O-GlcNAcylation has been implicated in the tumorigenesis of various tissue origins, but its function in liver tumorigenesis is not clear. Here, we demonstrate that O-GlcNAcylation can enhance the expression, stability and function of Yes-associated protein (YAP), the downstream transcriptional regulator of the Hippo pathway and a potent oncogenic factor in liver cancer. O-GlcNAcylation induces transformative phenotypes of liver cancer cells in a YAP-dependent manner. An O-GlcNAc site of YAP was identified at Thr241, and mutating this site decreased the O-GlcNAcylation, stability, and pro-tumorigenic capacities of YAP, while increasing YAP phosphorylation. Importantly, we found via in vitro cell-based and in vivo mouse model experiments that O-GlcNAcylation of YAP was required for high-glucose-induced liver tumorigenesis. Interestingly, a positive feedback between YAP and global cellular O-GlcNAcylation is also uncovered. We conclude that YAP O-GlcNAcylation is a potential therapeutic intervention point for treating liver cancer associated with high blood glucose levels and possibly diabetes.

BackgroundOxaliplatin resistance is a major challenge for treatment of advanced colorectal cancer (CRC). Both acquisition of epithelial-mesenchymal transition (EMT) and suppressed drug accumulation in cancer cells contributes to development of oxaliplatin resistance. Aberrant expression of small noncoding RNA, miR-128-3p, has been shown to be a key regulator in tumorigenesis and cancer development. However, its roles in the progression of CRC and oxaliplatin-resistance are largely unknown.MethodsOxaliplatin-resistant CRC and normal intestinal FHC cells were transfected with a miR-128-3p expression lentivirus. After transfection, FHC-derived exosomes were isolated and co-cultured with CRC cells. miR-128-3p expression in resistant CRC cells, FHC cells, and exosomes was quantified by quantitative real-time PCR (RT-qPCR). The mRNA and protein levels of miR-128-3p target genes in resistant CRC cells were quantified by RT-qPCR and western blot, respectively. The effects of miR-128-3p on CRC cell viability, apoptosis, EMT, motility and drug efflux were evaluated by CCK8, flow cytometry, Transwell and wound healing assays, immunofluorescence, and atomic absorption spectrophotometry. Xenograft models were used to determine whether miR-128-3p loaded exosomes can re-sensitize CRC cells to oxaliplatin in vivo.ResultsIn our established stable oxaliplatin-resistant CRC cell lines, in vitro and vivo studies revealed miR-128-3p suppressed EMT and increased intracellular oxaliplatin accumulation. Importantly, our results indicated that lower miR-128-3p expression was associated with poor oxaliplatin response in advanced human CRC patients. Moreover, data showed that miR-128-3p-transfected FHC cells effectively packaged miR-128-3p into secreted exosomes and mediated miR-128-3p delivery to oxaliplatin-resistant cells, improving oxaliplatin response in CRC cells both in vitro and in vivo. In addition, miR-128-3p overexpression up-regulated E-cadherin levels and inhibited oxaliplatin-induced EMT by suppressing Bmi1 expression in resistant cells. Meanwhile, it also decreased oxaliplatin efflux through suppressed expression of the drug transporter MRP5.ConclusionOur results demonstrate that miR-128-3p delivery via exosomes represents a novel strategy enhancing chemosensitivity in CRC through negative regulation of Bmi1 and MRP5. Moreover, miR-128-3p may be a promising diagnostic and prognostic marker for oxaliplatin-based chemotherapy.Electronic supplementary materialThe online version of this article (10.1186/s12943-019-0981-7) contains supplementary material, which is available to authorized users.

Recently, expression signatures of exosomal long non-coding RNAs (lncRNAs) have been proposed as potential non-invasive biomarkers for cancer detection. In this study, we aimed to develop a urinary exosome (UE)-derived lncRNA panel for diagnosis and recurrence prediction of bladder cancer (BC). Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to screen and evaluate the expressions of eight candidate lncRNAs in a training set (208 urine samples) and a validation set (160 urine samples). A panel consisting of three differently expressed lncRNAs (MALAT1, PCAT-1 and SPRY4-IT1) was established for BC diagnosis in the training set, showing an area under the receiver-operating characteristic (ROC) curve (AUC) of 0.854. Subsequently, the performance of the panel was further verified with an AUC of 0.813 in the validation set, which was significantly higher than that of urine cytology (0.619). In addition, Kaplan-Meier analysis suggested that the up-regulation of PCAT-1 and MALAT1 was associated with poor recurrence-free survival (RFS) of non-muscle-invasive BC (NMIBC) (p < 0.001 and p = 0.002, respectively), and multivariate Cox proportional hazards regression analysis revealed that exosomal PCAT-1 overexpression was an independent prognostic factor for the RFS of NMIBC (p = 0.018). Collectively, our findings indicated that UE-derived lncRNAs possessed considerable clinical value in the diagnosis and prognosis of BC.Electronic supplementary materialThe online version of this article (10.1186/s12943-018-0893-y) contains supplementary material, which is available to authorized users.

