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研究生： 蘇茂凱
Su, Mao-Kai
論文名稱： BMP7訊息於癌症生長中不同作用之研究
Distinct roles of BMP7 signaling in cancer growth
指導教授： 周裕珽
Chou, Yu-Ting
口試委員: 潘憲堂
Pan, Shien-Tung
陳惠珍
Chen, Hui-Chen
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： 2022
畢業學年度： 110
語文別： 英文
論文頁數： 40
中文關鍵詞： 肺癌 、骨形態發生蛋白7 、II型骨形態發生蛋白受體 、SMAD5 、乙型轉化生長因子 、腫瘤異質性
外文關鍵詞： Lung cancer, Bone morphogenetic protein 7, Bone morphogenetic protein receptor 2, SMAD5, Transforming growth factor beta, Tumour heterogeneity
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    • 癌症異質性在癌症發展過程中的耐藥性和轉移中起關鍵作用。肺癌是全球癌症死亡的主要原因。然而，細胞因子的刺激如何調節肺腫瘤中的癌症異質性仍不清楚。在這裡，我們指出BMP7在高增殖性的親代肺癌細胞CL1-0中高度表現，它分泌BMP7來抑制高侵襲性後代細胞CL1-5的生長。qRT-PCR顯示BMP7在CL1-0中的表現量高於其後代CL1-5細胞。克隆形成測定顯示，來自CL1-0細胞的條件培養基會抑制CL1-5細胞的生長，而在CL1-0細胞中沉默BMP7表現會降低CL1-0條件培養基的生長抑制作用。敲落BMP7或訊號分子BMPR2和SMAD5可增強CL1-5和CL1-0細胞的生長能力。克隆形成測定顯示，與CL1-0細胞相比，用Dorsomorphin對BMP受體的藥理學抑制強烈促進了更多的CL1-5集落生長，而Dorsomorphin處理抑制了子宮內膜癌細胞Ishikawa-02的集落生長。Kaplan-Meier分析顯示，高BMP7表現預示著肺癌患者的良好無進展生存結果，而高BMP7表現與子宮內膜癌患者較差的生存結果相關。聚類分析顯示BMP7表達更接近肺腫瘤中的上皮標誌物和遠離間充質標誌物。這些數據顯示BMP7參與調節肺癌異質性。我們的研究結果顯示BMP7訊號傳導作為肺癌治療中潛在的生物標誌物和治療靶點的潛力。

    Cancer heterogeneity plays a critical role in drug resistance and metastasis during cancer progression. Lung cancer is the leading cause of cancer deaths in the world. However, how cytokine stimulation regulates cancer heterogeneity in lung tumors is still unclear. Here, I report that BMP7 is highly expressed in high-proliferating parental lung cancer cell CL1-0, which secreted BMP7 to inhibit growth of high-invasive descendant cell CL1-5. qRT-PCR showed that BMP7 was more highly expressed in CL1-0 than its descendent CL1-5 cells. Clonogenic assays showed that the conditioned medium from CL1-0 cells inhibited growth of CL1-5 cells, whereas silencing BMP7 in CL1-0 cells deceased the growth inhibitory effect of the CL1-0 conditioned medium. Knockdown of BMP7 or the signaling molecule BMPR2 and SMAD5 enhanced the growth of CL1-5 and CL1-0 cells. Clonogenic assays showed that pharmacological inhibition of BMP receptor with dorsomorphin strongly promoted more colony growth of CL1-5 than CL1-0 cells, whereas dorsomorphin treatment inhibited the colony growth of endometrial carcinoma cell Ishikawa-O2. Kaplan-Meier analysis showed that high BMP7 expression predicted a good progress free survival outcome in lung cancer patients, while high BMP7 expression was associated with a poor survival outcome in patients with endometrial carcinoma. Hierarchy clustering revealed the BMP7 expression was more closed to epithelial markers and distant from mesenchymal markers in lung tumors. These data indicate the involvement of BMP7 in regulation of lung cancer heterogeneity. Our findings suggest the potential of BMP7 signaling as a potential biomarker and therapeutic target in lung cancer treatment.

    Abstract 1 中文摘要 2 致謝 3 目錄 4 List of Abbreviations 6 Introduction 7 The overview of lung cancer 7 Heterogeneity in lung cancer 7 Biological characteristics of TGF-β, BMP7 and SMAD1/5/9 in lung cancer 8 The relationship between BMP7 and different cancers 9 Dorsomorphin and Romidepsin 10 Materials and Methods 12 Cell Culture 12 Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) 12 Clonogenic Analysis 12 Immunoblotting 13 Cell cycle assay 13 Statistical analysis 13 Table 1. Primer and Probes Used in qRT-PCR Assay. 14 Table 2. Primary Antibody Used in This Study. 14 Results 15 Expression of BMP7 signaling molecules in lung cancer. 15 Lung cancer cells exhibits heterogeneity. 17 Differential BMP7 expression in paired lung cancer cells with heterogeneity. 20 Paracrine of BMP7 affects lung cancer cell growth 21 BMP7 signaling inhibits growth of lung cancer cells 21 BMP7 signaling inhibits TGFBR2 expression in lung cancer cells. 27 BMP7 signaling is essential for growth of endometrial carcinoma cells. 29 BMP7 signaling inhibits TGFBR2 expression in endometrial carcinoma cells. 32 Effect of HDAC1/2 inhibitors on BMP7 and TGFBR2 expression in lung cancer 33 BMP7 and TGFBR2 expression are clustered with epithelial and mesenchymal 34 Discussion 35 Reference 38

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