Sunitinib resistance is a major challenge for advanced renal cell carcinoma (RCC). Understanding the underlying mechanisms and developing effective strategies against sunitinib resistance are highly desired in the clinic. Here we identified an lncRNA, named lncARSR (lncRNA Activated in RCC with Sunitinib Resistance), which correlated with clinically poor sunitinib response. lncARSR promoted sunitinib resistance via competitively binding miR-34/miR-449 to facilitate AXL and c-MET expression in RCC cells. Furthermore, bioactive lncARSR could be incorporated into exosomes and transmitted to sensitive cells, thus disseminating sunitinib resistance. Treatment of sunitinib-resistant RCC with locked nucleic acids targeting lncARSR or an AXL/c-MET inhibitor restored sunitinib response. Therefore, lncARSR may serve as a predictor and a potential therapeutic target for sunitinib resistance.

BackgroundRecent evidences showed that long noncoding RNAs (lncRNAs) are frequently dysregulated and play important roles in various cancers. Clear cell renal cell carcinoma (ccRCC) is one of the leading cause of cancer-related death, largely due to the metastasis of ccRCC. However, the clinical significances and roles of lncRNAs in metastatic ccRCC are still unknown.MethodslncRNA expression microarray analysis was performed to search the dysregulated lncRNA in metastatic ccRCC. quantitative real-time PCR was performed to measure the expression of lncRNAs in human ccRCC samples. Gain-of-function and loss-of-function experiments were performed to investigate the biological roles of lncRNAs on ccRCC cell proliferation, migration, invasion and in vivo metastasis. RNA pull-down, RNA immunoprecipitation, chromatin immunoprecipitation, and western blot were performed to explore the molecular mechanisms underlying the functions of lncRNAs.ResultsThe microarray analysis identified a novel lncRNA termed metastatic renal cell carcinoma-associated transcript 1 (MRCCAT1), which is highly expressed in metastatic ccRCC tissues and associated with the metastatic properties of ccRCC. Multivariate Cox regression analysis revealed that MRCCAT1 is an independent prognostic factor for ccRCC patients. Overexpression of MRCCAT1 promotes ccRCC cells proliferation, migration, and invasion. Depletion of MRCCAT1 inhibites ccRCC cells proliferation, migration, and invasion in vitro, and ccRCC metastasis in vivo. Mechanistically, MRCCAT1 represses NPR3 transcription by recruiting PRC2 to NPR3 promoter, and subsequently activates p38-MAPK signaling pathway.ConclusionsMRCCAT1 is a critical lncRNA that promotes ccRCC metastasis via inhibiting NPR3 and activating p38-MAPK signaling. Our results imply that MRCCAT1 could serve as a prognostic biomarker and therapeutic target for ccRCC.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-017-0681-0) contains supplementary material, which is available to authorized users.

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Renal tumour-initiating cells (T-ICs) contribute to tumorigenesis, progression and drug resistance of renal cell carcinoma (RCC). However, the underlying mechanism for the propagation of renal T-ICs remains unclear. Here we show that long non-coding RNA lncARSR is upregulated in primary renal T-ICs and associated with a poor prognosis of clear cell RCCs (ccRCC). Knockdown of lncARSR attenuates the self-renewal, tumorigenicity and metastasis of renal T-ICs. Conversely, forced lncARSR expression enhances T-IC properties of RCC cells. Mechanistically, the binding of lncARSR to YAP impedes LATS1-induced YAP phosphorylation and facilitates YAP nuclear translocation. Reciprocally, YAP/TEAD promotes lncARSR transcription, thus forming a feed-forward circuit. The correlation between lncARSR and YAP is validated in a ccRCC cohort, where the combination of these two parameters exhibits improved prognostic accuracy. Our findings indicate that lncARSR plays a critical role in renal T-ICs propagation and may serve as a prognostic biomarker and potential therapeutic target.

