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Fiber is anaerobically digested by gut bacteria when it reaches the colon, yeilding short-chain fatty acids (SCFAs) by-creation. SCFAs also include acetate, propionate, and butyrate. The interaction of food, intestinal microbiota, and energy metabolism has been the focus of recent SCFA research. Specifically, SCFAs can physiologically stabilize the gut macroscopically and affect metabolism microscopically. This article will specifically explain SCFAs’ regulation of SCFAs on glucose and its functions related to the lipid metabolism and mechanisms and effects on weight control. The report also highlights the sequencing effects among diets, SCFAs and intestinal homeostasis. Specifically, the higher the intake of high-fiber foods, the more SCFAs are created, and as SCFAs have regulatory effects on various body parts, so SCFAs will have influence on intestinal homeostasis. SCFAs can mainly help maintain the balance of glucose and lipid metabolism. The formation of SCFAs can be increased by increasing dietary fiber content in diets, which can maintain intestinal homeostasis and control body weight and some gastrointestinal function by binding to GPCRs like FFAR2/3.

In this study, with silicon carbide as a pyroelectric catalyst, the reactor was alternatively removed between a hot water bath and a cold water bath, which ensured the cold-hot circulation within 300–333 K at room temperature. Then the pyroelectric performance of silicon carbide was utilized in hydrogen evolution from water splitting. With methanol as the sacrificial agent, the hydrogen yield after 20 cycles was up to 32.84 μmol/g. Silicon carbide demonstrates high catalytic activity and together with its chemical stability, it shows potential in hydrogen production from water splitting under cold-hot alternation.

The effects and mechanisms of folic acid (FA) as a chemopreventive agent for tumorigenesis of hepatocellular carcinoma (HCC) remain unclear. In this study, the QSG-7701, a human normal liver cell line, was cultured in different FA levels (High, Normal or No) for 6 months. Then, the biological characteristics, the expression of main stem cell-like genes or epithelial-mesenchymal transition (EMT) related genes and the tumorigenicity in vivo of cells cultured in different treatment groups were detected. Our results showed that No FA improved the malignant transformation of cells but High FA depressed the malignant transformation. Meanwhile, cells in different treatment groups were mapped by transcriptome sequencing. Then the relativity of increased LCN2 and decreased FA level was identified and confirmed in vitro and vivo. We also revealed that intracellular control of LCN2 would recover the effects of FA on cell proliferation, cell cycle and tumor formation in vitro and vivo. Finally, our studies displayed that increased FA level induced the down-regulation of LCN2 not by DNA hypermethylation of LCN2 promoter but by promoting the level of histone H3 lysine 9 di-methylation (H3K9Me2) in LCN2 promoter. In conclusion, our studies disclosed the chemopreventive effect of FA supplementation on hepatocarcinogenesis, which partial attributed to the inhibition of LCN2 by regulating histone methylation in promoter. Our results provide a potential mechanism of the chemoprevention of FA supplementation on tumorigenesis of HCC and may be helpful in developing treatment target against HCC.

With the continuous growth of global energy demand, the artificial photosynthetic system of photocatalytic decomposition of hydrogen production has been widely concerned, CdZnS, a photocatalyst based on solid solution, has shown good performance. In order to avoid the rapid recombination of photogenerated electron and hole, metal boride is added as a catalyst to enhance its photocatalytic hydrogen production performance. We prepared CdZnS photocatalyst by hydrothermal method, and synthesized different proportions of NiB/CdZnS catalyst by programmed heating method and calcined it at 773K. Characterized by XRD, XPS, uv–vis diffuse reflection and other methods, CZS solid solution and NiB/CdZnS were synthesized, and the absorption edge of NiB/CZS was redshifted relative to the pure CdZnS. The addition of NiB can effectively inhibit the recombination of electrons and holes to improve the separation efficiency of photogenerated charge, and its content has an impact on photocatalytic activity. We found that under visible light irradiation, when the content is 15 wt%, the hydrogen production was the highest. The optimal quantum efficiency was 13.3%, and the hydrogen production reacheed 8137 μmol/g/h, which is 17 times that of pure CdZnS. The addition of NiB greatly improved the photocatalytic performance of CdZnS.

