While the androgen receptor (AR) might promote renal cell carcinoma (RCC) initiation and progression, the molecular mechanisms involved remain largely unclear. Here, we discovered the novel LncRNA-SARCC, which was suppressed and associated with better prognosis in RCC. Preclinical studies using multiple RCC cells and in vivo mouse model indicated that LncRNA-SARCC could attenuate RCC cell invasion, migration and proliferation in vitro and in vivo. Mechanistically, LncRNA-SARCC bound and destabilized AR protein with an inhibition of AR function, which led to transcriptionally de-repress miR-143-3p expression, thus inhibition of its downstream signals including AKT, MMP-13, K-RAS and P-ERK. In addition, bisulfite sequencing analysis substantiated that LncRNA-SARCC promoter was highly methylated in renal cancer tissues compared with paired non-cancerous renal tissues. Notably, treating with Sunitinib, the multi-targeted receptor tyrosine kinase inhibitor, increased the expression of LncRNA-SARCC, which decreased RCC cells resistance to Sunitinib. Thus, our study presented a road map for targeting this newly identified LncRNA-SARCC and its pathway, which expands potential therapeutic strategies for RCC treatment.

Background Previous study demonstrated that extracellular ATP could promote cell migration and invasion in multiple human cancers. Till now, the pro-invasive mechanisms of ATP and P2RX6, a preferred receptor for ATP, are still poorly studied in RCC. Methods Bioinformatics analysis was performed to identify the differentially expressed genes during RCC different stages. Tissue microarray, IHC staining and survival analysis was respectively used to evaluate potential clinical function. In vitro and in vivo assays were performed to explore the P2RX6 biological effects in RCC progression. Results We found that ATP might increase RCC cells migration and invasion through P2RX6. Mechanism dissection revealed that ATP-P2RX6 might modulate the Ca 2+ -mediated p-ERK1/2/MMP9 signaling to increase the RCC cells migration and invasion. Furthermore, METTL14 implicated m 6 A modification in RCC and down-regulated P2RX6 protein translation. In addition, human clinical survey also indicated the positive correlation of this newly identified signaling in RCC progression and prognosis. Conclusions Our findings revealed that the newly identified ATP-P2RX6-Ca 2+ -p-ERK1/2-MMP9 signaling facilitates RCC cell invasion and metastasis. Targeting this novel signaling pathway with small molecules might help us to develop a new approach to better suppress RCC progression. Electronic supplementary material The online version of this article (10.1186/s13046-019-1223-y) contains supplementary material, which is available to authorized users.

The effects of in ovo injection of different carbohydrate solutions on hatchability of fertilized eggs (HF), rate of hatch, BW, body moisture, yolk sac weight, and yolk sac moisture of Ross × 708 broiler chicks, hatched from eggs laid by a 34-wk-old breeder flock, were investigated. Eggs containing live embryos were injected, using an automated multiple-egg injector, in the amnion on d 18.5 of incubation with 0.1, 0.4, 0.7, or 1.0 mL of commercial diluent or a carbohydrate dissolved in diluent. The commercial diluent containing 0.25 g/mL of one of the following carbohydrates was injected into eggs: glucose, fructose, sucrose, maltose, or dextrin. The results showed that no carbohydrate type or solution volume affected rate of hatch. Absolute and proportional BW on day of hatch were positively related to injection volume (P < 0.001). However, HF was negatively related to injection volume (P < 0.001). To realize an HF of 90%, the injection volume could not exceed 0.4 mL for fructose or sucrose and could not exceed 0.7 mL for glucose, maltose, or dextrin. Yolk-free BW was negatively related to injection volume of fructose and sucrose (P < 0.004), but was not related to injection volume of diluent, glucose, maltose, and dextrin. Conversely, absolute and proportional yolk sac weights were positively related to injection volume of fructose, sucrose, and dextrin (P < 0.01), but were also not significantly related to injection volume of diluent, glucose, and maltose. Yolk sac moisture was positively related to injection volume for all injectables, including the diluent (P < 0.03). However, body moisture and yolk-free body moisture were not related to injection type or volume. In conclusion, the use of carbohydrates added to a commercial diluent for the in ovo injection of broiler hatching eggs requires the use of appropriate volumes to promote growth and nutrient utilization without adversely affecting HF.

