Identification of SGMS2 as a molecule involved in natural killer cell recruitment and its in-deep analysis in the liver cancer microenvironment: Evidence from large populations cohort.

BACKGROUND: Liver cancer, a common malignancy within the digestive system, presents with a particularly grim prognosis. Within the immune microenvironment, the role of natural killer (NK) cells in liver cancer remains unclear. METHODS: We sourced data on clinical parameters and gene expressions for liver cancer patients from The Cancer Genome Atlas Program database and carried out all analyses using R software and its relevant codes. RESULTS: In our research, we delved into the genes intertwined with NK cells in hepatocellular carcinoma (HCC). Leveraging the QUANTISEQ and MCPCOUNTER algorithms to quantify NK cells, we spotlighted genes vital to the recruitment of NK cells. Among these genes, GDE1, WDFY3, DNAJB14, PKD2, DGAT2, SGMS2 and MKNK2 showed a strong correlation with patient outcomes. We also mapped out the single-cell expression trajectories of these genes within the HCC milieu. From our findings, SGMS2 emerged as a key gene warranting further scrutiny. Our in-depth analysis of SGMS2 shed light on its influence over specific biological pathways, its contribution to the immune landscape and its role in genomic instability within HCC. Drawing from this, we formulated a predictive model rooted in SGMS2-associated genes. This model showcased remarkable precision across both training and validation cohorts. CONCLUSIONS: Overall, our investigation underscored the profound implications of SGMS2, a gene pivotal to NK cell infiltration, in the landscape of HCC, thereby positioning it as a potential linchpin in oncological strategies.

POFUT1 promotes gastric cancer progression through Notch/Wnt dual signaling pathways dependent on the parafibromin-NICD1-ß-catenin complex.

BACKGROUND: Aberrant glycosylation performed by glycosyltransferases is a leading cause of gastric cancer (GC). Protein O-fucosyltransferase 1 (POFUT1) expression is increased in GC specimens and cells. In this study, the biological effects and mechanisms of POFUT1 underlying the development of GC were investigated. METHODS: POFUT1 downregulated and upregulated GC cells were established. The effects of POFUT1 on cell proliferation, metastasis and apoptosis were examined using cell counting kit-8 (CCK8) assay, transwell assay, and flow cytometry. Subcutaneous xenograft tumor models were established followed by immunohistochemistry staining of resected tumors. Facilitating modulators and transcription factors were detected by western blot, immunofluorescence, luciferase reporter assay, and co-immunoprecipitation. RESULTS: POFUT1 played a pro-oncogenic role both in vivo and in vitro, which promoted proliferation and metastasis, as well as inhibited apoptosis in GC cells. POFUT1 promoted Cyclin D3 expression and inhibited the expression of apoptotic proteins, such as Bcl-2-associated X protein (Bax) and cleaved caspase 3, facilitating tumor growth. Moreover, POFUT1 accelerated matrix metalloproteases expression and attenuated E-cadherin expression, contributing to GC metastasis. In addition, POFUT1 expression promoted the expression and nuclear translocation of Notch1 intracellular domain (NICD1) and ß-catenin and inhibited ß-catenin phosphorylation degradation, accompanied by the activation of recombination signal binding protein-Jκ (RBP-J) and T-cell factor (TCF) transcription factors, respectively. It is notable that parafibromin integrated NICD1 and ß-catenin, enabling the concerted activation of Wnt and Notch signaling targeted proteins. CONCLUSION: These observations indicated that POFUT1 promoted GC development through activation of Notch and Wnt signaling pathways, which depended on the parafibromin-NICD1-ß-catenin complex. This work provides new evidence for the further diagnosis and treatment of GC.

Retraction Notice to: Inflammatory-Related P62 Triggers Malignant Transformation of Mesenchymal Stem Cells through the Cascade of CUDR-CTCF-IGFII-RAS Signaling.

[This retracts the article DOI: 10.1016/j.omtn.2018.03.002.].

Intelligent COVID-19 screening platform based on breath analysis.