Antibiotic production wastewater usually contains high concentrations of antibiotic residues, which can cause instability and deterioration of biological wastewater treatment units and also domestication and proliferation of antibiotic-resistance bacteria. An effective pretreatment on antibiotics production wastewater is expected to selectively reduce the concentration of antibiotics and decrease the toxicity, rather than mitigate organic and other contaminants before further treatments. In this work, two polymer-based solid acids, PS-S and CPS-S bearing high concentrations of -SOH

Inactive ovaries (IO) accounts for 50% of ovarian disease in postpartum dairy cows, which seriously affects their reproductive efficiency. To investigate the metabolic changes in the serum and follicular fluid of dairy cows with IO during lactation, six estrus (E) cows and six IO cows at 50 to 55 days in milk were selected based on B ultrasonic detection and clinical manifestations. The differential metabolites in serum and follicular fluid between the E cows and IO cows were identified by ultra-high-pressure liquid chromatography–quadrupole time-of-flight mass spectrometry, combined with multidimensional statistical methods. The results showed that dairy cows with IO were in a subclinical ketosis status where beta-hydroxybutyrate (BHB) exceeded 1.20 mmol/L, 14 differential metabolites in the serum of IO cows included 10 increased metabolites and 4 decreased metabolites, and 14 differential metabolites in the follicular fluid of IO cows included 8 increased metabolites and 6 decreased metabolites. These differential metabolites mainly involved nine metabolic pathways. The common enrichment pathway of different metabolites in serum and follicular fluid were glycerophospholipid metabolism and pentose and glucuronate interconversions. In conclusion, there were significant differences in the differential metabolites and enrichment pathways between serum and follicular fluid of IO cows, implying that there were complex changes in blood metabolism and local follicular metabolism of IO cows, whose interactions need further investigation.

Non-coding RNAs (ncRNAs), including transfer RNAs, ribosomal RNAs, small nucleolar RNAs (snoRNAs), and long noncoding RNAs (lncRNAs), are referred to as RNAs without a coding potent.It is widely acknowledged that they play important regulation roles in different biological processes of human life, such as individual development, growth and reproduction; apoptosis, differentiation and reprogramming of cells. Of great importance, ncRNAs are shown to closely associated with human diseases. In recent years, with the development of Chinese economy and the tendency of population aging; cardiovascular diseases, tumors, metabolic diseases and other diseases rise to major chronic non-communicable diseases that threaten the health of Chinese residents. In addition, due to the huge population of China, some rare diseases such as Prader-Willi syndrome (PWS) also affect the health of its residents. Chinese scientists have found that non-coding RNAs are highly associated with these diseases in exploring the development of these diseases, and they notice that ncRNAs are involved in the regulation of a series of cardiovascular diseases, tumors, metabolic diseases, infectious immunological diseases and PWS. This review focuses on advances in ncRNAs contributed by Chinese scholars. We summarize the formation, processing as well as the functions of non-coding RNAs and review the important regulatory roles of these non-coding RNAs in PWS, cardiovascular diseases, tumors, metabolic diseases as well as infectious immune diseases.

Long noncoding RNA (lncRNA) has been suggested to play an important role in a variety of diseases over the past decade. In a previous study, we identified a novel lncRNA, termed HOXA11‐AS, which was significantly up‐regulated in calcium oxalate (CaOx) nephrolithiasis. However, the biological function of HOXA11‐AS in CaOx nephrolithiasis remains poorly defined. Here, we demonstrated that HOXA11‐AS was significantly up‐regulated in CaOx nephrolithiasis both in vivo and in vitro. Gain‐/loss‐of‐function studies revealed that HOXA11‐AS inhibited proliferation, promoted apoptosis and aggravated cellular damage in HK‐2 cells exposed to calcium oxalate monohydrate (COM). Further investigations showed that HOXA11‐AS regulated monocyte chemotactic protein 1 (MCP‐1) expression in HK‐2 cell model of CaOx nephrolithiasis. In addition, online bioinformatics analysis and dual‐luciferase reporter assay results showed that miR‐124‐3p directly bound to HOXA11‐AS and the 3'UTR of MCP‐1. Furthermore, rescue experiment results revealed that HOXA11‐AS functioned as a competing endogenous RNA to regulate MCP‐1 expression through sponging miR‐124‐3p and that overexpression of miR‐124‐3p restored the inhibitory effect of proliferation, promotion effects of apoptosis and cell damage induced by HOXA11‐AS overexpression. Taken together, HOXA11‐AS mediated CaOx crystal–induced renal inflammation via the miR‐124‐3p/MCP‐1 axis, and this outcome may provide a good potential therapeutic target for nephrolithiasis.

Granulosa cells (GCs) play a critical role in driving the formation of ovarian follicles and building the cumulus-oocyte complex surrounding the ovum. We are particularly interested in assessing oocyte quality by examining the detailed gene expression profiles of human cumulus single cells. Using single-cell RNAseq techniques, we extensively investigated the single-cell transcriptomes of the cumulus GC populations from two women with normal ovarian function. This allowed us to elucidate the endogenous heterogeneity of GCs by uncovering the hidden GC subpopulation. The subsequent validation results suggest that CD24(+) GCs are essential for triggering ovulation. Treatment with human chorionic gonadotropin (hCG) significantly increases the expression of CD24 in GCs. CD24 in cultured human GCs is associated with hCG-induced upregulation of prostaglandin synthase (ARK1C1, PTGS2, PTGES, and PLA2G4A) and prostaglandin transporter (SLCO2A1 and ABCC4) expression, through supporting the EGFR-ERK1/2 pathway. In addition, it was observed that the fraction of CD24(+) cumulus GCs decreases in PCOS patients compared to that of controls. Altogether, the results support the finding that CD24 is an important mediator of ovulation and that it may also be used for therapeutic target of ovulatory disorders.

