Omega-6-derived oxylipin changes in serum of patients with hepatitis B virus-related liver diseases

Introduction

Chronic hepatitis B virus (HBV) infection is the main etiologic risk factor for hepatocellular carcinoma (HCC). Early studies indicated that the increase of omega-6-derived oxylipins may be involved in the pathogenesis of HBV-related HCC, yet their changes during the distinct clinical phases of chronic HBV infection remain unclear. To fill this gap, in this study we investigated the omega-6-derived oxylipin profiles in patients with three major clinical stages of chronic HBV infection (chronic hepatitis B, liver cirrhosis, and HCC).

Methods

Eighteen omega-6-derived oxylipins were quantified in serum samples of 34 patients with chronic hepatitis B, 46 patients with HBV-related liver cirrhosis, 38 patients with HBV-related HCC, and 50 healthy controls using liquid chromatography tandem mass spectrometry.

Results

Seven oxylipins were found to be altered in patients with HBV-related liver diseases, including 9,10-dihydroxyoctadecenoic acid (9,10-DiHOME), 12,13-DiHOME, 14,15-dihydroxyeicosatrienoic acid (14,15-DiHETrE), 13-hydroxyoctadecadienoic acid (13-HODE), 12-hydroxyeicosatetraenoic acid (12-HETE), 11-HETE, and thromboxane B₂ (TXB₂). Of these, three oxylipins derived from the cytochrome P450 (CYP450) pathways including 9,10-DiHOME, 12,13-DiHOME, and 14,15-DiHETrE were found to be associated with the levels of α-fetoprotein (AFP), a tumor marker. In combination with AFP, age, and gender, a combination of these seven differential oxylipins could significantly enhance the prediction of HBV-related liver diseases, particularly for liver cirrhosis (p?<?0.05).

Conclusion

This study for the first time shows the correlations between CYP450-derived oxylipins and the progression of chronic HBV infection, and sheds a new light on the surveillance of HBV-related live diseases using oxylipins.

     

Targeted metabolomics reveals altered oxylipin profiles in plasma of mild cognitive impairment patients

Introduction and objective

Mild cognitive impairment (MCI) is considered to be a prodromal stage of Alzheimer’s disease (AD), which is the most common type of dementia. Although MCI is a common clinical manifestation in the elderly, the pathology and molecular mechanisms are not fully understood. Oxylipins are a major class of lipid-derived signaling mediators, which have been implicated in the pathology of MCI and AD. In this study, we investigated the changes of oxylipin profiles in plasma of MCI patients.

Methods

We performed a targeted liquid chromatography—mass spectrometry analysis to quantify 49 oxylipins and 4 polyunsaturated fatty acids in plasma samples of 60 clinically diagnosed MCI patients and 56 age- and gender-matched cognitively normal individuals.

Results

We found that the levels of linoleic acid (LA) and 7 oxylipins were significantly altered in MCI patients when compared to the controls. Notably, oxylipins synthesized through 5-lipoxygenase (5-LOX) and cytochrome P450 (CYP450) pathways of arachidonic acid (AA) or LA were elevated in MCI patients, which is in accordance with previously reports that oxylipins from the same pathways were increased in the brain tissues of AD and MCI patients, suggesting the potential correlations of oxylipin changes in 5-LOX and CYP450 pathways between the peripheral blood and the brain tissues in MCI and AD patients.

Conclusion

This study is the first report on plasma oxylipin profiles in MCI patients, and disease-relevant changes of oxylipins and oxylipin pathways were identified. The results represent potentially an efficient method to monitor certain oxylipin changes in the brain tissues of MCI or AD patients.

     

miR-1260b promotes cell migration and invasion of hepatocellular carcinoma by targeting the regulator of G-protein signaling 22

Objectives

To investigate whether miR-1260b can regulate migration and invasion of hepatocellular carcinoma (HCC) by targeting RGS22.

