Highlights d RABV-G ecto-domain protein structure is revealed using a fusion-loop substitution strategy d Crystal structures of RABV-G at both basic and acidic pHs are solved d Structural comparison reveals basis of pH-dependent structural transitions in RABV-G d Complex structure shows 523-11 antibody binds a bipartite epitope for neutralization
The chronic inflammatory microenvironment within or surrounding the primary renal cell carcinoma (RCC) site promotes oncogenic transformation as well as contributes to the development of metastasis. G3BP stress granule assembly factor 1 (G3BP1) was found to be involved in the regulation of multiple cellular functions. However, its functions in RCC have not been previously explored. Here, we first showed that the expression of G3BP1 is elevated in human RCC and correlates with RCC progression. In cultured RCC cells, knockdown of G3BP1 results in inhibition of tumor cell proliferation, migration, and invasion, consistently with the alteration of epithelial–mesenchymal transition (EMT) and cell proliferative markers, including Cadherins, Vimentin, Snail, Slug, c-Myc, and cyclin D1. Remarkably, knockdown of G3BP1 dramatically impaired the signaling connection of pro-inflammatory cytokine IL-6 stimulation and downstream STAT3 activation in RCC, thus eventually contributing to the disruption of IL-6-elicited RCC migration and metastasis. In addition, in vivo orthotopic tumor xenografts results confirmed that knockdown of G3BP1 suppressed RCC tumor growth and metastasis in mice. Collectively, our findings support the notion that G3BP1 promotes tumor progression and metastasis through IL-6/G3BP1/STAT3 signaling axis in RCC.
BACKGROUND:The current study investigated the prevalence and prognostic value of chronic hepatitis B virus (HBV) infection in patients with nasopharyngeal carcinoma (NPC) from an area in southern China in which HBV and NPC are endemic. METHODS: A total of 1301 patients with nonmetastatic, histologically proven NPC who were treated with radiotherapy or chemoradiotherapy were retrospectively reviewed. RESULTS: In this series, 142 of the 1301 patients (10.9%) had chronic HBV infection (hepatitis B surface antigen [HBsAg] seropositive). The percentages of non-cancer-related deaths (15.0% vs 12.1%; P 5.618) and severe hepatic adverse events (3.5% vs 0.9%; P 5.145) were similar among patients with NPC with and without HBV infection. The 5-year overall survival (OS), progression-free survival (PFS), and locoregional recurrence-free survival (LRFS) rates for patients with NPC with or without HBV infection were 70.9% and 80.8% (P 5.003), 63.7% and 73.0% (P 5.016), and 81.7% and 88.2% (P 5.035), respectively. Multivariate analysis identified chronic HBV infection in patients with NPC as an independent unfavorable prognostic factor for OS (hazards ratio [HR], 1.684; P 5.003), PFS (HR, 1.451; P 5.015), and LRFS (HR, 1.573; P 5.048). Further analysis revealed that chronic HBV infection was an unfavorable, independent prognostic factor in patients with locoregionally advanced NPC, but not those with early-stage disease. In patients with stage III=IV NPC, HBsAg-positive patients had poorer OS (64.0% vs 77.2%; P 5.003), PFS (56.2% vs 70.6%; P 5.004), and LRFS (76.2% vs 88.3%; P 5.002) compared with HBsAg-negative patients. On multivariate analysis, chronic HBV infection was found to be an independent adverse prognostic predictor for OS (HR, 1.734; P 5.004), PFS (HR, 1.644; P 5.003), and LRFS (HR, 2.108; P 5.003) in patients with stage III=IV NPC. CONCLUSIONS: Chronic HBV infection is an independent adverse prognostic factor in patients with locoregionally advanced NPC. Cancer 2014;120:68-76.
Background
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. 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.
Methods
Renal 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.
Results
Knockdown 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.
Conclusions
YBX1 interacts with G3BP1 to promote metastasis of RCC by activating the YBX1/G3BP1–SPP1–NF-κB signaling axis.
Electronic supplementary material
The online version of this article (10.1186/s13046-019-1347-0) contains supplementary material, which is available to authorized users.
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