Abstract. Several types of evidence suggest that protein-tyrosine phosphorylation is important during the growth of neuronal processes, but few specific roles, or subcellular localizations suggestive of such roles, have been defined. We report here a localization of tyrosine-phosphorylated protein at the tips of growth cone filopodia. Immunocytochemistry using a rnAb to phosphorylated tyrosine residues revealed intense staining of the tips of most filopodia of Aplysia axons growing slowly on a polylysine substrate, but of few filopodia of axons growing rapidly on a substrate coated with Aplysia hemolymph, which has growthpromoting material. Cytochalasin D, which causes F-actin to withdraw rapidly from the growth cone, caused the tyrosine-phosphorylated protein to withdraw rapidly from filopodia, suggesting that the protein associates or interacts with actin filaments. Phosphotyrosine has previously been found concentrated at adherens junctions, where bundles of actin filaments terminate, but video-enhanced contrastdifferential interference contrast and confocal interference reflection microscopy demonstrated that the filopodial tips were not adherent to the substrate. Acute application of either hemolymph or inhibitors of protein-tyrosine kinases to neurons on polylysine resulted in a rapid loss of intense staining at filopodial tips concomitant with a lengthening of the filopodia (and their core bundles of actin filaments). These results demonstrate that tyrosine-phosphorylated protein can be concentrated at the barbed ends of actin filaments in a context other than an adherens junction, indicate an association between changes in phosphorylation and filament dynamics, and provide evidence for tyrosine phosphorylation as a signaling mechanism in the filopodium that can respond to environmental cues controlling growth cone dynamics.

Although the use of sorafenib appears to increase the survival rate of renal cell carcinoma (RCC) patients, there is also a proportion of patients who exhibit a poor primary response to sorafenib therapy. It is therefore critical to elucidate the mechanisms underlying sorafenib resistance and find representative biomarkers for sorafenib treatment in RCC patients. Herein, we identified a long non-coding RNA referred to as lncRNA-SRLR (sorafenib resistance-associated lncRNA in RCC) that is upregulated in intrinsically sorafenib-resistant RCCs. lncRNA-SRLR knockdown sensitized nonresponsive RCC cells to sorafenib treatment, whereas the overexpression of lncRNA-SRLR conferred sorafenib resistance to responsive RCC cells. Mechanistically, lncRNA-SRLR directly binds to NF-κB and promotes IL-6 transcription, leading to the activation of STAT3 and the development of sorafenib tolerance. A STAT3 inhibitor and IL-6-receptor antagonist both restored the response to sorafenib treatment. Moreover, a clinical investigation demonstrated that high levels of lncRNA-SRLR correlated with poor responses to sorafenib therapy in RCC patients. Collectively, lncRNA-SRLR may serve as not only a predictive biomarker for inherent sorafenib resistance but also as a therapeutic target to enhance responses to sorafenib in RCC patients.

Lithium supports both the survival and regeneration of RGC axons through a Bcl-2-dependent mechanism. This suggests that lithium may be used to treat glaucoma, optic nerve neuritis, the degeneration of RGCs and their nerve fibers, and other brain and spinal cord disorders involving nerve damage and neuronal cell loss. To achieve full regeneration of the severed optic nerve, it may be essential to combine lithium therapy with other drugs that mediate induction of a permissive environment in the mature central nervous system.

Retinal and choroidal neovascularization are the most frequent causes of severe and progressive vision loss. Studies have demonstrated that Tie2, an endothelial-specific receptor tyrosine kinase, plays a key role in angiogenesis. In this study, we determined whether adenovirus-mediated gene delivery of extracellular domain of the Tie2 receptor (ExTek) could inhibit experimental retinal and choroidal neovascularization. Immunofluorescence histochemistry with a monoclonal antibody to human Tie2 showed that Tie2 expression is prominent around and within the base of newly formed blood vessels of retinal and choroidal neovascular lesions. A single intramuscular injection of adenovirus expressing ExTek genes achieved plasma levels of ExTek exceeding 500 microg/ml in mice for 10 days (in neonates) and 7 days (in adults). This treatment inhibited retinal neovascularization by 47% (p < 0.05) in a murine model of ischemia-induced retinopathy. The same treatment reduced the incidence and extent of sodium fluorescein leakage from choroidal neovascular lesions by 52% (p < 0.05) and 36% (p < 0.01), respectively, in a laser-induced murine choroidal neovascularization model. The same mice showed a 45% (p < 0.001) reduction of integrated area of the choroidal neovascularization. These findings indicate that Tie2 signaling is a common component of the angiogenic pathway in both retinal and choroidal neovascularization, providing a potentially useful target in the treatment of intraocular neovascular diseases.