| Summary: | 碩士 === 國立臺灣大學 === 生命科學系 === 105 === Cancer stem cells (CSCs) is a subpopulation of cancer cells which might have stem-like characteristics and initiate tumorigenesis. Recent studies suggested that epithelial-mesenchymal transition (EMT) is not only as a crucial step in tumor metastasis, but also responsible for generating stemness properties in various cancer cells. Bone marrow-derived mesenchymal stem cells (BM-MSCs) contribute for tumor progression through paracrine factors secretion in tumor microenvironment, however, signaling pathways that involved in response to MSCs-secreting factors are poorly understood. Here, we first showed that conditioned medium of MSCs (MSC-CM) altered the expression of EMT markers and sphere-forming ability in epithelial-type lung cancer cells (LM cells). Furthermore, we performed cytokine array and found that MSC-CM contained several cytokines which might induce the signaling pathway. To further elucidate the MSC-CM-regulating signaling pathways that are involved in the formation of lung cancer stem cells, we performed phosphoproteomics and identified a total of 1926 phosphorylation sites on 700 phosphoproteins. By using gene set enrichment analysis, the gene sets of TGF-beta induced EMT and embryonic stem cell were enriched from pre-ranked phosphproteomic profiles. Moreover, integrative analysis of phosphoproteins and kinases suggested that MSC-CM enhanced phosphorylation of c-Fos through mitogen-activated protein kinase (MAPK) signaling pathway in LM cells. Phosphorylation of c-Fos on serine 374 and cell migration were decreased in LM cells treated with MSC-CM coupled with ERK1/2 inhibitor. Our studies implied that MSCs triggered the phosphorylation signal in MAPK pathway to generated EMT process in lung cancer cells which provide insight for formation of cancer stem cells.
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