Rationale: Although sunitinib has been shown to improve the survival rate of advanced renal cell carcinoma (RCC) patients, poor drug response is a major challenge that reduces patient benefit. It is important to elucidate the underlying mechanism so that the therapeutic response to sunitinib can be restored. Methods: We used an Illumina HumanMethylation 850K microarray to find methylation-differentiated CpG sites between sunitinib-nonresponsive and -responsive RCC tissues and Sequenom MassARRAY methylation analysis to verify the methylation chip results. We verified glutaminyl peptide cyclotransferase (QPCT) expression in sunitinib-nonresponsive and -responsive RCC tissues via qRT-PCR, western blot and immunohistochemical assays. Then, cell counting kit 8 (CCK-8), plate colony formation and flow cytometric assays were used to verify the function of QPCT in RCC sunitinib resistance after QPCT intervention or overexpression. Chromatin immunoprecipitation (ChIP) was performed to clarify the upstream regulatory mechanism of QPCT. A human proteome microarray assay was used to identify downstream proteins that interact with QPCT, and co-immunoprecipitation (co-IP) and confocal laser microscopy were used to verify the protein chip results. Results: We found that the degree of methylation in the QPCT promoter region was significantly different between sunitinib-nonresponsive and -responsive RCC tissues. In the sunitinib-nonresponsive tissues, the degree of methylation in the QPCT promoter region was significantly reduced, and the expression of QPCT was upregulated, which correlated with a clinically poor response to sunitinib. A knockdown of QPCT conferred sunitinib sensitivity traits to RCC cells, whereas an overexpression of QPCT restored sunitinib resistance in RCC cells. Mechanistically, reducing the methylation degree of the QPCT promoter region by 5-aza-2'-deoxycytidine (decitabine) in RCC cells could increase the expression of QPCT and NF-κB (p65) bound to the QPCT promoter region, positively regulating its expression, while the hypermethylation in the QPCT promoter region could inhibit the binding of NF-κB (p65). QPCT could bind to HRAS and attenuate the ubiquitination of HRAS, thus increasing its stability and leading to the activation of the ERK pathway in RCC cells. Conclusion: QPCT may be a novel predictor of the response to sunitinib therapy in RCC patients and a potential therapeutic target.

Background & Aims Genetic variability in the hepatitis B virus X gene (HBx) is frequently observed and is associated with hepatocellular carcinoma (HCC) progression. However, a genotype classification based on the full-length HBx sequence and the impact of genotypes on hepatitis B virus (HBV)-related HCC prognosis remain unclear. We therefore aimed to perform this genotype classification and assess its clinical impact. Methods We classified the genotypes of the full-length HBx gene through sequencing and a cluster analysis of HBx DNA from a cohort of patients with HBV-related HCC, which served as the primary cohort (n = 284). Two independent HBV-related HCC cohorts, a validation cohort (n = 171) and a serum cohort (n = 168), were used to verify the results. Protein microarray assay analysis was performed to explore the underlying mechanism. Results In the primary cohort, the HBx DNA was classified into 3 genotypes: HBx-EHBH1, HBx-EHBH2, and HBx-EHBH3. HBx-EHBH2 (HBx-E2) indicated better recurrence-free survival and overall survival for patients with HCC. HBx-E2 was significantly correlated with the absence of liver cirrhosis, a small tumor size, a solitary tumor, complete encapsulation and Barcelona Clinic Liver Cancer (BCLC) stage A-0 tumors. Additionally, HBx-E2 served as a significant prognostic factor for patients with BCLC stage B HCC after hepatectomy. Mechanistically, HBx-E2 is unable to promote proliferation in HCC cells and normal hepatocytes. It also fails to activate the Janus kinase 1 (JAK1)/signal transducer and activator of transcription 3 (STAT3)/STAT5 pathway. Conclusion Our study identifies a novel HBx genotype that is unable to promote the proliferation of HCC cells and suggests a potential marker to preoperatively predict the prognosis of patients with BCLC stage B, HBV-associated, HCC. Lay summary We classified a novel genotype of the full-length hepatitis B virus X gene (HBx), HBx-E2. This genotype was identified in tumor and nontumor tissues from patients with hepatitis B virus-related hepatocellular carcinoma. HBx-E2 could preoperatively predict the prognosis of patients with intermediate stage hepatocellular carcinoma, after resection.