The spread of coronavirus disease 2019 (COVID-19) results in an increasing incidence and mortality. The typical diagnosis technique for severe acute respiratory syndrome coronavirus 2 infection is reverse transcription polymerase chain reaction, which is relatively expensive, time-consuming, professional, and suffered from false-negative results. A reliable, non-invasive diagnosis method is in urgent need for the rapid screening of COVID-19 patients and controlling the epidemic. Here we constructed an intelligent system based on the volatile organic compound (VOC) biomarkers in human breath combined with machine learning models. The VOC profiles of 122 breath samples (65 of COVID-19 infections and 57 of controls) were identified with a portable gas chromatograph-mass spectrometer. Among them, eight VOCs exhibited significant differences (p< 0.001) between the COVID-19 and the control groups. The cross-validation algorithm optimized support vector machine (SVM) model was employed for the prediction of COVID-19 infection. The proposed SVM model performed a powerful capability in discriminating COVID-19 patients from healthy controls, with an accuracy of 97.3%, a sensitivity of 100%, a specificity of 94.1%, and a precision of 95.2%, and anF1 score of 97.6%. The SVM model was also compared with other common machine models, including artificial neural network,k-nearest neighbor, and logistic regression, and demonstrated obvious superiority in the prediction of COVID-19 infection. Furthermore, user-friendly software was developed based on the optimized SVM model. The developed intelligent platform based on breath analysis provides a new strategy for the point-of-care screening of COVID and shows great potential in clinical application.

ERRFI1 induces apoptosis of hepatocellular carcinoma cells in response to tryptophan deficiency.

Tryptophan metabolism is an essential regulator of tumor immune evasion. However, the effect of tryptophan metabolism on cancer cells remains largely unknown. Here, we find that tumor cells have distinct responses to tryptophan deficiency in terms of cell growth, no matter hepatocellular carcinoma (HCC) cells, lung cancer cells, or breast cancer cells. Further study shows that ERRFI1 is upregulated in sensitive HCC cells, but not in resistant HCC cells, in response to tryptophan deficiency, and ERRFI1 expression level positively correlates with HCC patient overall survival. ERRFI1 knockdown recovers tryptophan deficiency-suppressed cell growth of sensitive HCC cells. In contrast, ERRFI1 overexpression sensitizes resistant HCC cells to tryptophan deficiency. Moreover, ERRFI1 induces apoptosis by binding PDCD2 in HCC cells, PDCD2 knockdown decreases the ERRFI1-induced apoptosis in HCC cells. Thus, we conclude that ERRFI1-induced apoptosis increases the sensitivity of HCC cells to tryptophan deficiency and ERRFI1 interacts with PDCD2 to induce apoptosis in HCC cells.

CXCL5/NF-κB Pathway as a Therapeutic Target in Hepatocellular Carcinoma Treatment.

BACKGROUND: Hepatocellular carcinoma (HCC) is a common malignant cancer worldwide. CXCL5 has a role in inhibiting cell viability and metastasis in many tumors. In the present study, we investigated the role of CXCL5 in HCC and explored the underlying mechanism. Material and Methods. RT-qPCR and western blot were performed to evaluate the mRNA and protein levels of CXCL5. CCK-8 and transwell assay were applied to measure the proliferative and invasive abilities. Meanwhile, the Kaplan-Meier method was used to assess the survival of HCC patients. RESULTS: CXCL5 was upregulated in HCC tissues, which predicted a shorter overall survival in HCC. CXCL5 was a target gene of miR-577, and its expression was mediated by miR-577 in HCC. Knockdown of CXCL5 suppressed HuH-7 cell proliferation, invasion, and EMT and inhibited the NF-κB signaling pathway in cells. Moreover, knockdown of CXCL5 inhibited the xenograft growth of HuH-7 cells. CONCLUSION: Overexpression of CXCL5 predicts poor prognosis in HCC patients. Knockdown of CXCL5 inhibits cell proliferation and invasion through the NF-κB signaling pathway in HCC. The newly identified role of the CXCL5/miR-577/NF-κB axis provides novel insights into the targeted therapy of HCC.

The kynurenine derivative 3-HAA sensitizes hepatocellular carcinoma to sorafenib by upregulating phosphatases.

