脂肪细胞通过Fas信号介导肥胖促进结直肠癌进展的作用及机制研究

Among obesity-related disorders, a direct and independent relationship has been ascertained for some cancer, including colorectal cancer (CRC) and the underlying mechanism of obestiy promoting CRC remains unclear.The expression of Fas in adipocyte tissue was related to obesity and Fas activation in adipocytes interfered with insulin stimulated glucose uptake and induced basal lipolysis.It is still not clear the role of adipocytes in obesity promoting tumor via Fas signaling.Our recent work showed that Fas signaling improved the program of CRC in obesity mice, Fas signaling can enhance the activation of NF-κB and MAPK and releasing of TNF-α in adipocytes.We sought the tyrosine kinase Bmx bound with Fas through reverse-phase nanospray liquid chromatography–tandemmass spectrometry in adipocytes and Bmx can contribute to active NF-κB and MAPK pathway. So we suggest a new mechansim of obesity promoting CRC progress：increasing Fas expression of adiopcytes in Obesity-enhancing Fas signaling in adipocytes -improving phosphorylation of Fas on tyrosine sites-binding and activating Bmx-NF-κB or MAPK pathway- increasing TNF-α release-improving tumor progression. In this proposal, we will explore the role of Fas signaling of adipocytes in obesity promoting CRC and the underlying mechanisms. Our study will contribute to the current understanding of obesity and tumor, and faciliate the development of effective therapeutic protocol for treating obesity related tumor. Meanwhile, we alos suggest a new mechanism of Fas signaling improve inflammation and the low grade inflammation in obestiy.

肥胖已被认为是包括结直肠癌在内的多种肿瘤的风险因素，但机制还不很清楚。肥胖时脂肪细胞Fas表达增加，增强的Fas信号促进胰岛素抵抗和脂质分解。肥胖时脂肪细胞是否通过Fas信号促进肿瘤进展尚无相关报道。前期研究发现，肥胖Fas配体缺陷小鼠结肠癌较野生型生长慢，提示脂肪细胞可能通过Fas信号参与肥胖促进结直肠癌进展。脂肪细胞中Fas能够与酪氨酸激酶Bmx结合，Fas信号活化促进脂肪细胞NF-κB、MAPK活化，分泌TNF-α增加。基于以上研究背景，我们提出肥胖促进结直肠癌进展的一种新途径：肥胖时脂肪细胞Fas表达增加-Fas信号增强-Fas酪氨酸磷酸化增强-促进结合/活化Bmx-NF-κB/MAPK-分泌TNF-α等脂肪因子增加-促进结直肠癌进展。本课题将详细探讨其机制。本课题的完成，将有助于更好理解肥胖促进肿瘤进展机制。本课题还提出了Fas信号促进炎症进展的新途径，完善了肥胖时低炎状态机制。

肥胖已被认为是包括结直肠癌在内的多种肿瘤的风险因素，但机制还不很清楚。肥胖时脂肪细胞Fas表达增加，增强的Fas信号促进胰岛素抵抗和脂质分解。肥胖时脂肪细胞是否通过Fas信号促进肿瘤进展尚无相关报道。我们研究证实肥胖状态下脂肪组织Fas信号增强，促进了脂肪组织炎症细胞因子（IL-6、TNF-α）分泌增加，增加的TNF-α可以进一步促进Fas表达上调，形成正反馈。进一步研究证实肥胖状态下脂肪组织Fas信号促进了结肠癌肺转移。机制探讨发现，Fas信号磷酸化脂肪细胞Fas,Fas Tyr189位点能够与酪氨酸激酶Bmx SH2结构域结合，活化Bmx，激活NF-κB、ERK和P38信号通路，促进TNF-α增加，影响了结肠癌肺转移。.该研究提出肥胖促进结直肠癌进展的一种新途径：肥胖时脂肪细胞Fas表达增加-Fas信号增强-Fas酪氨酸磷酸化增强-促进结合/活化Bmx-NF-κB/MAPK-分泌TNF-α等脂肪因子增加-促进结直肠癌进展。本课题的完成，有助于更好理解肥胖促进肿瘤进展机制。本课题还提出了Fas信号促进炎症进展的新途径，完善了肥胖时低炎状态机制。