Mesenchymal Stem Cells-derived Microenvironment Promotes Lung Cancer Cell Progression via c-Fos S374 Phosphorylation in MAPK Signaling Pathway
| Autor: | Chia-Chi Wang, 王嘉琪 |
|---|---|
| Rok vydání: | 2019 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 107 Tumor microenvironment contains tumor cells and a mixture of heterogeneous stromal cells, including mesenchymal stem cells (MSCs) and MSC-derived fibroblast. These stromal cells are able to regulate tumor growth, angiogenesis, metastasis and invasion by paracrine secretion of cytokines, chemokine and growth factors. Here, we attempt to dissect the roles of MSCs in the tumor microenvironment of lung cancer. At first, we found that the MSCs conditioned medium (MSC-CM) enhanced lung cancer cell proliferation and migration. However, the signaling pathways mediated by MSC-secreting factors are still unclear. To further elucidate MSC regulatory pathways, we performed quantitative phosphoproteomics for MSC-CM treated lung cancer cells, and a total of 1926 phosphorylation sites on 700 phosphoproteins were identified. Moreover, integrative analysis of phosphoproteins and predicted kinases suggested that phosphorylation of c-Fos at serine 374 was induced by MSC-CM through activating mitogen-activated protein kinases (MAPK) signaling pathway in lung cancer cells. Consistently, our results showed that MSC-induced cell proliferation and migration were abrogated by inhibiting c-Fos phosphorylation using ERK1/2 inhibitor. In addition, the dephosphorylated form of c-Fos at serine 374 led to decreased cell proliferation, cell motility and colony forming ability compared to wild-type form of c-Fos in MSC-CM treated lung cancer cells. Collectively, our study demonstrated that MSCs might trigger the MAPK pathway followed by the phosphorylation of c-Fos at serine 374 to promote cancer proliferation and migration. Recent studies have reported that extracellular ATPs accumulate in the tumor microenvironment and stimulate the P2X7 receptor on the cancer cell membrane through purinergic signaling. In our data, we observed that ectopic ATP synthase was overexpressed on the cell surface of MSCs. In addition, extracellular ATPs in the lung cancer microenvironment trigger the MAPK pathway to phosphorylate c-Fos on serine 374. In conclusion, our study suggested that ectopic ATP synthase on the surface of MSCs released extracellular ATPs into the lung cancer microenvironment and promoted cancer progression through c-Fos S374 phosphorylation in the MAPK signaling pathway. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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