Long noncoding RNAs (lncRNAs) are implicated in renal cell carcinoma (RCC), but remain largely unclear. Using publicly available transcriptome sequencing data from renal cancer (n = 703) and integrating bioinformatics analyses, we screened and identified a valuable lncRNA, EGFR-AS1. In our validation cohort (n = 204), EGFR-AS1 was significantly upregulated in RCC tissues (P < 0.001). Gain-of-function and loss-of-function studies showed that EGFR-AS1 promoted cell proliferation and invasion in vitro and in vivo. Based on previous studies and sequence complementarity of EGFR with EGFR-AS1, we demonstrated that EGFR-AS1 directly bound to EGFR mRNA and inhibited its degradation. Furthermore, RNA pull-down and mass spectrometry analyses showed that EGFR-AS1 interacted with HuR, which was responsible for the mRNA stability of EGFR. Multivariate analysis suggested that higher EGFR-AS1 expression predicted a poor prognosis in RCC patients (high vs low: P = 0.018, HR = 2.204, 95% CI: 1.145–4.241). In conclusion, EGFR-AS1 enhances the malignant phenotype of RCC cells by enhancing HuR-mediated mRNA stability of EGFR. Our data also provide biological rationales for EGFR-AS1 as a prognostic biomarker and a potential therapeutic target for RCC.

Objective: Neck management in cT1-2N0 tongue squamous cell carcinoma (SCC) remains controversial. Our goal was to compare the survival difference between PET-CT–guided neck dissection and elective neck dissection (END) for the treatment of cT1-2 tongue SCC. Methods: Patients with surgically treated cT1-2N0 tongue SCC were retrospectively enrolled. These patients were divided into two groups. Group A: The decision of whether to perform neck dissection was mainly based on the results of preoperative PET-CT examinations. Group B: Patients received END treatment without preoperative PET-CT examinations. The study endpoints were regional control (RC) and disease-specific survival (DSS). The Kaplan–Meier method was used to calculate the survival rates. Results: Group A consisted of 66 patients, and 16 patients underwent neck dissection owing to positive PET-CT results. Group B consisted of 169 patients. The 5-year RC rates in group A and group B were 86 and 87%, respectively, and the difference was not significant (p = 0.731). The 5-year DSS rates in group A and group B were 93 and 90%, respectively, and the difference was not significant (p = 0.583). Conclusions: Neck dissection can be safely avoided when the PET-CT scan reveals no neck lymph node involvement.

Background Hepatocellular carcinoma (HCC) is the most common type of liver cancer with increasing incidence and poor prognosis. Ubiquitination regulators are reported to play crucial roles in HCC carcinogenesis. UBE2D1, one of family member of E2 ubiquitin conjugating enzyme, mediates the ubiquitination and degradation of tumor suppressor protein p53. However, the expression and functional roles of UBE2D1 in HCC was unknown. Methods Immunohistochemistry (IHC), western blotting, and real-time PCR were used to detect the protein, transcription and genomic levels of UBE2D1 in HCC tissues with paired nontumor tissues, precancerous lesions and hepatitis liver tissues. Four HCC cell lines and two immortalized hepatic cell lines were used to evaluate the functional roles and underlying mechanisms of UBE2D1 in HCC initiation and progression in vitro and in vivo. The contributors to UBE2D1 genomic amplification were first evaluated by performing a correlation analysis between UBE2D1 genomic levels with clinical data of HCC patients, and then evaluated in HCC and hepatic cell lines. Results Expression of UBE2D1 was significantly increased in HCC tissues and precancerous lesions and was associated with reduced survival of HCC patients. Upregulation of UBE2D1 promoted HCC growth in vitro and in vivo by decreasing the p53 in ubiquitination-dependent pathway. High expression of UBE2D1 was attributed to the recurrent genomic copy number gain, which was associated with high serum IL-6 level of HCC patients. Further experiments showed that continuous IL-6 activated the DNA damage response and genomic instability by repressing DNA damage checkpoint protein RAD51B. Moreover, continuous IL-6 could significantly facilitate the HCC growth especially with the genomic gain of UBE2D1. Conclusions Our findings showed that UBE2D1 played a crucial role in HCC progression, and suggested a novel pattern of continuous IL-6 to promote cancers by inducing the genomic alterations of specific oncogenes. Electronic supplementary material The online version of this article (10.1186/s13046-018-0951-8) contains supplementary material, which is available to authorized users.