Results

miR-1260b was up-regulated in HCC tissues compared with their corresponding non-cancerous tissues. Over-expression of miR-1260b increased migration and invasion of HepG2 and SMMC-7721 cells associated with HCC. Regulator of G-protein signaling 22 (RGS22) was identified as a directly target of miR-1260b and was inhibited by miR-1260b. Knockdown of RGS22 increased proliferation of HCC cells.

Conclusions

The new identified miR-1260b/RGS22 axis provides useful therapeutic methods for treatment of HCC deepening on our understanding of underlying mechanisms of HCC tumorigenesis.

     

Distinct differences in serum eicosanoids in healthy,enteritis and colorectal cancer individuals

Background

Eicosanoids as inflammatory mediators take part in the regulation of disease progression. However, the application of serum eicosanoid in disease progression identification was still uncertain.

Methods

Serum from 52 healthy volunteers, 34 enteritis patients and 55 colorectal cancer (CRC) patients were collected. Ultra-high performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was used to analyze the change of serum eicosanoids.

Results

Of 158 eicosanoids, we found that lower levels of anti-inflammatory eicosanoids 13-HOTrE, 9-HOTrE, DHA, 11-HETE and 12-HHT were observed in enteritis and CRC group compared with healthy group, meanwhile the content of 5-iPF2α-VI as oxidative stress mediator in enteritis and CRC group was greater than that in healthy groups. Moreover, 9-HODE, 13-HODE, 12,13-diHOME, 8-HETE and 15-HETE were dramatically decrease in CRC group compared with non-CRC group. Additionally, the change of 5-, 12- and 15-HETE content in serum sample was associated with progression from healthy to enteritis, finally to CRC. No significant difference between serum eicosanoids and the expression of CerbB-2 and Ki67 were observed.

Conclusion

Serum eicosanoids might be used as a possible biomarker for identifying among health, enteritis and CRC.

     

Impact of post-collection freezing delay on the reliability of serum metabolomics in samples reflecting the California mid-term pregnancy biobank

Background

Population-based biorepositories are important resources, but sample handling can affect data quality.

Objective

Identify metabolites of value for clinical investigations despite extended postcollection freezing delays, using protocols representing a California mid-term pregnancy biobank.

Methods

Blood collected from non-pregnant healthy female volunteers (n?=?20) underwent three handling protocols after 30 min clotting at room temperature: (1) ideal—samples frozen (??80 °C) within 2 h of collection; (2) delayed freezing—samples held at room temperature for 3 days, then 4 °C for 9 days, the median times for biobank samples, and then frozen; (3) delayed freezing with freeze–thaw—the delayed freezing protocol with a freeze–thaw cycle simulating retrieved sample sub-aliquoting. Mass spectrometry-based untargeted metabolomic analyses of primary metabolism and complex lipids and targeted profiling of oxylipins, endocannabinoids, ceramides/sphingoid-bases, and bile acids were performed. Metabolite concentrations and intraclass correlation coefficients (ICC) were compared, with the ideal protocol as the reference.

Results

Sixty-two percent of 428 identified compounds had good to excellent ICCs, a metric of concordance between measurements of samples handled with the different protocols. Sphingomyelins, phosphatidylcholines, cholesteryl esters, triacylglycerols, bile acids and fatty acid diols were the least affected by non-ideal handling, while sugars, organic acids, amino acids, monoacylglycerols, lysophospholipids, N-acylethanolamides, polyunsaturated fatty acids, and numerous oxylipins were altered by delayed freezing. Freeze–thaw effects were assay-specific with lipids being most stable.

Conclusions

Despite extended post-collection freezing delays characteristic of some biobanks of opportunistically collected clinical samples, numerous metabolomic compounds had both stable levels and good concordance.

     

Prognostic significance of microvascular invasion in tumor stage for hepatocellular carcinoma

Background

The presence of microvascular invasion (McVI) in hepatocellular carcinoma (HCC) has been proposed as a cause of recurrence and poor survival, although this has not been officially emphasized in staging systems. Thus, we conducted a retrospective study to investigate the prognostic importance of McVI in tumor staging in patients with HCC who underwent hepatic resection.