Objectives: Sorafenib is the only FDA-approved first-line target drug for HCC patients. However, sorafenib merely confers 3-5 months of survival benefit with less than 30% of HCC patients sensitive to sorafenib therapy. Thus, it's necessary to develop a sensitizer for hepatocellular carcinoma (HCC) to sorafenib. Methods: The principal component analysis, gene ontology, and KEGG analysis are utilized following RNA-sequencing. The mass spectrometry analysis following immunoprecipitation is performed to discover the phosphatase targets. Most importantly, both the cell line-derived xenograft (CDX) and the patient-derived xenograft (PDX) mouse model are used to determine the effect of 3-HAA on sorafenib-resistant HCC in vivo. Results: In nude mice carrying HCC xenograft, tumor growth is inhibited by sorafenib or 3-HAA alone. When used in combination, the treatment particularly prevents the xenograft from growing. Combined treatment also suppresses the growth of sorafenib-resistant (≥30mg/kg) PDXs. In a set of mechanistic experiments, we find enhanced AKT activation and decreased apoptotic cells in de novo and acquired sorafenib-resistant HCC cells and tissues. 3-HAA decreases AKT phosphorylation and increases the apoptosis of HCC in both cultured cells and mouse xenografts by upregulation of phosphatases PPP1R15A/DUSP6. PPP1R15A/PPP1α directly reduces Akt phosphorylation while DUSP6 decreases Akt activity through inhibiting PDK1. The AKT activator abolishes 3-HAA inhibition of HCC growth in vitro and in mice. Conclusion: This study demonstrates that 3-HAA sensitizes HCC cells to sorafenib by upregulation of phosphatases, suggesting it as a promising molecule for HCC therapy.

Targeted theranostics of lung cancer: PD-L1-guided delivery of gold nanoprisms with chlorin e6 for enhanced imaging and photothermal/photodynamic therapy.

Peptide modified nanoparticles have emerged as powerful tools for enhanced cancer diagnosis and novel treatment strategies. Here, human programmed death-ligand 1 (PD-L1) peptides were used for the first time for the modification of gold nanoprisms (GNPs) to enhance targeting efficiency. A multifunctional nanoprobe was developed that the GNPs@PEG/Ce6-PD-L1 peptide (GNPs@PEG/Ce6-P) was used for imaging-guided photothermal/photodynamic therapy by using the targeting effect of PD-L1. Both confocal imaging and flow cytometry experiments demonstrated a remarkable affinity of the as-prepared nanoprobes GNPs@PEG/Ce6-P to lung cancer cells (HCC827), which have a high PD-L1 expression. Subsequent in vitro and in vivo experiments further demonstrated that the nanoprobes GNPs@PEG/Ce6-P not only allowed for real-time visualization via fluorescence (FL) imaging and photoacoustic (PA) imaging, but also served as phototherapy agents for synergistic photothermal therapy (PTT) and photodynamic therapy (PDT). Furthermore, treatments on human lung cancer cells-derived tumors demonstrated that the nanoprobes GNPs@PEG/Ce6-P could significantly suppress tumor growth through PTT and PDT from GNPs and Ce6, respectively. In conclusion, the as-prepared new nanoprobes show promising potential for nanomedicine with remarkable targeting ability for dual-mode imaging and enhanced PDT and PTT effects on lung cancer.

MicroRNA-182 Promotes Cell Migration by Targeting Programmed Cell Death 4 in Hepatocellular Carcinoma Cells.

PURPOSE: Hepatocellular carcinoma (HCC) is the most common primary liver tumor and the third greatest cause of cancer-related death worldwide. Programmed cell death 4 (PDCD4) was reported as a potential tumor-suppressor in hepatocarcinogenesis. However, relatively little is known about mechanisms that regulate PDCD4 expression in HCC. The aim of the present study is to investigate the expression of PDCD4 and miR-182 in human HCC cell lines and clinical HCC specimens and determine whether PDCD4 is a direct target of miR-182 in HCC cell lines. MATERIALS: The expression of miR-182 and PDCD4 in human HCC cell lines and HCC tissues were examined using qRT-PCR and Western blot method. Transwell and wound healing assays were carried out to explore the influence of miR-182 on hepatoma cells migration. A luciferase reporter assay was conducted to confirm target association. RESULTS: In our research, we found that PDCD4 was downregulated, whereas miR-182 was upregulated in liver cancer cell lines and HCC tissues. Transwell and wound healing assays illustrated that miR-182 contributed to migration activities of liver cancer cell lines. Loss or increase of miR-182 can lead to a negative expression of PDCD4 protein level. The luciferase reporter assay showed that PDCD4 is a direct target of miR-182. CONCLUSION: All these findings suggest that miR-182 may act as an oncogenic role in liver cancer cells by directly and negatively regulating expression of PDCD4.

