肿瘤周围脂肪组织调节肾癌生物学行为的机制研究

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.

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。

肥胖是肾癌发生进展的重要危险因素，确定肥胖和肾癌的相关性及机制分析有助于优化针对性的防治策略。本项目的研究结果分为三个部分：1）通过多中心研究发现高内脏脂肪显著增加透明细胞癌的发生率（OR=1.86），筛选血脂组分证实低密度脂蛋白高的人群中肾癌发生比值比达到9.311，随后进一步证实内脏型脂肪增多能够显著影响晚期患者的预后（p=0.002），并通过多危险因素分析确定肥胖和年龄、性别、地区差异的相互影响。2）从遗传角度分析证实脂联素ADIPOQ遗传多态性显著增加透明细胞癌患病风险（OR=1.36），通过内分泌筛选证实血清adiponectin水平和透明细胞癌亚型密切相关（OR=1.12），随后通过细胞和动物实验证实FTO-NFkB、LDLR—miRNA-330两组肥胖影响肾癌进展的关键通路，并开展RNA和甲基化筛选高侵袭性肾癌的相关基因，构建的分子预测模型准确率达到81.8%。3）前瞻性通过肥胖、营养、体质评估证实严重营养不良患者的死亡风险增加3.157倍，证实肌肉减少能够独立预测患者死于疾病（HR=2.367）。本项目从临床问题出发，通过基础研究初步阐述了可能的分子机制，为后续临床中针对性的早期识别、早期干预肾癌危险因素提供了依据，为进一步研发治疗靶点和联合治疗模式提供了具有前景的方向。