Methods

A retrospective analysis was performed of patients who underwent hepatic resection for HCC at our center from 1994 to 2012. Patients with HCC were classified into four groups based on the presence of McVI and extent of gross vascular invasion (VI).

Results

The 5-year overall and recurrence-free survival rates of 676 patients were 63.3 and 42.6%, respectively. There was no difference in tumor recurrence or survival rate between patients with HCC and McVI without gross VI and those with gross VI confined to segmental/sectional branches. Multivariate analysis revealed that the extent of VI based on the presence of McVI and gross VI was independently associated with tumor recurrence and overall survival.

Conclusions

McVI was revealed to be an important risk factor similar to gross VI confined to a segmental/sectional branch in patients with HCC who underwent hepatic resection. This finding should be considered when estimating the stage for prognosis.

     

miR-93 enhances hepatocellular carcinoma invasion and metastasis by EMT via targeting PDCD4

Objectives

To clarify the potential biological function of miR-93 and its related molecular mechanism underlying metastasis in human hepatocellular carcinoma (HCC).

Results

miR-93 was significantly up-regulated in HCC tissues and was associated with poor 5-year overall survival in HCC patients. Transwell assays showed that over-expression of miR-93 increased HCC cell migration and invasion in vitro. Programmed cell death 4 (PDCD4) was a target gene of miR-93 and miR-93 could down-regulate the expression of PDCD4 by directly targeting its 3′-UTR. The re-expression of PDCD4 could attenuate the HCC cell invasion and migration induced by miR-93, while the knockdown of PDCD4 would promote HCC cell migration and invasion via the epithelial-mesenchymal transition (EMT) pathway.

Conclusions

miR-93 provides new insight into the molecular mechanisms of pathogenesis and progression in HCC and offer a potential therapeutic target for the treatment of HCC patients.

     

Left atrium remodeling predicts late recurrence of paroxysmal atrial fibrillation after second generation cryoballoon ablation

Background

Atrial fibrillation (AF) is the most common arrhythmia worldwide. Nowadays, AF ablation is a valuable treatment option. It has been shown that the left atrium (LA) diameter is a predictor of AF recurrence after cryoballoon ablation (CBA). Since it does not reflect the true LA size, we compared the role of different LA anatomical parameters using echocardiography for the prediction of AF recurrence after CBA.

Methods

We retrospectively included 209 patients (mean age 56.1?±?13.6 years, male 62%) with paroxysmal AF undergoing CBA. A transthoracic echocardiography was performed in all patients.

Results

At a mean follow-up of 16.9?±?6.3 months, AF recurred in 25.4% of the patients. LA anterior - posterior diameter (LAD), LA minimum volume (LAmin) and early AF recurrence were independent predictors of recurrence. Based on receiver operating characteristics, cut – off values for LAD and, LAmin were 41 mm, 23.69 mL, respectively. The negative predictive values for recurrence were 73% and 87.3% respectively. In patients with AF recurrence, a significant proportion (30.2%) showed LA longitudinal remodeling (LA superior – inferior diameter) even though classically measured LAD was normal.

Conclusions

Longitudinal LA remodeling plays an additional role for predicting AF recurrence after CBA, in patients without LAD dilation. Moreover, LAmin had a high negative predictive value and was an independent predictor of AF recurrence. Therefore, a more complete LA anatomical assessment allows a better prediction of AF recurrences after CBA.

     

Silencing TRIP13 inhibits cell growth and metastasis of hepatocellular carcinoma by activating of TGF-β1/smad3

Background

TRIP13 is highly expressed in several cancers and is closely connected with cancer progression. However, its roles on the growth and metastasis of hepatocellular carcinoma (HCC), and the underlying mechanism are still unclear.

Methods

Combining bioinformatics with previous studies, the correlation between TRIP13 and HCC was predicted. TRIP13 expressions from 52 HCC patients and several cell lines were determined. The effects of silencing TRIP13 on cell viability, apoptosis, migration and invasion were respectively detected using CCK-8, flow cytometry and Transwell. qRT-PCR and western blot were performed to reveal associated mechanism. A HCC model was established in BALB/c-nu mice by transplanting HepG2 cells. TRIP13 protein expression and apoptosis in mice tissues were accordingly detected by Immunohistochemistry and TUNEL.