Exponential amplification reaction and triplex DNA mediated aggregation of gold nanoparticles for sensitive colorimetric detection of microRNA.

Abnormal expression of specific microRNAs (miRNAs) is associated with the occurrence, development and prognosis of many diseases. In this study, a miRNA detection method based on exponential amplification reaction (EXPAR) and triplex DNA mediated aggregation of gold nanoparticles (AuNPs) was established. Specifically, one class of AuNPs is conjugated with an EXPAR probe, on which there is a complementary sequence of the target miRNA. The EXPAR reaction is triggered and duplex DNA is formed on the surface of AuNPs when the target miRNA exists. Then, single DNA probe on another class of AuNPs interacts with the duplex DNA to form triplex DNA, leading to the aggregation of the two classes of AuNPs, which could be quantified by UV-vis. The proposed method is highly selective and can afford a detection limit of 0.23 fM. Notably, all the ingredients needed for the analysis can pre-add to a tube and only 30 min is needed for the whole detection process. The method is simple, fast and with considerable selectivity and accuracy, so a great potential for this method is expected to meet the need of point-of-care testing of miRNA.

The long coding RNA AFAP1-AS1 promotes tumor cell growth and invasion in pancreatic cancer through upregulating the IGF1R oncogene via sequestration of miR-133a.

Long non-coding RNAs (lncRNAs) have been shown to play a significant role in the progression of many cancers, including pancreatic cancer (PC). However, the biological function and regulatory mechanisms of lncRNAs in PC remains largely unclear. The aim of this study was to identify and evaluate the potential functions of lncRNAs in PC and reveal the underlying mechanisms of their effects. Screening of published microarray data (GEO accession Nos. GSE16515 and GSE32688), revealed lncRNA AFAP1-AS1 to be one of the most upregulated lncRNAs in PC tissues. High expression of AFAP1-AS1 was correlated with advanced stages, tumor size and lymph node metastasis, as well as with poorer overall survival in patients with PC. Functionally, knockdown of AFAP1-AS1 by transfection with siRNA inhibited the proliferative and invasive capacities of PaCa-2 and SW1990 PC cells, promoted apoptosis of PC cells in vitro, and impaired in-vivo tumorigenicity. In particular, it was hypothesized that AFAP1-AS1 may act as a competitive endogenous RNA (ceRNA), effectively becoming a sink for miR-133a whose expression was found to be downregulated in PC tissues and cell lines, and which was negatively correlated with the expression of AFAP1-AS1. We also found that the IGF1R oncogene which is an important regulator of MEK/ERK signaling pathway, was positively regulated by AFAP1-AS1 through ameliorating miR-133a-mediated IGF1R repression in PC tissues. Moreover, we demonstrated that knockdown of IGF1R by transfection with si-IGF1R suppressed cell proliferation, invasion and migration of PaCa-2 and SW1990 PC cells, suggesting that IGF1R may function as an oncogene in PC cells. Further investigations revealed that miR-133a reversed the biological effects of AFAP1-AS1 on PC cells. Collectively, the findings provide new evidence that AFAP1-AS1 could regulate the progression of pancreatic cancer by acting as a ceRNA, and suggest it has potential for use as both a biomarker for the early detection PC and for the development of individualized therapies for PC.

Inflammatory-Related P62 Triggers Malignant Transformation of Mesenchymal Stem Cells through the Cascade of CUDR-CTCF-IGFII-RAS Signaling.

Inflammatory and autophagy-related gene P62 is highly expressed in most human tumor tissues. Herein, we demonstrate that P62 promotes human mesenchymal stem cells' malignant transformation via the cascade of P62-tumor necrosis factor alpha (TNF-α)-CUDR-CTCF-insulin growth factor II (IGFII)-H-Ras signaling. Mechanistically, we reveal P62 enhances IGFII transcriptional activity through forming IGFII promoter-enhancer chromatin loop and increasing METTL3 occupancy on IGFII 3' UTR and enhances H-Ras overexpression by harboring inflammation-related factors, e.g., TNFR1, CLYD, EGR1, NFκB, TLR4, and PPARγ. Furthermore, the P62 cooperates with TNF-α to promote malignant transformation of mesenchymal stem cells. These findings, for the first time, provide insight into the positive role that P62 plays in malignant transformation of mesenchymal stem cells and reveal a novel link between P62 and the inflammation factors in mesenchymal stem cells.

miR372 Promotes Progression of Liver Cancer Cells by Upregulating erbB-2 through Enhancement of YB-1.

