-5細胞表達。Clonogenic分析顯示，CL1-0培養基中的BMP7表現量下降使得CL1-5細胞生長不會受到抑制。 Kaplan-Meier分析顯示，BMP7表現量與NSCLC患者的recurrence-free survival有正相關。我們的研究結果表明BMP7在肺癌細胞異質性和腫瘤發展中具有關鍵作用，具有作為肺癌復發和轉移的預測生物標誌的潛力。
The cancer cellular heterogeneity in tumors has been linked to tumor progression, such as metastasis, chemoresistance and recurrence. However, how the crosstalk between heterogeneous cancer cells in tumors affects tumor progression in unknown. In this study, we report that BMP-7 is highly expressed in a subgroup of lung tumors, in which BMP-7 expression is inversely associated with lymph node metastasis. In high proliferative CL1-0 lung cancer cells, BMP7 silencing promoted invasion. The conditioned medium from CL1-0 cells suppressed the growth of its high invasive descendant CL1-5 cells. Cell cycle analysis revealed that CL1-0 conditioned medium inhibits the S phase thus attenuating the cell cycle progression of CL1-5. Quantitative-PCR (Q-PCR) assays showed that CL1-0 conditioned medium induced p21CIP1 expression in CL1-5. Through gene expression profiling analysis followed by Q-PCR, we identified BMP-7 as one of genes differently expressed between CL1-0 and CL1-5 cells. Clonogenic analysis revealed that BMP-7-silencing in CL1-0 conditioned medium unleashed the growth inhibitory effect on CL1-5. Kaplan-Meier analysis showed that the BMP-7 expression correlated with a better recurrence-free survival in NSCLC patients. Our findings suggest a critical role of BMP-7 in lung cancer cellular heterogeneity and tumor progression with a potential to serve as a predictive biomarker for recurrence and metastasis of lung cancer.
1. Zarogoulidis, K., Zarogoulidis, P., Darwiche, K., Boutsikou, E., Machairiotis, N., Tsakiridis, K., Katsikogiannis, N., Kougioumtzi, I., Karapantzos, I., Huang, H., et al. (2013). Treatment of non-small cell lung cancer (NSCLC). J. Thorac. Dis. 5, 2–9.
2. Chansky, K., Sculier, J.P., Crowley, J.J., Giroux, D., Meerbeeck, J.Van, andGoldstraw, P. (2010). The International Association for the Study of Lung Cancer Staging Project: Prognostic factors and pathologic TNM stage in surgically managed non-small cell lung cancer. Chinese J. Lung Cancer 13, 9–18.
3. Uramoto, H., andTanaka, F. (2014). Recurrence after surgery in patients with NSCLC. Transl. Lung Cancer Res. 3, 242–249
4. Lengauer, C., Kinzler, K.W., andVogelstein, B. (1998). Genetic instabilities in human cancers. Nature 396, 643–649.
5. Burrell, R.A., andSwanton, C. (2014). Tumour heterogeneity and the evolution of polyclonal drug resistance. Mol. Oncol. 8, 1095–1111.
6. Lin, S.C., Chou, Y.T., Jiang, S.S., Chang, J.L., Chung, C.H., Kao, Y.R., Chang, I.S., and Wu, C.W. (2016). Epigenetic Switch between SOX2 and SOX9 Regulates Cancer Cell Plasticity. Cancer Res 76, 7036-7048.
7. Shipitsin, M., Campbell, L.L., Argani, P., Weremowicz, S., Bloushtain-Qimron, N., Yao, J., Nikolskaya, T., Serebryiskaya, T., Beroukhim, R., Hu, M., et al. (2007). Molecular
8. Thomson, S., Buck, E., Petti, F., Griffin, G., Brown, E., Ramnarine, N., Iwata, K.K., Gibson, N., and Haley, J.D. (2005). Epithelial to mesenchymal transition is a determinant of sensitivity of non-small-cell lung carcinoma cell lines and xenografts to epidermal growth factor receptor inhibition. Cancer Res 65, 9455-9462.
9. Wen, H., Chiu, Y.F., Kuo, M.H., Lee, K.L., Lee, A.C., Yu, C.C., Chang, J.L., Huang, W.C., Hsiao, S.H., Lin, S.E., et al. (2017). Expression of neuroendocrine factor VGF in lung cancer cells confers resistance to EGFR kinase inhibitors and triggers epithelial-to-mesenchymal transition. Cancer Res 5, 0008-5472.