Results

High expression of TRIP13 in HCC affected the survival rate and it was enriched in RNA degradation and fatty acid metabolism according to bioinformatics and prediction from previous literature. Increased expression of TRIP13 in HCC patient tissues was associated with the progression of HCC. Silencing TRIP13 inhibited cell viability, migration and invasion, and induced cell apoptosis. TRIP13 knockdown also suppressed the formation of tumor in vivo. Meanwhile, silencing TRIP13 decreased the expressions of Ki67 and MMP-2 and increased the expressions of TIMP-2, active-caspase-3 and TGF-β1/smad3 signaling- related genes.

Conclusions

Silencing TRIP13 acts as a tumor suppresser of HCC to repress cell growth and metastasis in vitro and in vivo, and such a phenomenon possibly involved activation of TGF-β1/smad3 signaling.

     

Metabolic signatures of four major histological types of lung cancer cells

Introduction

Histologically lung cancer is classified into four major types: adenocarcinoma (Ad), squamous cell carcinoma (SqCC), large cell carcinoma (LCC), and small cell lung cancer (SCLC). Presently, our understanding of cellular metabolism among them is still not clear.

Objectives

The goal of this study was to assess the cellular metabolic profiles across these four types of lung cancer using an untargeted metabolomics approach.

Methods

Six lung cancer cell lines, viz., Ad (A549 and HCC827), SqCC (NCl-H226 and NCl-H520), LCC (NCl-H460), and SCLC (NCl-H526), were analyzed using liquid chromatography quadrupole time-of-flight mass spectrometry, with normal human small airway epithelial cells (SAEC) as the control group. The principal component analysis (PCA) was performed to identify the metabolic signatures that had characteristic alterations in each histological type. Further, a metabolite set enrichment analysis was performed for pathway analysis.

Results

Compared to the SAEC, 31, 27, 34, 34, 32, and 39 differential metabolites mainly in relation to nucleotides, amino acid, and fatty acid metabolism were identified in A549, HCC827, NCl-H226, NCl-H520, NCl-H460, and NCl-H526 cells, respectively. The metabolic signatures allowed the six cancerous cell lines to be clearly separated in a PCA score plot.

Conclusion

The metabolic signatures are unique to each histological type, and appeared to be related to their cell-of-origin and mutation status. The changes are useful for assessing the metabolic characteristics of lung cancer, and offer potential for the establishment of novel diagnostic tools for different origin and oncogenic mutation of lung cancer.

     

RNA-binding protein Dnd1 inhibits epithelial–mesenchymal transition and cancer stem cell-related traits on hepatocellular carcinoma cells

Objectives

To investigate the roles of Dead end 1 (Dnd1) in modulating cancer stem cell-related traits of hepatocellular carcinoma (HCC).

Results

Dead end (Dnd1) inhibited spheroid formation, suppressed the expression of stemness-related genes, and increased sensitivity to sorafenib in HCC cells. Mechanistically, Dnd1 could bind to 3′-UTR of LATS2, the key kinase of Hippo pathway, thus elevating LATS2 mRNA stability and its expression, subsequently leading to phosphorylation of YAP and its cytoplasmic retention. As a result, epithelial–mesenchymal transition (EMT) was weakened and therefore the generation of HCC stem cell properties was suppressed.

Conclusions

Dnd1 functions as a tumor suppressor by prohibiting CSC-like characteristics via activating Hippo pathway in HCC cells. Dnd1 could thus be a novel therapeutic target for HCC patients.

     

Optimization of fecal sample preparation for untargeted LC-HRMS based metabolomics

Introduction

Collecting feces is easy. It offers direct outcome to endogenous and microbial metabolites.

Objectives

In a context of lack of consensus about fecal sample preparation, especially in animal species, we developed a robust protocol allowing untargeted LC-HRMS fingerprinting.

Methods

The conditions of extraction (quantity, preparation, solvents, dilutions) were investigated in bovine feces.