MicroRNAs are known to be involved in carcinogenesis. Recently, microRNA-372 (miR372) has been proven to play a substantial role in several human cancers, but its functions in liver cancer remain unclear. Herein, our results demonstrate that miR372 accelerates growth of liver cancer cells in vitro and in vivo. Mechanistically, miR372 enhances expression of Y-box-binding protein 1 (YB-1) by targeting for phosphatase and tensin homolog (PTEN) directly and consequently promotes phosphorylation of YB-1 via HULC looping dependent on ERK1/2 and PTEN. In particular, HULC knockdown or PTEN overexpression abrogated this miR372 action. Moreover, miR372 inhibits the degradation of ß-catenin dependent on phosphorylation of YB-1 and then enhances the expression and activity of pyruvate kinase M2 isoform (PKM2) by ß-catenin-LEF/TCF4 pathway. Furthermore, the loading of LEF/TCF4 on PKM2 promoter region was significantly increased in miR372 overexpressing Hep3B, and thus, glycolytic proton efflux rate (glycoPER) was significantly increased in rLV-miR372 group compared to the rLV group. Moreover, ß-catenin knockdown abrogates this function of miR372. Ultimately, miR372 promotes the expression of erbB-2 through PKM2-pH3T11-acetylation on histone H3 lysine 9 (H3K9Ac) pathway. Of significance, both YB-1 knockdown and erbB-2 knockdown abrogate oncogenic action of miR372. Our observations suggest that miR372 promotes liver cancer cell cycle progress by activating cyclin-dependent kinase 2 (CDK2)-cyclin E-P21/Cip1 complex through miR372-YB-1-ß-catenin-LEF/TCF4-PKM2-erbB-2 axis. This study elucidates a novel mechanism for miR372 in liver cancer cells and suggests that miR372 can be used as a novel therapeutic target of liver cancer.

DNMT1 mediated promoter methylation of GNAO1 in hepatoma carcinoma cells.

Hepatocellular carcinoma (HCC) is one of the most lethal and prevalent cancers worldwide and has recently become the second most common cause of cancer-related deaths in men of developing countries. Guanine nucleotide-binding protein (G protein) has been reported to be associated with the early process of HCC. In our previous study, GNAO1, one of members of G protein, was found to be down-regulated in HCC. Thus, the present study aimed to throw light upon the mechanism of the abnormal expression of GNAO1 in HCC. First, qPCR results from two HCC cell lines (SMMC-7721 and QGY-7703) confirmed the down-expression of GNAO1, followed by the validation of the methylation status of the promoter region by bisulfite sequence PCR (BSP). Moreover, 5-Aza-2'-deoxycytidine (DAC) with Trichostatin A (TSA) treatment made it much clear that GNAO1 transcription was inhibited by promoter hypermethylation, contributing to its low expression. It was further revealed that the silencing effect was regulated by methyltransferase 1 (DNMT1), and was further enhanced by transforming growth factor ß (TGF-ß). In addition, the up-regulation of GNAO1 with the help of recombinant plasmid was also found to accelerate cell apoptosis, confirmed by flow cytometry and western blotting analysis. All these results above indicated that the promoter hypermethylation of GNAO1 might play an important role in HCC, suggesting that it might be used as a promising biomarker for HCC diagnosis and targeted therapy.

The extent of liver injury determines hepatocyte fate toward senescence or cancer.

