Background: More and more evidences show that metabolic syndrome (MS) is closely related to clear cell renal cell carcinoma (ccRCC), but the impact of MS on Fuhrman grade and TNM stage of ccRCC is rarely reported. Purpose: To explore the relationship between MS and its components of Fuhrman grade and TNM stage in ccRCC. Objective: The clinical data of 247 patients with ccRCC diagnosed in our hospital from January 2016 to November 2020 were retrospectively collected and analyzed. Based on diagnostic criteria of MS, the patients were divided into MS and non-MS group. Logistic regression analysis was used to analyze the independent risk factors of ccRCC. Results: The incidence of MS was 32.79% (81/247). There was no significant difference in age, gender, smoking and drinking between MS group and non-MS group (P > 0.05). In MS group, BMI ≥25kg/m 2 , hypertension, diabetes, hyperlipidemia, tumor diameter, poorly differentiated renal cancer, high-stage renal cancer, triglyceride, fasting blood glucose, glycated hemoglobin, fasting insulin and homeostasis model assessment index were significantly higher than those in non-MS group (P < 0.001), while in high density lipoprotein cholesterol (p < 0.005), islet beta cell secretory index (P < 0.001), well-differentiated renal cell carcinoma (P= 0.009), and low-stage renal cell carcinoma (P = 0.019) were significantly lower than that of non-MS group. Logistic regression analysis showed that hypertension (P = 0.005), diabetes (P = 0.012), hyperlipidemia (P = 0.021) are independent risk factors for Fuhrman grade of ccRCC, while diabetes (P = 0.002), hyperlipidemia (P = 0.007) are independent risk factors for TNM staging of ccRCC. Conclusion:The patients with ccRCC and MS had higher Fuhrman grade and TNM stage. MS is an independent risk factor for Fuhrman grade and TNM stage of ccRCC.

Renal cell carcinoma (RCC) is one of the most common malignant tumors of the urinary system. Although deregulation of the Notch signaling pathway is common in RCC and is involved in the tumorigenic process, the exact role of Notch3 and its underlying molecular mechanism in RCC, particularly in hypoxia, remain unknown. In the present study, RO4929097, a Notch3 inhibitor, was used to alter NICD3 expression. A Cell Counting Kit-8 assay, EdU incorporation assay, colony formation assay, flow cytometry and western blot analysis were used to investigate the effects of altered NICD3 expression on cell proliferation, cell cycle progression and HIF-2α protein expression. The results of western blot analysis showed that RO4929097 dose-dependently decreased the expression of Notch3 intracellular domain (NICD3) in 786-O and ACHN cells, which originate from clear cell RCC (ccRCC). The results of the Cell Counting Kit-8, EdU incorporation and colony formation assays demonstrated that downregulation of NICD3 significantly suppressed cell proliferation in both normoxia and hypoxia. In addition, flow cytometry and western blot analysis demonstrated that hypoxia (2% O 2) promoted cell cycle progression in ccRCC cells with the increased expression of G 1-S transition-associated proteins, namely cyclin-dependent kinase (CDK)4 and cyclin D1, while downregulation of NICD3 exerted negative effects on cell cycle progression, and the expression levels of CDK4 and cyclin D1. Furthermore, western blot analysis revealed that 2% O 2-induced upregulated hypoxia-inducible factor-2α (HIF-2α) expression decreased following downregulation of NICD3 in 786-O and ACHN cells. Following transfection of the vector containing the NICD3 coding sequence, HIF-2α, CDK4, cyclin D1 and proliferating cell nuclear antigen expression,that were inhibited by RO4929097 in hypoxia, were rescued. Collectively, the results of the present study suggest that Notch3 is closely associated with the cell proliferation of ccRCC cells by regulating the cell cycle and HIF-2α.

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