以系統生物學方法探討人類骨髓間充質幹細胞 對於肺癌幹細胞的初始與轉移中所扮演的角色

Investigating the role of human bone marrows-mesenchymal stem cells for the initialization and metastasis of lung cancer stem cells: a systems biology approach

洪敏翔(Min-Xiang Hong)

指導教授 ： 林澤

國立清華大學/電機資訊學院/通訊工程研究所/碩士(2015年)

https://doi.org/10.6843/NTHU.2015.00539

摘要

近年來,
研究指出間充質幹細胞扮演著自我更新,
分化,
提高運輸蛋白的活
性並且有能力使癌症細胞產生轉移,
值得注意的是,
許多研究表明說骨髓間充質
幹細胞會移動到癌症腫瘤的周圍,
被認為是癌症轉移的重要微環境,
間充質幹細
胞不止影響了癌症細胞的自我更新跟分化,
並且會對於腫瘤幹細胞進行轉移。
我們利用系統生物學的方式來做進一步的探討,
根據MSCs-treated
microarray data 跟Control microarray data 我們可以建構出兩個不同的蛋白質之
間的交互網路, 並且透過兩個網路的差別, 找出間充質幹細胞在肺癌中所扮演的
重要角色, 在研究中我們發現了許多重要的腫瘤幹細胞的標記物以及Pathway 被
活化, 這些發現可以幫助我們對於未來的癌症治療有進一步的發展．

關鍵字

間充質幹細胞 ； 腫瘤幹細胞 ； 肺癌 ； 系統生物學

並列摘要

Background:
Evidence is emerging that stem cell and systems biology could provide new insights into the design of novel therapeutic strategies for cancer patients. Recent studies indicated that mesenchymal stem cells (MSCs) might play a crucial role in the ability of self-renewal, differentiation, increased membrane transporter activity and the ability to metastasize for cancer cells. It is worth noting that studies have shown that bone marrow-derived MSCs are recruited towards cancer tumors and are thought to be an important microenvironment in the initiation of metastasis. MSCs may not only promote the ability of self-renewal and differentiation of cancer cells, but also be involved in initiation of metastasis of cancer stem cells (CSCs).
Cancers are attributable to a large extent to multiple spontaneous and inherited mutations that control central cellular events. There are complicated cross-talks between pathways and biochemical processes that drive the formation and growth of tumors in cancers. As opposed to conventional biology, we apply a systems perspective into the cancerous cells, and systems biology approaches would help us explore how protein-protein interactions (PPIs) and pathways are induced and controlled during the initialization or formation of lung CSCs. In this study, our main goal is to investigate the complex intracellular mechanisms leading to the formation of lung CSCs. Specifically, we seek to study the crucial signaling pathways and possible cross-talks between these pathways that initiate the metastasis or formation of CSCs.
Result:
Based on MSCs-treated microarray data and Control microarray data, we constructed two intracellular PPI networks. The resulting intracellular MSCs-treated PPI network was comprised of 2586 proteins and 7296 interactions; on the other hand, the intracellular Control PPI network was comprised of 3982 proteins and 11498 interactions. By comparing these two networks, we could find out and predict the role
i
of the MSCs-secreted factors in the initialization or metastasis of lung CSCs. Our results showed that JAK/STAT pathway might play a crucial role in this setting. Furthermore, we identified STAT3 in our extracted sub-network and crucial proteins, CREBBP, FGFR2, CD44, and NFKB1, were also identified to be pertinent during lung CSCs formation via our centrality analysis.
Conclusion:
Based on our constructed PPI networks, pathway and centrality analysis, we were able to identify crucial proteins that are highly related to the formation of lung CSCs during treatment of MSCs-secreted factors. We believe that our findings not only provide insights into our comprehension of the formation of CSCs in lung cancers but also shed lights on our path towards better therapeutic strategies for cancer treatment in general.

並列關鍵字

Mesenchymal Stem Cells (MSCs) ； Cancer stem cells ； Lung cancer ； CSCs markers ； Systems biology

參考文獻

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