Results

A rapid and simple protocol involving feces extraction with methanol (1/3, M/V) followed by centrifugation and a step filtration (10 kDa) was developed.

Conclusion

The workflow generated repeatable and informative fingerprints for robust metabolome characterization.

     

Hypoxia promotes the migration and invasion of human hepatocarcinoma cells through the HIF-1α–IL-8–Akt axis

Background

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third most common cause of cancer-related death worldwide. The 5-year survival rate remains low despite considerable research into treatments of HCC, including surgery, radiotherapy and chemotherapy. Many mechanisms within HCC still require investigation, including the influence of hypoxia, which has a crucial role in many cancers and is associated with metastasis. Hypoxia inducible factor-1α (HIF-1α) is known to regulate the expression of many chemokines, including interleukin-8 (IL-8), which is associated with tumor metastasis. Although many studies have reported that HIF-1α is associated with HCC migration and invasion, the underlying mechanisms remain unknown.

Methods

The expression level of HIF-1α was determined in HCC cells. The correlation of IL-8 and HIF-1α expressions was assessed via knockdown of HIF-1α. HCC cells were also used to assess the influence of HIF-1α on HCC cell migration and invasion. LY294002, an inhibitor of the Akt pathway, was used to confirm the associated signaling pathways.

Results

We observed a significant attenuation of cell migration and invasion after silencing of HIF-1α. Exogenously expressing IL-8 restored migration and invasion. Akt was found to be involved in this process.

Conclusion

Hypoxia promotes HCC cell migration and invasion through the HIF-1α–IL-8–Akt axis.

     

Bone marrow-derived stem cells ameliorate hepatic fibrosis by down-regulating interleukin-17

Background

Accumulating evidences have identified the immunoregulatory features of stem cells. In this study, the immunoregulation of bone marrow-derived stem cells (BMSCs) transplanted into patients with HBV-related decompensated cirrhosis and mouse model of liver injury induced by carbon tetrachloride (CCl₄) administration was observed.

Results

Compared with healthy controls, patients with HBV-related decompensated cirrhosis showed significantly higher levels of TNF-alpha, IL-12, TGF-beta1, IL-17, and IL-8. However, only IL-17 was markedly decreased after autologous BMSCs transplantation during their follow-up. The same results were found in the CCl₄-treated mice. Furthermore, we found that exogenous IL-17 partly abolished the therapeutic effect of BMSCs whereas IL-17-specific antibody promoted improvement of liver injury in CCl₄-treated mice, resembling the therapeutic effect of BMSCs transplantation.

Conclusions

These data suggested that BMSCs transplantation induces a decrease of IL-17 level, which at least in part delineates the mechanisms of stem cells-mediated therapeutic benefit on liver disease.

     

Monoacylglycerol lipase promotes progression of hepatocellular carcinoma via NF-κB-mediated epithelial-mesenchymal transition

Background

Monoacylglycerol lipase (MAGL), a critical lipolytic enzyme, has emerged as a key regulator of tumor progression, yet its biological function and clinical significance in hepatocellular carcinoma (HCC) is still unknown.

Methods

In this study, we used a tissue microarray containing samples from 170 HCC patients to evaluate the expression of MAGL and its correlation with other clinicopathologic characteristics. In addition, we investigated the regulating effects of MAGL on various HCC lines. Finally, we identified the NF-κB signaling pathway participated in MAGL-mediated epithelial-mesenchymal transition (EMT) using HCC cell lines with different metastatic potentials.

Results

The expression of MAGL was significantly higher in HCC tumors than in matched peritumor tissues. Specifically, high MAGL expression was found in tumors with larger tumor size, microvascular invasion, poor differentiation, or advanced TNM stage. In addition, the clinical prognosis for the MAGL^high group was markedly poorer than that for the MAGL^low group in the 1-, 3-, and 5-year overall survival times and recurrence rates of HCC patients. MAGL expression was an independent prognostic factor for both survival and recurrence after curative resection. Furthermore, the upregulation of MAGL in HCC cells promoted cell growth and invasiveness abilities, and accompanied by EMT. In contrast, downregulation of MAGL obviously inhibited these characteristics. Moreover, further investigations verified that MAGL facilitates HCC progression via NF-κB-mediated EMT process.

