Earthworms Enhance Crop Resistance to Insects Under Microplastic Stress by Mobilizing Physical and Chemical Defenses.

To assess the ecological risk of microplastics (MPs) in agricultural systems, it is critical to simultaneously focus on MP-mediated single-organism response and different trophic-level organism interaction. Herein, we placed earthworms in soils contaminated with different concentrations (0.02% and 0.2% w/w) of polyethylene (PE) and polypropylene (PP) MPs to investigate the effect of earthworms on tomato against Helicoverpa armigera (H. armigera) under MPs stress. We found that earthworms alleviated the inhibitory effects of MPs stress on tomato growth and disrupted H. armigera growth. Compared to individual MPs exposure, earthworm incorporation significantly increased the silicon and lignin content in herbivore-damaged tomato leaves by 19.1% and 57.6%, respectively. Metabolites involved in chemical defense (chlorogenic acid) and phytohormones (jasmonic acid) were also activated by earthworm incorporation. Furthermore, earthworms effectively reduced oxidative damage induced by H. armigera via promoting antioxidant metabolism. Overall, our results suggest that utilizing earthworms to regulate above- and below-ground interactions could be a promising strategy for promoting green agriculture.

Does a "Western Lifestyle" Confer a Higher Burden of Colorectal Cancer? A Comparison of EU15+ Countries versus Global Trends between 1990 and 2019.

The incidence of colorectal cancer (CRC) in the U.S. is declining in adults 50 years and older; however, recent studies suggest an increasing disease burden among adults under age 50. This study aims to compare the incidence, mortality, and mortality-to-incidence ratios (MIRs) of CRC in EU15+ countries to determine if similar age-stratified occurrences are observed across these countries with similar "Western lifestyle"-related risk factors. Incidence and mortality rates for CRC between 1990 and 2019 were extracted using the Global Burden of Disease database. The data were age-stratified into groups between ages 25-49, 50-69, and greater than 69 years. We observed that the incidence of CRC increased globally for all age groups, with the highest increase observed for males (75.9%) and females (27.7%) aged 25-49. A similar trend was observed in 15 of the 19 EU15+ countries for males and 16 of the 19 EU15+ countries for females aged 25-49. Global mortality rates decreased for all age groups in females but increased for males in all age groups. This raises concerns regarding potentially modifiable risk factors contributing to increased CRC development and underscores the importance of implementing standardized screening at an earlier stage to ensure adequate detection in the younger population.

Effects of polystyrene, polyethylene, and polypropylene microplastics on the soil-rhizosphere-plant system: Phytotoxicity, enzyme activity, and microbial community.

The widespread presence of soil microplastics (MPs) has become a global environmental problem. MPs of different properties (i.e., types, sizes, and concentrations) are present in the environment, while studies about the impact of MPs having different properties are limited. Thus, this study investigated the effects of three common polymers (polystyrene, polyethylene, and polypropylene) with two concentrations (0.01% and 0.1% w/w) on growth and stress response of lettuce (Lactuca sativa L.), soil enzymes, and rhizosphere microbial community. Lettuce growth was inhibited under MPs treatments. Moreover, the antioxidant system, metabolism composition, and phyllosphere microbiome of lettuce leaves was also perturbed. MPs reduced phytase activity and significantly increased dehydrogenase activity. The diversity and structure of rhizosphere microbial community were disturbed by MPs and more sensitive to polystyrene microplastics (PSMPs) and polypropylene microplastics (PPMPs). In general, the results by partial least squares pathway models (PLS-PMs) showed that the presence of MPs influenced the soil-rhizosphere-plant system, which may have essential implications for assessing the environmental risk of MPs.

An endoplasmic reticulum stress-related signature featuring ASNS for predicting prognosis and immune landscape in prostate cancer.