Background Poor drug response of sorafenib is a major challenge which reduces clinical benefit of renal cell carcinoma (RCC) patients. It is therefore of great clinical significance to elucidate the underlying mechanism to restore the therapeutic response to sorafenib. Methods Angiopoietin-like protein 3 (ANGPTL3) protein levels were measured by western blot and immunohistochemistry in two cohorts of RCC patients. Loss-of-function and gain-of-function experiments were performed to investigate the biological roles of ANGPTL3 in response to sorafenib treatment in RCC cells. Human proteome microarray and immunoprecipitation analysis were performed to explore the molecular mechanisms underlying the functions of ANGPTL3. Results ANGPTL3 was upregulated in sorafenib-responsive RCC, which correlated with clinically good sorafenib response. Knockdown of ANGPTL3 conferred sorafenib-tolerance traits to RCC cells, whereas overexpression of ANGPTL3 restored sorafenib sensitivity in RCC cells. Mechanistically, ANGPTL3 bound to Focal Adhesion Kinase(FAK) and restained sorafenib induced nuclear translocation of FAK, leading to attenuate the ubiquitination of p53, which contributed to cellular apoptosis and enhanced sorafenib response. Conclusions ANGPTL3 may be a novel predictor for the response of sorafenib therapy in RCC patients, and a potential target in improving its therapeutic effect.

Dysregulation of the neddylation pathway is related to various cancers. However, the specific role of the neddylation pathway in human hepatocellular carcinoma (HCC) remains largely unclear. In this study, the neddylation pathway in HCC and adjacent noncancerous liver (ANL) tissues was evaluated by immunohistochemistry (IHC), Western blotting, and qRT‐PCR (quantitative real‐time polymerase chain reaction). The results showed that the entire neddylation pathway, including NEDD8 (the IHC staining of NEDD8 represents the global‐protein neddylation), E1 NEDD8‐activating enzymes (NAE1 and UBA3), E2 NEDD8‐conjugating enzymes (UBE2F and UBE2M), E3 NEDD8‐ligases (MDM2, RBX1 and RNF7), and deneddylation enzymes (COPS5, UCHL1 and USP21), was overactivated in HCC. Furthermore, the upregulation of NEDD8 in HCC was correlated with aggressive characteristics and was an independent risk factor for overall survival (OS) and recurrence‐free survival (RFS) in patients with HCC after hepatectomy. The upregulation of NAE1, UBE2M, and UCHL1 in HCC was associated with aggressive characteristics and poor OS and RFS in patients with HCC after hepatectomy. In conclusion, our research reveals that the entire neddylation pathway is overactivated in HCC and associated with clinical characteristics and prognosis of patients with HCC.

The incidence of Inactive ovaries of dairy cows in China is relatively high. There is no complete early warning system for the occurrence of ovarian quiescence in clinical cows. This test provides early warning indicators for clinical prediction of ovary cessation in dairy cows. This experiment selected blood samples of dairy cows from 60 to 90 days postpartum in the inactive ovaries group and control group. Differential proteins were selected on the basis of proteomics, three energy indexes: AST, Glu, NEFA. Four reproductive hormones: E2, P4, FSH, LH, and four differentially expressed proteins: IGFBP-2, AHSG, APO-A4, and RBP-4. Key enzyme activities: ALDOB, LDHB, ITIH3, GPX3, SPAM1, PKM2. The ELISA test kit was used to detect the content and activity of the above markers in the test bovine serum. Through correlation analysis, binary logistic regression modeling and ROC analysis, a single indicator early warning technique for APOA4 and ITIH3 was established. The early warning values were APOA4 > 28.825 μg/L and ITIH3 > 195.07 ng/L. A multi-index early warning system based on potential biomarkers of APOA4 + ITIH3 and APOA4 + ITIH3 + E2 was established. The former had an early warning value of: APOA4 > 19.55 μg/I; ITIH3 > 191.14 ng/L; the latter has an early warning value: APOA4 > 47.56 μg/L, ITIH4 > 187.80 ng/L, E2 < 69.63 ng/L.

M2 macrophages play critical roles in the progression of hepatocellular carcinoma (HCC), and they are associated with poor outcomes. TGF-β-induced epithelial-mesenchymal transition (EMT) has been shown to be critically important to cancer cell dissemination in HCC. However, the relationship between stromal-like HCC cells and M2 macrophages formation is not clear. Here, we interrogated the molecular link between mesenchymal-like HCC cells and the formation of M2 macrophages. We demonstrated that mesenchymal-like HCC cells secrete connective tissue growth factor (CTGF) to polarized macrophages. Reciprocally, Chemokine ligand 18 (CCL18) from M2 macrophages promotes HCC progression. Furthermore, CTGF and CCL18 were increased significantly in HCC compared to adjacent normal liver tissues. In summary, our study discovered a positive feedback loop between CTGF and CCL18 in HCC metastasis. Targeting CTGF or CCL18 might provide beneficial effects for the clinical treatment of HCC.