Conclusions

Our findings demonstrate MAGL could promote HCC progression by the induction of EMT and suggest a potential therapeutic target, as well as a biomarker for prognosis, in patients with HCC.

     

Hepatitis B virus x protein induces epithelial-mesenchymal transition of hepatocellular carcinoma cells by regulating long non-coding RNA

Background

It has been widely accepted that hepatitis B virus X protein (HBx) plays an important role in hepatocellular carcinoma (HCC). This study aimed to explore the function of long non-coding RNAs (lncRNAs) in the epithelial-mesenchymal transition (EMT) induced by HBx.

Methods

The association between HBx and EMT markers was detected using immunohistochemistry in HCC tissues. The effect of HBx on HCC EMT was assessed through morphological analysis, transwell assay, metastatic in vivo study and detection of EMT markers. LncRNA microarray was used to screen the differently expressed lncRNAs. Small interfering RNA and Western blot were used to analyse the function and mechanism of the locked lncRNA.

Results

HBx was negatively correlated with the epithelial marker E-cadherin but positively correlated with the mesenchymal marker vimentin in HCC tissues. HBx induced the mesenchymal phenotype and improved the metastatic ability of HCC cells. Meanwhile, HBx down-regulated E-cadherin, whereas it up-regulated vimentin. In HCC cells, HBx altered the expression of 2002 lncRNAs by more than 2-fold. One of them was ZEB2-AS1. Inhibition of ZEB2-AS1 can compensate for the EMT phenotype and reverse the expression of EMT markers regulated by HBx. Additionally, HBx affected the Wnt signalling pathway.

Conclusions

HBx promotes HCC cell metastasis by inducing EMT, which is at least partly mediated by lncRNAs.

     

Comprehensive utilization of waste hemicelluloses during ethanol production to increase lactic acid yield: from pretreatment to fermentation

Background

Reducing the cost of producing cellulosic ethanol is essential for the industrialization of biorefinery. Several processes are currently under investigation, but few of these techniques are entirely satisfactory in terms of competitive cost or environmental impact. In this study, a new ethanol and lactic acid (LA) coproduction is proposed. The technique involved addition of waste alkaline peroxide pretreated hydrolysate (mainly LA and hemicelluloses) to the reaction mixture after ethanol fermentation (mainly LA and xylose) to reduce the ethanol production cost.

Results

The following processes were investigated to optimize LA production: no addition of hemicelluloses or hydrolysate, addition of recycled hemicelluloses, and addition of concentrated hydrolysate. The addition of concentrated hydrolysate at 48 hours, which resulted in a maximum LA concentration of 22.3 g/L, was the most environment-friendly and cost-effective process. After the improved fermentation, 361 mg LA and 132 mg ethanol were produced from 1 g of raw poplar wood. That is, the production of one gallon of ethanol produced $9 worth of LA.

Conclusions

The amount of LA produced from the pretreated hydrolysate and reaction mixture after ethanol fermentation cannot be underestimated. The recovery of hydrolysate rich in LA and hemicelluloses (or xylose) significantly improved LA yield and further reduced the ethanol production cost.

     

Metabolic perturbations of postnatal growth restriction and hyperoxia-induced pulmonary hypertension in a bronchopulmonary dysplasia model

Introduction

Neonatal pulmonary hypertension (PH) is a common manifestation of bronchopulmonary dysplasia (BPD) and contributes to increased morbidity and mortality of preterm birth. Postnatal growth restriction (PNGR) and hyperoxia are independent contributors to PH development, as indicated by our previous work in a rat model of BPD.

Objective

To explore the metabolic consequences of induction of PH with hyperoxia and PNGR in a rat model of BPD.

