肥胖是肾癌发病的重要危险因素，肾脏本身就包裹在丰富的脂肪组织内。我们的前期研究工作发现肿瘤周围脂肪组织与肾癌的生物学行为密切相关，其表达特定的脂肪分泌因子谱并能促进肾癌细胞株的增殖和迁移。本课题将继续深入探讨不同分泌因子对肾癌细胞的影响，筛选起主要促癌作用的脂肪分泌因子。由于前期工作提示肿瘤周围脂肪组织的促癌作用在VHL失活的细胞株中更为明显，我们将分析脂肪分泌因子和VHL-HIF通路的相互作用，确认后续激活的信号通路和关键基因。随后在荷瘤动物模型中加以验证，进一步比较不同部位脂肪组织的分泌差异，对肾癌侵袭和转移的影响。再通过控制肥胖、阻断配体和阻断信号传导这3个层次来观察能否逆转脂肪组织形成的促癌微环境。最后将在组织标本水平探讨脂肪分泌因子的预后价值，为临床应用提供有力依据。本研究有助于揭示肿瘤周围脂肪组织在肾癌病变发展中的独特作用和具体途径，为肾癌的预防和治疗提供崭新的思路。

Obesity is an important risk factor for kidney cancer, and the kidney itself is surrounded by abundant adipose tissue. Our previous research has implicated a strong association between peritumor adipose tissue (PAT) and biological behavior of kidney cancer. The alterations in the secretory profile of PAT could promote the proliferation and migration of renal cancer cells. The current project is going to assess the impact of adipokines on renal cancer cells lines in detail, to find out which adipokines act as a main carcinogenic factor. Since preliminary analysis demonstrated the tumor promoting effect of PAT was more significant in VHL-null cell lines, we will evaluate the cross-talk between adipokines and the VHL-HIF pathway, and identify the activated signal pathway with key regulate genes. Using murine renal cancer model, we will validate the secretory profile and tumor promoting effect of PAT in vitro. Then, we will evaluate whether controlling high-fat intake, down-regulating the receptors of adipokines and down-regulating key genes in signal transduction will reverse the tumor promoting microenvironment. Finally, the prognostic value of adipokines from PAT will be analyzed in tumor specimens to find out whether it could aid in clinical practice. The project may help our understanding of the unique role and underlying mechanism of PAT in the progression of kidney cancer. It provides a new approach for the prevention and management of kidney cancer.