It is well known that induction of hepatocyte senescence could inhibit the development of hepatocellular carcinoma (HCC). Until now, it is still unclear how the degree of liver injury dictates hepatocyte senescence and carcinogenesis. In this study, we investigated whether the severity of injury determines cell fate decisions between hepatocyte senescence and carcinogenesis. After testing of different degrees of liver injury, we found that hepatocyte senescence is strongly induced in the setting of severe acute liver injury. Longer-term, moderate liver injury, on the contrary did not result into hepatocyte senescence, but led to a significant incidence of HCC instead. In addition, carcinogenesis was significantly reduced by the induction of severe acute injury after chronic moderate liver injury. Meanwhile, immune surveillance, especially the activations of macrophages, was activated after re-induction of senescence by severe acute liver injury. We conclude that severe acute liver injury leads to hepatocyte senescence along with activating immune surveillance and a low incidence of HCC, whereas chronic moderate injury allows hepatocytes to proliferate rather than to enter into senescence, and correlates with a high incidence of HCC. This study improves our understanding in hepatocyte cell fate decisions and suggests a potential clinical strategy to induce senescence to treat HCC.

Inflammatory factor receptor Toll-like receptor 4 controls telomeres through heterochromatin protein 1 isoforms in liver cancer stem cell.

Toll-like receptor 4 (TLR4) which acts as a receptor for lipopolysaccharide (LPS) has been reported to be involved in carcinogenesis. However, the regulatory mechanism of it has not been elucidated. Herein, we demonstrate that TLR4 promotes the malignant growth of liver cancer stem cells. Mechanistically, TLR4 promotes the expression of histone-lysine N-methyltransferase (SUV39 h2) and increases the formation of trimethyl histone H3 lysine 9-heterochromatin protein 1-telomere repeat binding factor 2 (H3K9me3-HP1-TRF2) complex at the telomeric locus under mediation by long non coding RNA urothelial cancer-associated 1 (CUDR). At the telomeric locus, this complex promotes binding of POT1, pPOT1, Exo1, pExo1, SNM1B and pSNM1B but prevents binding of CST/AAF to telomere, thus controlling telomere and maintaining telomere length. Furthermore, TLR4 enhances interaction between HP1α and DNA methyltransferase (DNMT3b), which limits RNA polymerase II deposition on the telomeric repeat-containing RNA (TERRA) promoter region and its elongation, thus inhibiting transcription of TERRA. Ultimately, TLR4 enhances the telomerase activity by reducing the interplay between telomerase reverse transcriptase catalytic subunit (TERT) and TERRA. More importantly, our results reveal that tri-complexes of HP1 isoforms (α, ß and γ) are required for the oncogenic action of TLR4. This study elucidates a novel protection mechanism of TLR4 in liver cancer stem cells and suggests that TLR4 can be used as a novel therapeutic target for liver cancer.

Long noncoding RNA MEG3 suppresses liver cancer cells growth through inhibiting ß-catenin by activating PKM2 and inactivating PTEN.

Maternally expressed gene 3 (MEG3) encodes an lncRNA which is suggested to function as a tumor suppressor and has been showed to involve in a variety of cancers. Herein, our findings demonstrate that MEG3 inhibits the malignant progression of liver cancer cells in vitro and in vivo. Mechanistically, MEG3 promotes the expression and maturition of miR122 which targets PKM2. Therefore, MEG3 decreases the expression and nuclear location of PKM2 dependent on miR122. Furthermore, MEG3 also inhibits CyclinD1 and C-Myc via PKM2 in liver cancer cells. On the other hand, MEG3 promotes ß-catenin degradation through ubiquitin-proteasome system dependent on PTEN. Strikingly, MEG3 inhibits ß-catenin activity through PKM2 reduction and PTEN increase. Significantly, we also found that excessive ß-catenin abrogated the effect of MEG3 in liver cancer. In conclusion, our study for the first time demonstrates that MEG3 acts as a tumor suppressor by negatively regulating the activity of the PKM2 and ß-catenin signaling pathway in hepatocarcinogenesis and could provide potential therapeutic targets for the treatment of liver cancer.

TGFBR-IDH1-Cav1 axis promotes TGF-ß signalling in cancer-associated fibroblast.

TGF-ß signalling plays an important role in fibroblasts activation and tumour progression. Here, we report that the TGFBR-IDH1-Cav1 axis promotes TGF- ß signalling in fibroblasts. Our data demonstrated that IDH1 was downregulated by TGF-ß signalling in fibroblasts, and downregulation of IDH1 increased cellular concentration of α-ketoglutarate (α-KG) by accelerating glutamine metabolization. Interestingly, α-KG suppressed Cav1 expression through reducing the trimethylation of histone H3K4. Furthermore, Cav1 downregulation inhibited TGFBR protein degradation. In turn, the activated TGFBR promoted TGF-ß signalling. These findings demonstrated that metabolic enzyme IDH1 regulates TGF-ß signalling by feedback mechanism through α-KG and TGFBR-IDH1-Cav1 axis is important for TGF-ß signalling.