Methods

Sprague–Dawley rat pups (n?=?4/group) underwent three modes of PH induction: (1) growth restriction-induced by larger litter size; (2) hyperoxia-induced by 75% oxygen exposure; (3) combined growth restriction and hyperoxia. Primary metabolism, complex lipids, biogenic amines, and lipid mediators were characterized in plasma and lung tissue using GC- and LC-MS technologies.

Results

Specific to hyperoxic induction, pulmonary metabolomics suggested increased reactive oxygen species (ROS) generation as indicated by: (1) increased indicators of β-oxidation and mitochondrial respiration; (2) changes in ROS-sensitive pathway activity and metabolites including the polyol pathway and xanthine oxidase pathways, and reduced glutathione; (3) decreased plasmalogens. Unlike the lung, circulating metabolite changes were induction mode-specific or additive in the combined modes (e.g. 1) growth-restriction reduced phosphatidylcholine; (2) hyperoxia increased oxylipins and trimethylamine-N-oxide (TMAO); (3) additive effects on 3-hydroxybutyric acid and arginine.

Conclusion

The present study highlights the variety of metabolic changes that occur due to PNGR- and hyperoxia-induced PH, identifying numerous metabolites and pathways influenced by treatment-specific or combined effects. The rat model used in this study presents a robust means of uncovering the mechanisms that contribute to the pathology of PH.

     

Blockade of ARHGAP11A reverses malignant progress via inactivating Rac1B in hepatocellular carcinoma

Background

The molecular signaling events involving in high malignancy and poor prognosis of hepatocellular carcinoma (HCC) are extremely complicated. Blockade of currently known targets has not yet led to successful clinical outcome. More understanding about the regulatory mechanisms in HCC is necessary for developing new effective therapeutic strategies for HCC patients.

Methods

The expression of Rho GTPase-activating protein 11A (ARHGAP11A) was examined in human normal liver and HCC tissues. The correlations between ARHGAP11A expression and clinicopathological stage or prognosis in HCC patients were analyzed. ARHGAP11A was downregulated to determine its role in the proliferation, invasion, migration, epithelial-to-mesenchymal transition (EMT) development, and regulatory signaling of HCC cells in vitro and in vivo.

Results

ARHGAP11A exhibited high expression in HCC, and was significantly correlated with clinicopathological stage and prognosis in HCC patients. Moreover, ARHGAP11A facilitated Hep3B and MHCC97-H cell proliferation, invasion, migration and EMT development in vitro. ARHGAP11A knockdown significantly inhibited the in vivo growth and metastasis of HCC cells. Furthermore, ARHGAP11A directly interacted with Rac1B independent of Rho GTPase- activating activity. Rac1B blockade effectively interrupted ARHGAP11A-elicited HCC malignant phenotype. Meanwhile, upregulation of Rac1B reversed ARHGAP11A knockdown mediated mesenchymal-to-epithelial transition (MET) development in HCC cells.

Conclusion

ARHGAP11A facilitates malignant progression in HCC patients via ARHGAP11A-Rac1B interaction. The ARHGAP11A/Rac1B signaling could be a potential therapeutic target in the clinical treatment of HCC.

     

STARD13 promotes hepatocellular carcinoma apoptosis by acting as a ceRNA for Fas

Objectives

To study the roles of STARD13 in cellular apoptosis of hepatocellular carcinoma (HCC).

Results

Quantitative real-time PCR and immunohistochemistry analyses showed that the expression levels of STARD13 and Fas were lower in clinical HCC tissues than in normal tissues and were positively correlated, which is consistent with the results analyzed by The Cancer Genome Atlas (TCGA) data. Patients with higher STARD13 or Fas expression levels had longer overall survival. Additionally, STARD13 3′-UTR enhanced cellular apoptosis and the 3′-UTRs of STARD13 and Fas were predicted to harbor nine similar miRNA binding sites. And STARD13 3′-UTR promoted Fas expression in a 3′-UTR- and miRNA-dependent way and increased the sensitivity of HCC cells to chemotherapy. Importantly, the coding sequence of STARD13 did not increase Fas expression.

Conclusions

STARD13 3′-UTR promotes HCC apoptosis through acting as a ceRNA for Fas.