10. Witta, S.E., Gemmill, R.M., Hirsch, F.R., Coldren, C.D., Hedman, K., Ravdel, L., Helfrich, B., Dziadziuszko, R., Chan, D.C., Sugita, M., et al. (2006). Restoring E-cadherin expression increases sensitivity to epidermal growth factor receptor inhibitors in lung cancer cell lines. Cancer Res 66, 944-950.
11. Yauch, R.L., Januario, T., Eberhard, D.A., Cavet, G., Zhu, W., Fu, L., Pham, T.Q., Soriano, R., Stinson, J., Seshagiri, S., et al. (2005). Epithelial versus mesenchymal phenotype determines in vitro sensitivity and predicts clinical activity of erlotinib in lung cancer patients. Clin Cancer Res 11, 8686-8698.
12. Yu, P.B., Beppu, H., Kawai, N., Li, E., andBlocht, K.D. (2005). Bone morphogenetic protein (BMP) type II receptor deletion reveals BMP ligand-specific gain of signaling in pulmonary Artery smooth muscle cells. J. Biol. Chem. 280, 24443–24450.
13. Rahman, M.S., Akhtar, N., Jamil, H.M., Banik, R.S., andAsaduzzaman, S.M. (2015). TGF-β/BMP signaling and other molecular events: regulation of osteoblastogenesis and bone formation. Bone Res. 3, 15005.
14. Pardali, K., Kowanetz, M., Heldin, C.H., andMoustakas, A. (2005). Smad pathway-specific transcriptional regulation of the cell cycle inhibitor p21WAF1/Cip1. J. Cell. Physiol. 204, 260–272.
15. Burrell, R.A., andSwanton, C. (2014). Tumour heterogeneity and the evolution of polyclonal drug resistance. Mol. Oncol. 8, 1095–1111.
16. Chansky, K., Sculier, J.P., Crowley, J.J., Giroux, D., Meerbeeck, J.Van, andGoldstraw, P. (2010). The International Association for the Study of Lung Cancer Staging Project: Prognostic factors and pathologic TNM stage in surgically managed non-small cell lung cancer. Chinese J. Lung Cancer 13, 9–18.
17. Chen, J., Ye, L., Xie, F., Yang, Y., Zhang, L., andJiang, W.G. (2010). Expression of bone morphogenetic protein 7 in lung cancer and its biological impact on lung cancer cells. Anticancer Res. 30, 1113–1120.
18. Chu, Y.W., Yang, P.C., Yang, S.C., Shyu, Y.C., Hendrix, M.J.C., Wu, R., andWu, C.W. (1997). Selection of Invasive and Metastatic Subpopulations from a Human Lung Adenocarcinoma Cell Line. Am. J. Respir. Cell Mol. Biol. 17, 353–360.
19. Kawabata, M., Imamura, T., andMiyazono, K. (1998). Signal transduction by bone morphogenetic proteins. Cytokine Growth Factor Rev. 9, 49–61.
20. Lengauer, C., Kinzler, K.W., andVogelstein, B. (1998). Genetic instabilities in human cancers. Nature 396, 643–649.
21. Pardali, K., Kowanetz, M., Heldin, C.H., andMoustakas, A. (2005). Smad pathway-specific transcriptional regulation of the cell cycle inhibitor p21WAF1/Cip1. J. Cell. Physiol. 204, 260–272.
22. Rahman, M.S., Akhtar, N., Jamil, H.M., Banik, R.S., andAsaduzzaman, S.M. (2015). TGF-β/BMP signaling and other molecular events: regulation of osteoblastogenesis and bone formation. Bone Res. 3, 15005.
23. Uramoto, H., andTanaka, F. (2014). Recurrence after surgery in patients with NSCLC. Transl. Lung Cancer Res. 3, 242–249.
24. Ying, X., Sun, Y., andHe, P. (2015). Bone morphogenetic protein-7 inhibits EMT-associated genes in breast cancer. Cell. Physiol. Biochem. 37, 1271–1278.
25. Yu, P.B., Beppu, H., Kawai, N., Li, E., andBlocht, K.D. (2005). Bone morphogenetic protein (BMP) type II receptor deletion reveals BMP ligand-specific gain of signaling in pulmonary Artery smooth muscle cells. J. Biol. Chem. 280, 24443–24450.
26. Zarogoulidis, K., Zarogoulidis, P., Darwiche, K., Boutsikou, E., Machairiotis, N., Tsakiridis, K., Katsikogiannis, N., Kougioumtzi, I., Karapantzos, I., Huang, H., et al. (2013). Treatment of non-small cell lung cancer (NSCLC). J. Thorac. Dis. 5, 2–9.