Gender dysphoria (GD) is characterized by an incongruence between the gender assigned at birth and the gender with which one identifies. The biological mechanisms of GD are unclear. While common genetic variants are associated with GD, positive findings have not always been replicated. To explore the role of rare variants in GD susceptibility within the Han Chinese population, whole-genome sequencing of 9 Han female-to-male transsexuals (FtMs) and whole-exome sequencing of 4 Han male-to-female transsexuals (MtFs) were analyzed using a pathway burden analysis in which variants are first collapsed at the gene level and then by Gene Ontology terms. Novel nonsynonymous variants in ion transport genes were significantly enriched in FtMs (P- value, 2.41E-10; Fold enrichment, 2.8) and MtFs (P- value, 1.04E-04; Fold enrichment, 2.3). Gene burden analysis comparing 13 GD cases and 100 controls implicated RYR3, with three heterozygous damaging mutations in unrelated FtMs and zero in controls (P = 0.001). Importantly, protein structure modeling of the RYR3 mutations indicated that the R1518H mutation made a large structural change in the RYR3 protein. Overall, our results provide information about the genetic basis of GD.

Understanding the roles of splicing factors and splicing events during tumorigenesis would open new avenues for targeted therapies. Here we identify an oncofetal splicing factor, MBNL3, which promotes tumorigenesis and indicates poor prognosis of hepatocellular carcinoma patients. MBNL3 knockdown almost completely abolishes hepatocellular carcinoma tumorigenesis. Transcriptomic analysis revealed that MBNL3 induces lncRNA-PXN-AS1 exon 4 inclusion. The transcript lacking exon 4 binds to coding sequences of PXN mRNA, causes dissociation of translation elongation factors from PXN mRNA, and thereby inhibits PXN mRNA translation. In contrast, the transcript containing exon 4 preferentially binds to the 3' untranslated region of PXN mRNA, protects PXN mRNA from microRNA-24-AGO2 complex-induced degradation, and thereby increases PXN expression. Through inducing exon 4 inclusion, MBNL3 upregulates PXN, which mediates the pro-tumorigenic roles of MBNL3. Collectively, these data demonstrate detailed mechanistic links between an oncofetal splicing factor, a splicing event and tumorigenesis, and establish splicing factors and splicing events as potential therapeutic targets.

To explore whether plasma circular RNAs (circRNAs) can diagnose hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), microarray and qPCR were used to identify plasma circRNAs that were increased in HBV-related HCC patients compared to controls (including healthy controls, chronic hepatitis B and HBV-related liver cirrhosis). A logistic regression model was constructed using a training set (n = 313) and then validated using another two independent sets (n = 306 and 526, respectively). Area under the receiver operating characteristic curve (AUC) was used to evaluate diagnostic accuracy. We identified a plasma circRNA panel (CircPanel) containing three circRNAs (hsa_circ_0000976, hsa_circ_0007750 and hsa_circ_0139897) that could detect HCC. CircPanel showed a higher accuracy than AFP (alpha-fetoprotein) to distinguish individuals with HCC from controls in all three sets (AUC, 0.863 [95% confidence interval, CI: 0.819-0.907] vs. 0.790 [0.738-0.842], p = 0.036 in training set; 0.843 [0.796-0.890] vs. 0.747 [0.691-0.804], p = 0.011 in validation set 1 and 0.864 [0.830-0.898] vs. 0.769 [0.728-0.810], p < 0.001 in validation set 2). CircPanel also performed well in detecting Small-HCC (solitary, ≤3 cm), AFP-negative HCC and AFP-negative Small-HCC.

To explore whether plasma circular RNAs (circRNAs) can diagnose hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), microarray and qPCR were used to identify plasma circRNAs that were increased in HCC patients compared with controls (including healthy controls, chronic hepatitis B, HBV-related liver cirrhosis and HCC patients). A logistic regression model was constructed using a training set (n=313) and then validated using another two independent sets (n=306 and 526, respectively). Area under the receiver operating characteristic curve (AUC) was used to evaluate diagnostic accuracy. We identified a plasma circRNA panel (CircPanel) containing three circRNAs (hsa_circ_0000976, hsa_circ_0007750 and hsa_circ_0139897) that could detect HCC. CircPanel showed a higher accuracy than AFP (alpha-fetoprotein) to distinguish individuals with HCC from controls in all three sets (AUC 0.863 [95% CI 0.819–0.907] vs 0.790 [0.738–0.842], P=0.036 in training set; 0.843 [0.796–0.890] vs 0.747 [0.691–0.804], P=0.011 in validation set 1 and 0.864 [0.830–0.898] vs 0.769 [0.728–0.810], PSignificance of this studyWhat is already known about this subject?The diagnostic accuracy of alpha-fetoprotein (AFP) in detecting hepatocellular carcinoma (HCC) is unsatisfactory.Circular RNA (circRNA) expression profiles in HCC and adjacent nontumor liver tissues are significantly different.Plasma circRNAs are enriched, stable and can be biomarkers for various diseases.What are the new findings?The expression of circRNAs in the plasma from HCC patients and chronic hepatitis B is significantly different.Plasma circRNA panel (CircPanel, including hsa_circ_0000976, hsa_circ_0007750 and hsa_circ_0139897) has a higher accuracy than AFP to distinguish individuals with HCC or Small-HCC (solitary, ≤3cm) from controls (healthy controls, chronic hepatitis B and HBV-related liver cirrhosis).CircPanel also performs well in diagnosing AFP-negative HCC and AFP-negative Small-HCC.How might it impact on clinical practice in the foreseeable future?Plasma CircPanel can be a diagnostic biomarker in detecting HCC and improves the diagnostic accuracy.