Exosomes are small membrane vesicles released by many cells. These vesicles can mediate cellular communications by transmitting active molecules including long non‐coding RNAs (lncRNAs). In this study, our aim was to identify a panel of lncRNAs in serum exosomes for the diagnosis and recurrence prediction of bladder cancer (BC). The expressions of 11 candidate lncRNAs in exosome were investigated in training set (n = 200) and an independent validation set (n = 320) via quantitative real‐time PCR. A three‐lncRNA panel (PCAT‐1, UBC1 and SNHG16) was finally identified by multivariate logistic regression model to provide high diagnostic accuracy for BC with an area under the receiver‐operating characteristic curve (AUC) of 0.857 and 0.826 in training set and validation set, respectively, which was significantly higher than that of urine cytology. The corresponding AUCs of this panel for patients with Ta, T1 and T2‐T4 were 0.760, 0.827 and 0.878, respectively. In addition, Kaplan‐Meier analysis showed that non‐muscle‐invasive BC (NMIBC) patients with high UBC1 expression had significantly lower recurrence‐free survival (P = 0.01). Multivariate Cox analysis demonstrated that UBC1 was independently associated with tumour recurrence of NMIBC (P = 0.018). Our study suggested that lncRNAs in serum exosomes may serve as considerable diagnostic and prognostic biomarkers of BC.

Some types of long noncoding RNAs (lncRNAs) are aberrantly expressed in human diseases, including cancer. However, the overall biological roles and clinical significances of most lncRNAs in colorectal cancer (CRC) are not fully understood. First, The Cancer Genome Atlas (TCGA) was analyzed to identify differentially expressed lncRNAs between CRC tissues and noncancerous tissues. We identified that LINC02418 was highly expressed in CRC tissues and cell lines. Next, we evaluated the effect of LINC02418 on CRC tumorigenesis and its regulatory functions of absorbing microRNA and indirectly stimulating protein expression by acting as a ceRNA. Mechanistically, LINC02418 acted as a ceRNA to upregulate MELK expression by absorbing miR-1273g-3p. In addition, the diagnostic performance of cell-free LINC02418 and exosomal LINC02418 were both evaluated by the receiver operating characteristic curve and the area under the curve (AUC). Exosomal LINC02418 could distinguish the patients with CRC from the healthy controls (AUC = 0.8978, 95% confidence interval = 0.8644–0.9351) better than cell-free LINC02418 (AUC = 0.6784, 95% confidence interval = 0.6116–0.7452). Collectively, we determined that LINC02418 was significantly overexpressed in CRC and that the LINC02418–miR-1273g-3p–MELK axis played a critical role in CRC tumorigenesis. Finally, exosomal LINC02418 is a promising, novel biomarker that can be used for the clinical diagnosis of CRC.

The Amur Grape (Vitis amurensis Rupr.) cultivars 'ShuangFeng' and 'ZuoShanyi' were grown in shelter greenhouse under natural sunlight and subjected to drought. Sap flow rate, net photosynthetic rate (P N ), and chlorophyll (Chl) fluorescence were measured on Amur Grape leaves subjected to different drought treatments. Significant decreases in P N were associated with increasing intercellular CO 2 concentration (C i ), suggesting that the reduction in P N was caused by nonstomatal limitation. Analysis of OJIP transients according to the JIP-test protocol revealed that specific (per PSII reaction center) energy fluxes for light absorption, excitation energy trapping and electron transport have significantly changed. The appearance of a pronounced K-step and J-step in polyphasic rise of fluorescence transient suggested the oxygen-evolving complex and electron transport were inhibited. Drought stress has relatively little effect on the parameter maximal quantum yield of PSII photochemistry (F v /F m ), but the performance index (PI ABS ) is more sensitive in different drought treatment. There are cultivar differences in the response of PSII activity to drought, the photosynthetic apparatus of 'ZuoShanyi' cultivar is more resistant to drought than that of 'ShuangFeng', and JIP-test could be a useful indicator for evaluation and selection to drought tolerance.

Circular RNAs (circRNAs) are emerging as cardinal areas of focus in the non-coding RNA field. Growing evidences have revealed exosomal circRNAs as potential biomarkers for detection of various cancers. However, the clinical importance of most serum exosomal circRNAs in colorectal cancer (CRC) have rarely been investigated. In this study, we examined the possible clinical application of serum exosomal circRNAs in the diagnosis of CRC. Firstly, we conducted RNA sequencing (RNA-seq) analysis using fifty CRC and fifty healthy control serum samples to identify CRC-related circRNAs. The sequencing data showed 122 differentially expressed circRNAs including 100 up-regulated and 22 down-regulated circRNA transcripts in CRC patients. Then, eight most dysregulated circRNAs were selected for validation by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) assay. Validation analysis revealed that the serum exosomal circ-PNN (hsa_circ_0101802) levels were significantly up-regulated in CRC cases compared with those in the healthy control groups. Receiver operating characteristic curve (ROC) analysis suggested that circ-PNN had significant value in CRC diagnosis with areas under the ROC curve (AUC) of 0.855 and 0.826 in the training and validation sets, respectively. We also found that the AUC of serum exosomal circ-PNN for early-stage CRC was 0.854. Finally, a network map based on circ-PNN was constructed to determine its potential miRNA-mRNAs binding. We also demonstrated that the expression of hsa-miR-6833-3P, hsa-let-7i-3p and hsa-miR-1301-3P were negatively correlated with circ-PNN in CRC patients. Collectively, our findings indicated that serum exosomal circ-PNN might be a potential non-invasive biomarker for the detection of CRC and may play a crucial role in the pathogenesis of CRC.

Wang (2019) Mesenchymal stem cells derived exosomal miR-323-3p promotes proliferation and inhibits apoptosis of cumulus cells in polycystic ovary syndrome (PCOS), Artificial Cells,