The effect of carvedilol and propranolol on portal hypertension in patients with cirrhosis: a meta-analysis.

PURPOSE: Several randomized controlled clinical trials have been conducted to investigate the role of carvedilol and propranolol on the effect of portal pressure in patients with cirrhosis, leading to controversial results. Current meta-analysis was performed to compare the efficacy of the two drugs on portal pressure. PATIENTS AND METHODS: Two-hundred and ninety eligible patients were recruited. Published studies were selected based on PubMed, the Cochrane Library, Chinese Journal Full-text Database, and Wanfang Database. The outcome measurements included the mean difference (MD) in the percentage of hepatic vein pressure gradient reduction (%HVPG reduction), the risk ratio (RR) of nonresponders in hemodynamic assessment, and the percentage of mean arterial pressure reduction (%MAP reduction). Subgroup analysis was performed. RESULTS: Seven trials were identified (including five acute and three long-term drug administration randomized controlled trials). A summary of pooled MD between the %HVPG reduction is as follows: overall -8.62 (confidence interval [CI] -11.76, -5.48, P<0.00001), acute -10.05 (CI -14.24, -5.86, P<0.00001), and long term -6.80 (CI -11.53, -2.07, P=0.005), while summary of pooled RR of hemodynamic nonresponders with carvedilol was as follows: overall 0.64 (CI 0.51, 0.81, P=0.0002), acute 0.63 (CI 0.47, 0.85, P=0.002), and long term 0.67 (CI 0.47, 0.97, P=0.03). Both of the outcome measurements favored carvedilol. Significant heterogeneity (P<0.1, I (2)=92%) existed between the two treatment groups in %MAP reduction. No considerable difference could be observed in the %MAP reduction through the poor overlapping CI boundaries. CONCLUSION: Carvedilol has a greater portal hypertensive effect than propranolol. Further comparative trials of the two drugs are required to identify the effect of MAP reduction.

Wnt5a Promotes Cytokines Production and Cell Proliferation in Human Hepatic Stellate Cells Independent of Canonical Wnt Pathway.

BACKGROUND: Wnt5a is involved in the activation of human hepatic stellate cells (HSC) and related with the occurrence of liver fibrosis. As the function and mechanism that Wnt5a mediates HSC activation remains unclear, we sought to investigate them. METHODS: Wnt5a levels were determined in the HSC cell line LX-2 after lipopolysaccharide (LPS) and TNF-α stimulation. HSC cells showing stable and efficient overexpression or featuring knockdown of Wnt5a were constructed by a lentivirus system. Regulation of cytokine and collagen expressions were confirmed by quantitative PCR or ELISA in stable LX-2 cell lines showing Wnt5a overexpression or knockdown. Proliferation was determined by 5-ethynyl-2'-deoxyuridine labeling. Relevant signaling pathways were identified using specific protein antibodies. RESULTS: LPS and TNF-α induced Wnt5a expression in LX-2 cells. Compared with control cells, an increase in IL-10, IL-6, COL1, and COL3 secretion in a stable LX-2 cell line showing Wnt5a overexpression was observed. Knockdown of Wnt5a obviously reduced the production of IL-1ß, IL-6, COL1, and COL3. Wnt5a overexpression promoted LX-2 proliferation, while Wnt5a knockdown dramatically inhibited cell proliferation. Compared with the effects of Wnt5a knockdown cells, Wnt5a-overexpressing cells triggered the phosphorylation of c-Jun N-terminal kinase (JNK) and ß-catenin, which leads to ß-catenin degradation and inactivates the canonical Wnt/ß-catenin pathway. CONCLUSIONS: Wnt5a regulates inflammatory cytokine and collagen production and cell proliferation, which is independent of the canonical Wnt signaling pathway. The results reveal a new signaling mechanism in HSC activation and could provide a new strategy for hepatic fibrosis treatment.