Non-coding RNAs (ncRNAs) have been shown to regulate gene expression involved in tumor progression of multiple malignancies. Numerous studies have indicated that N-acetylglucosaminyltransferase V (MGAT5), is an important tumorigenesis and metastasis-associated enzyme in breast cancer (BC). But, the underlying molecular mechanisms by which ncRNAs modulate MGAT5 expression in BC remain undetermined. In this study, we demonstrated that miR-124 expression at a low level in BC tissue was associated with poor prognosis of BC patients. Meanwhile, miR-124 reduced BC cell proliferation and metastasis. MGAT5 was confirmed as a direct target of miR-124. MGAT5 restoration attenuated the inhibitory effects of miR-124 on BC proliferation and metastasis in vitro and vivo. Overall, we provide new insight into the mechanisms by which miR-124 inhibits BC progression, suggesting the potential of miR-124 and MGAT5 as biomarkers for early diagnosis of breast cancer to provide innovative ideas and methods for the diagnosis and treatment of BC.

N6 -Methyladenosine (m6 A) modification has been implicated in many biological processes. However, its role in cancer has not been well studied. Here, we demonstrate that m6 A modifications are decreased in hepatocellular carcinoma, especially in metastatic hepatocellular carcinoma, and that methyltransferase-like 14 (METTL14) is the main factor involved in aberrant m6 A modification. Moreover, METTL14 down-regulation acts as an adverse prognosis factor for recurrence-free survival of hepatocellular carcinoma and is significantly associated with tumor metastasis in vitro and in vivo. We confirm that METTL14 interacts with the microprocessor protein DGCR8 and positively modulates the primary microRNA 126 process in an m6 A-dependent manner. Further experiments show that microRNA 126 inhibits the repressing effect of METTL14 in tumor metastasis. Conclusion These studies reveal an important role of METTL14 in tumor metastasis and provide a fresh view on m6 A modification in tumor progression. (Hepatology 2017;65:529-543).

// Jie Cai 1, * , Sheng-Xian Yuan 1, * , Fu Yang 2, * , Qi-Fei Tao 1, * , Yuan Yang 1 , Qing-Guo Xu 1 , Zhen-Guang Wang 1 , Jian Yu 1 , Kong-Ying Lin 1 , Zong-Yan Wang 1 , Jin-Zhao Ma 2 , Chuan-Chuan Zhou 2 , Fang Wang 2 , Shu-Han Sun 2 , Wei-Ping Zhou 1 1 The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China 2 The Department of Medical Genetics, Second Military Medical University, Shanghai, China * These authors contributed equally to this work Correspondence to: Wei-Ping Zhou, email: ehphwp3@126.com Shu-Han Sun, email: shsun@vip.sina.com Keywords: paraoxonase 3, hepatocellular carcinoma, prognostic predictor, cell proliferation, cDNA microarray Received: February 26, 2016 Accepted: September 02, 2016 Published: September 20, 2016 ABSTRACT Paraoxonase 3 (PON3) exerts prominent anti-inflammation and anti-oxidation properties mainly at the cellular level, and is primarily expressed in the liver. However, its role in HCC remains unexplored. Here, we investigated the expression pattern, clinical significance, and function of PON3 in HCC. PON3 mRNA and protein levels were respectively determined in two large cohorts using quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC) of tissue microarray. We found that PON3 was downregulated in most HCCs. Kaplan-Meier and log-rank test showed that PON3 downregulation predicted shorter recurrence-free survival (RFS) and overall survival (OS) time in all HCC patients, especially early-stage HCC patients. Cox regression analysis revealed that the PON3 downregulation was an independent risk factor for RFS and OS. Gain- and loss-of-function experiments revealed that PON3 suppressed cell proliferation in vivo and in vitro , which was attributed to its cell-cycle arrest effect. In addition, microarray analysis showed that some pro-proliferative genes were elevated when PON3 was knockdown, and these genes possibly involved in the underlying mechanisms. In conclusion, our studies reveal the cell proliferation inhibitory function of PON3 and offer a potential prognostic predictor and therapeutic target for HCC.