It is well established that hypoxia contributes to tumor progression in a hypoxia inducible factor-2α (HIF-2α)-dependent manner in renal cell carcinoma (RCC), yet the role of long noncoding RNAs (LncRNAs) involved in hypoxia-mediated RCC progression remains unclear. Here we demonstrate that LncRNA-SARCC (Suppressing Androgen Receptor in Renal Cell Carcinoma) is differentially regulated by hypoxia in a von Hippel-Lindau (VHL)-dependent manner both in RCC cell culture and clinical specimens. LncRNA-SARCC can suppress hypoxic cell cycle progression in the VHL-mutant RCC cells while derepress it in the VHL-restored RCC cells. Mechanism dissection reveals that LncRNA-SARCC can post-transcriptionally regulate androgen receptor (AR) by physically binding and destablizing AR protein to suppress AR/HIF-2α/C-MYC signals. In return, HIF-2α can transcriptionally regulate the LncRNA-SARCC expression via binding to hypoxia-responsive elements on the promoter of LncRNA-SARCC. The negative feedback modulation between LncRNA-SARCC/AR complex and HIF-2α signaling may then lead to differentially modulated RCC progression in a VHL-dependent manner. Together, these results may provide us a new therapeutic approach via targeting this newly identified signal from LncRNA-SARCC to AR-mediated HIF-2α/C-MYC signals against RCC progression.

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 aberrant expression of long noncoding RNAs (lncRNAs) has recently emerged as key molecules in human cancers; however, whether lncRNAs are implicated in the progression of clear cell renal cell carcinoma (ccRCC) remains unclear. Methods Candidate lncRNAs were selected using microarray analysis and quantitative real-time PCR (qRT-PCR) was performed to detect lncRNAs expression in human ccRCC tissues. Overexpression and knocking down experiments in vivo and in vitro were performed to uncover the biological roles of lncRNA-URRCC on ccRCC cell proliferation and invasion. Microarray, chromatin immunoprecipitation, Luciferase reporter assay and western blot were constructed to investigate the molecular mechanisms underlying the functions of lncRNA-URRCC. Results The microarray analysis and qRT-PCR identified a new lncRNA, URRCC, whose expression is upregulated in RCC samples and associated with poor prognosis, leading to promote ccRCC cell proliferation and invasion. Mechanistically, URRCC enhances the expression of EGFL7 via mediating histone H3 acetylation of EGFL7 promoter, activation of P-AKT signaling, and suppressing P-AKT downstream gene, FOXO3. In return, FOXO3 could inhibit the transcription of URRCC via binding to the special region on the promoter of URRCC. Conclusions Our data suggests that targeting this newly identified feed-back loop between LncRNA-URRCC and EGFL7/P-AKT/FOXO3 signaling may enhance the efficacy of existing therapy and potentially imparts a new avenue to develop more potent therapeutic approaches to suppress RCC progression. Electronic supplementary material The online version of this article (10.1186/s12943-019-0998-y) contains supplementary material, which is available to authorized users.

PurposeAlthough microRNAs (miRNAs) were revealed as crucial modulators in tumor metastasis and target therapy, our understanding of their roles in metastatic renal cell carcinoma (mRCC) and Sunitinib treatment was limited. Here we sought to identify human miRNAs that acted as key regulators in renal cancer metastasis and Sunitinib treatment.Experimental designWe focused on 2 published microarray data to select out our anchored miRNA and then explored the roles of miR-452-5p both in vitro and in vivo, which was downregulated after Sunitinib treatment while upregulated in metastasis renal cell carcinoma (RCC) tissues.ResultsHere, we discovered that treating with Sunitinib, the targeted receptor tyrosine kinase inhibitor (TKI), inhibited renal cancer cell migration and invasion via attenuating the expression of miR-452-5p. The novel identified miR-452-5p was upregulated and associated with poor prognosis in RCC. Preclinical studies using multiple RCC cells and xenografts model illustrated that miR-452-5p could promote RCC cell migration and invasion in vitro and in vivo. Mechanistically, P65 could directly bind to the miR-452-5p promoter and thus transcriptionally induce miR-452-5p expression, which led to post-transcriptionally abrogate SMAD4 expression, thus inhibition of its downstream gene SMAD7.ConclusionOur study presented a road map for targeting this newly identified miR-452-5p and its SMAD4/SMAD7 signals pathway, which imparted a new potential therapeutic strategy for mRCC treatment.Electronic supplementary materialThe online version of this article (10.1186/s12943-018-0906-x) contains supplementary material, which is available to authorized users.

Our work presents a road map for the prediction and validation of a miR-532-5p/KRAS-NAP1L1/P-ERK/ETS1 axis feedback loop regulating cell proliferation, which could potentially provide better therapeutic avenues for treating RCC.