Abstract
BackgroundRenal cell carcinoma (RCC) is a deadly urological tumor that remains largely incurable. Our limited understanding of key molecular mechanisms underlying RCC invasion and metastasis has hampered efforts to identify molecular drivers with therapeutic potential. With evidence from our previous study revealing that nuclear overexpression of YBX1 is associated with RCC T stage and metastasis, we investigated the effects of YBX1 in RCC migration, invasion, and adhesion, and then characterized its interaction with RCC-associated proteins G3BP1 and SPP1.MethodsRenal cancer cell lines, human embryonic kidney cells, and clinical samples were analyzed to investigate the functional role of YBX1 in RCC metastasis. YBX1 knockdown cells were established via lentiviral infection and subjected to adhesion, transwell migration, and invasion assay. Microarray, immunoprecipitation, dual-luciferase reporter assay, and classical biochemical assays were applied to characterize the mechanism of YBX1 interaction with RCC-associated proteins G3BP1 and SPP1.ResultsKnockdown of YBX1 in RCC cells dramatically inhibited cell adhesion, migration, and invasion. Mechanistic investigations revealed that YBX1 interaction with G3BP1 upregulated their downstream target SPP1 in vitro and in vivo, which led to an activated NF-κB signaling pathway. Meanwhile, knockdown of SPP1 rescued the YBX1/G3BP1-mediated activation of NF-κB signaling pathway, and RCC cell migration and invasion. We further showed that YBX1 expression was positively correlated with G3BP1 and SPP1 expression levels in clinical RCC samples.ConclusionsYBX1 interacts with G3BP1 to promote metastasis of RCC by activating the YBX1/G3BP1–SPP1–NF-κB signaling axis.
Highlights
Renal cell carcinoma (RCC) is a deadly urological tumor that remains largely incurable
Y-box binding protein 1 (YBX1) is critical for RCC cell adhesion, migration, and invasion Our previous study demonstrated that nuclear levels of YBX1 were associated with T stage and metastasis of RCC, which prompted us to explore the functional effects of YBX1 [20, 28]
With evidence from our recent study showing that G3BP1 contributes to the metastasis of RCC in both in vitro assay and in vivo xenograft model [26], and others indicating that YBX1 and G3BP1 expression levels are highly correlated in human sarcomas [17], we examined whether YBX1 affects G3BP1 expression and cellular localization in RCC
Summary
Renal cell carcinoma (RCC) is a deadly urological tumor that remains largely incurable. Our limited understanding of key molecular mechanisms underlying RCC invasion and metastasis has hampered efforts to identify molecular drivers with therapeutic potential. Renal cell carcinoma (RCC) is a deadly urological tumor that is largely incurable [1]. It accounts for approximately 90% of all primary renal neoplasms [2], and its incidence has been increasing at an alarming rate across. Y-box binding protein 1 (YBX1) is one such molecular target that has been implicated in numerous human malignancies including breast cancer [8], prostate cancer [9], nasopharyngeal carcinoma [10], lung adenocarcinoma [11], and sarcoma [12]. In RCC, we recently showed that nuclear expression of YBX1 was correlated with T stage and metastasis [20], the underlying mechanism of YBX1 involvement in RCC metastasis remain largely unknown
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