// Jin-feng Huang 1, * , Yue Wang 1, * , Feng Liu 1, * , Yin Liu 1, * , Chen-xi Zhao 1 , Ying-jun Guo 1 , Shu-han Sun 1 1 The Department of Medical Genetics, Second Military Medical University, Shanghai, China * These authors contributed equally to this work Correspondence to: Shu-han Sun, e-mail: shsun@vip.sina.com Ying-jun Guo, e-mail: guoyingjun2000@yahoo.com.cn Keywords: ecotropic viral integration site 1, hepatocellular carcinoma, hepatitis B virus X protein, long non-coding RNA, transcription factor Received: August 04, 2015 Accepted: February 18, 2016 Published: March 08, 2016 ABSTRACT The involvement of the hepatitis B virus X (HBx) protein in epigenetic modifications during hepatocarcinogenesis has been previously characterized. Long noncoding RNAs (lncRNAs), a kind of epigenetic regulator molecules, have also been shown to play crucial roles in HBx-related hepatocellular carcinoma (HCC). In this study, we analyzed the key transcription factors of aberrantly expressed lncRNAs in the livers of HBx transgenic mice by bioinformatics prediction, and found that ecotropic viral integration site 1 (Evi1) was a potential main transcription regulator. Further investigation showed that EVI1 was positively correlated to HBx expression and was frequently up-regulated in HBV-related HCC tissues. The forced expression of HBx in liver cell lines resulted in a significant increase of the expression of EVI1. Furthermore, suppression of EVI1 expression decreased the proliferation of HCC cells overexpressing HBx in vitro and in vivo . Conclusion: Our findings suggest that EVI1 is frequently up-regulated and regulates a cluster of lncRNAs in HBV-related hepatocellular carcinoma (HCC). These findings highlight a novel mechanism for HBx-induced hepatocarcinogenesis through transcription factor EVI1 and its target lncRNAs, and provide a potential new approach to predict the functions of lncRNAs.

Systemic analyses using large-scale genomic profiles have successfully identified cancer-driving somatic copy number variations (SCNVs) loci. However, functions of vast focal SCNVs in “protein-coding gene desert” regions are largely unknown. The integrative analysis of long noncoding RNA (lncRNA) expression profiles with SCNVs in hepatocellular carcinoma (HCC) led us to identify the recurrent deletion of lncRNA-PRAL (p53 regulation-associated lncRNA) on chromosome 17p13.1, whose genomic alterations were significantly associated with reduced survival of HCC patients. We found that lncRNA-PRAL could inhibit HCC growth and induce apoptosis in vivo and in vitro through p53. Subsequent investigations indicated that the three stem-loop motifs at the 5′ end of lncRNA-PRAL facilitated the combination of HSP90 and p53 and thus competitively inhibited MDM2-dependent p53 ubiquitination, resulting in enhanced p53 stability. Additionally, in vivo lncRNA-PRAL delivery efficiently reduced intrinsic tumors, indicating its potential therapeutic application. Conclusions: lncRNA-PRAL, one of the key cancer-driving SCNVs, is a crucial stimulus for HCC growth and may serve as a potential target for antitumor therapy. (Hepatology 2016;63:850-863)

Intrauterine adhesion (IUA) causing infertility and recurrent miscarriage of reproductive female mammals usually results from endometrium injury. Nevertheless, there is no efficient therapeutic method to avoid IUA. Bone marrow derived mesenchymal stem cells (BMSCs) are an important cell source for tissue regeneration. This study designs and explores the ability of BMSC-loaded elastic poly(glycerol sebacate) (PGS) scaffold to prevent IUA and compares the effect of PGS with poly(lactic-co-glycolic acid) (PLGA) and collagen scaffolds in resumption of damaged rat uteruses. The 3D architecture provided by PGS scaffolds favors the attachment and growth of rat BMSCs. In vivo bioluminescence imaging shows that compared with direct BMSC intrauterine injection, PLGA, and collagen scaffolds, the PGS scaffold significantly prolongs the retention time of BMSCs in a wounded rat uterus model. More importantly, BMSCs can directly differentiate into endometrial stromal cells after transplantation of PGS/BMSCs constructs, but not PLGA/BMSCs and collagen/BMSCs. It is found that the level of transforming growth factor β1 (TGF-β1), basic fibroblast growth factor (bFGF), vascular endothelial growth factor, and insulin-like growth factors in the injured endometrium adjacent to PGS/BMSCs constructs is higher than those of rats receiving PLGA/BMSCs, collagen/BMSCs, or BMSCs intrauterine transplantation. Besides, transplantation of PGS/BMSCs leads to better morphology recovery of the damaged uterus than PLGA/BMSCs and collagen/BMSCs. The receptive fertility of PGS/BMSCs is 72.2 ± 6.4%, similar to the one of collagen/BMSCs, but significantly higher than 42.3 ± 3.9% in PLGA/BMSCs. Taken together, PGS/BMSCs may be a promising candidate for preventing IUA.