肥大细胞在高糖环境促进肾癌进展中的作用及机制研究

高血糖作为肾癌的常见伴发疾病，与肾癌的进展及不良预后有关，但其机制并不清楚。血管形成在肾癌的生长及转移中具有重要作用。我们既往研究发现肾癌细胞可通过招募肥大细胞促进血管形成及靶向治疗耐受，且高血糖患者肿瘤标本中具有更高的肥大细胞浸润与血管形成水平。体外高糖培养环境可降低肾癌细胞GSK3β活性并升高HIF1α表达及对肥大细胞的招募。此外，我们已初步证实E3泛素连接酶FBXL14可促进肾癌HIF1α降解，且该过程需要GSK3β对HIF1α磷酸化。因此，我们推测高糖环境可通过降低GSK3β活性抑制FBXL14对HIF1α的降解。升高的HIF1α进一步促进肥大细胞相关血管形成，最终引起肾癌进展及治疗抵抗。在本研究中，我们拟采用RNA-seq、Crispr/Cas9等技术探讨高血糖这一代谢性疾病促进肾癌进展的分子机制，以明确肾癌进展原理，为寻找新的肾癌治疗靶点奠定理论基础。

Hyperglycemia is associated with progression and poor prognosis in renal cell carcinoma (RCC). Angiogenesis plays crucial role on RCC growth and metastasis. In the past years, we found that RCC achieved angiogenesis and target therapy resistance by recruiting mast cells. Mast cell-related angiogenesis in RCC is associated with hyperglycemia of patients. Treatment of RCC cells with high glucose in vitro inhibited GSK3β activity but enhanced HIF1α expression and mast cell recruitment. In addition, HIF1α could be phosphorylated by GSK3β and then degraded by the E3 ligase FBXL14. Thus, we hypothesize that high glucose antagonizes FBXL14-mediated HIF1α degradation through GSK3β. Elevated HIF1α expression in RCC then promotes mast cell related angiogenesis, therapeutic resistance and cancer progression. In this study, we plan to explore the mechanisms of hyperglycemia-induced RCC progression by using RNA-seq and Crispr/Cas9 knockout system.