1. Cancer Center, Shandong Provincial Hospital affiliated to Shandong University, Jinan 250021, Shandong Province, China.
2. Cancer Institute, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China.
3. Department of Radiation Oncology, Xuzhou Cancer Hospital, Xuzhou 221005, Jiangsu Province, China.
4. Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
5. Department of Experiment, Tumor Hospital Affiliated to Guangxi Medical University, Nanning 530021, Guangxi Province, China.
*Feng Guo, Jinjin Liu and Xiao Han contributed equally to this work.
F-box only protein 22 (FBXO22), a substrate receptor of the SKP1-Cullin 1-F-box protein (SCF) E3 ubiquitin ligase that targets key regulators of cellular activities for ubiquitylation and degradation, plays important roles in the progression of human cancer. However, little is known about the role of FBXO22 in renal cell carcinoma (RCC). This study aims to explore the biological function of FBXO22 in RCC progression and its specific regulation mechanism. We performed immunohistochemistry analysis and found that the expression level of FBXO22 was significantly lower in RCC tissues than in normal renal tissues. Reduced FBXO22 expression in RCC tissues is related to tumor size and TNM stage and to worse overall and disease-free survival. Through an in vitro assay, we demonstrated that FBXO22 has no effect on renal cancer cells proliferation, whereas FBXO22 remarkably restricted RCC cell migration and invasion, thereby reversing EMT transition and elevating the activity of tissue inhibitor of matrix metalloproteinase-1, which subsequently inhibited metalloproteinase-9 (MMP-9) expression and activity in vitro. We also found that FBXO22 suppresses tube formation by disrupting the secretion of vascular endothelial growth factor. Meanwhile, in vivo studies verified that FBXO22 suppresses RCC metastasis. These findings suggested that FBXO22 is a novel prognostic indicator and plays an important role in RCC metastasis.
Keywords: FBXO22, proliferation, metastasis, angiogenesis, renal cell carcinoma