Abstract
Patients with renal cell carcinoma (RCC) often develop resistance to antivascular drugs and eventually succumb to disease. However, the underlying molecular mechanism remains poorly understood. In this study, we demonstrated that RASAL2, a RAS GTPase-activating protein, played a tumor-suppressive role in RCC by targeting tumor angiogenesis. Firstly, we showed that RASAL2 was frequently epigenetically silenced in RCC, and its loss was negatively correlated with overall survival of RCC patients. Furthermore, we discovered that RASAL2 could inhibit RCC angiogenesis in vitro and in vivo. Mechanistically, we identified that RASAL2 could activate GSK3β by reducing Ser9 phosphorylation and subsequently decrease the expression of c-FOS and vascular endothelial growth factor A (VEGFA). Interruption of the p-GSK3β/c-FOS pathway with the specific inhibitor or small interfering RNA could reverse the expression of VEGFA, which may provide a new insight to prevent RCC from resistance to antivascular therapy.
Highlights
Renal cell carcinoma (RCC) is a common malignancy in human genitourinary system
Since von Hippel-Lindau (VHL) mutations occurred in 60–70% clear-cell RCC (ccRCC) cases and hypoxia-inducible factor (HIF) activated by VHL mutations could induce vascular endothelial growth factor A (VEGFA) expression for RCC angiogenesis[3,16], we explored the association between RASAL2 and VHL status
Based on the analyses of VHL gene mutation data in RCC patients from TCGA database, we found a slight significant difference in terms of RASAL2 mRNA expression between VHL wild-type and mutation patients, whereas there was no significant difference in different mutation subtypes or mutation sublocations
Summary
Renal cell carcinoma (RCC) is a common malignancy in human genitourinary system. There are an estimated 63,990 new cases and 14,400 deaths from kidney and renal pelvic cancer in United States in 20171. RCC has several subtypes, and clear-cell RCC (ccRCC) accounts for almost 65−70% of all RCC2. Almost all familial ccRCC and over 60% of sporadic ccRCC harbor the suppressor gene von Hippel-Lindau (VHL)-inactivated mutation[3]. About 20−25% of newly diagnosed RCC patients have developed distant metastasis, which has a poor prognosis[4]. Angiogenesis is a crucial process for the progression and metastasis of RCC, and antivascular drugs are widely used in patients with metastatic RCC5. Drug resistance has been reported in recent years[6,7], and the underlying molecular mechanisms of the development and metastasis of RCC are still poorly understood
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