Prostate cancer (PRAD) is one of the common malignant tumors of the urinary system. In order to predict the treatment results for PRAD patients, this study proposes to develop a risk profile based on endoplasmic reticulum stress (ERS). Based on the Memorial Sloan-Kettering Cancer Center (MSKCC) cohort and the Gene Expression Omnibus database (GSE70769), we verified the predictive signature. Using a random survival forest analysis, prognostically significant ERS-related genes were found. An ERS-related risk score (ERscore) was created using multivariable Cox analysis. In addition, the biological functions, genetic mutations and immune landscape related to ERscore are also studied to reveal the underlying mechanisms related to ERS in PRAD. We further explored the ERscore-related mechanisms by profiling a single-cell RNA sequencing (scRNA-seq) dataset (GSE137829) and explored the oncogenic role of ASNS in PRAD through in vitro experiments. The risk signature composed of eight ERS-related genes constructed in this study is an independent prognostic factor and validated in the MSKCC and GSE70769 data sets. The scRNA-seq data additionally revealed that several carcinogenic pathways were noticeably overactivated in the group with high ERS scores. As one of the prognostic genes, ASNS will significantly inhibit the proliferation, migration and invasion abilities of PRAD cells after its expression is interfered with. In conclusion, this study developed a novel risk-specific ERS-based clinical treatment strategy for patients with PRAD.

Burden of AML, 1990-2019: Estimates From the Global Burden of Disease Study.

PURPOSE: AML accounts for 80% of acute leukemia in adults. While progress has been made in treating younger patients in the past 2 decades, there has been limited improvement for older patients until recently. This study examines the global and European Union (EU) 15+ trends in AML between 1990 and 2019. METHODS: We extracted age-standardized incidence rates (ASIRs), age-standardized death rates (ASMRs), and disability-adjusted life years, stratified by sex from the Global Burden of Disease Study database, and mortality-to-incidence ratio (MIR) were computed. Trends were compared using Joinpoint regression. RESULTS: The findings show a global increase in AML incidence for both sexes from 1990 to 2019. In the EU15+ countries, most countries exhibited an increase in ASIR for both sexes. Joinpoint revealed that globally for male patients, ASIR steadily increased until 2010, remained stable until 2015 followed by a decline till 2019. Similar trends were observed in female patients. For ASMR, although there was an increase globally and in most EU15+ countries, there was a statistically significant decrease in mortality rates globally and in the majority of EU15+ countries in recent years. MIR improved in both sexes globally. On age stratification, AML burden was highest among older groups (55 years and older), while the lowest rates were observed in younger than 20 years. CONCLUSION: The findings from our study indicate a global rise in AML incidence and mortality in both sexes and decrease in MIR from 1990 to 2019 suggesting a better survival. However, on Joinpoint analysis, there is no change in MIR in women in the past decade and past 4 years in men indicating plateau in survival trends despite recent advances.

Type-dependent effects of microplastics on tomato (Lycopersicon esculentum L.): Focus on root exudates and metabolic reprogramming.

Much attention has been paid to the prevalence of microplastics (MPs) in terrestrial systems. MPs have been shown to affect the physio-biochemical properties of plants. Different MPs may have distinctive behaviors and diverse effects on plant growth. In the present study, the effects of polystyrene (PS), polyethylene (PE), and polypropylene (PP) MPs on physio-biochemical properties, root exudates, and metabolomics of tomato (Lycopersicon esculentum L.) under hydroponic conditions were investigated. Our results show that MPs exposure has adverse effects on tomato growth. MPs exposure had a significant type-dependent effect (p < 0.001) on photosynthetic gas parameters, chlorophyll content, and antioxidant enzyme activities. After exposure to MPs, the content of low molecular weight organic acids in tomato root exudates was significantly increased, which was considered as a strategy to alleviate the toxicity of MPs. In addition, MPs treatment significantly changed the metabolites of tomato root and leaf. Metabolic pathway analysis showed that MPs treatment had a great effect on amino acid metabolism. We also found that plants exposed to PS and PP MPs produced more significant metabolic reprogramming than those exposed to PE MPs. This study provides important implications for the mechanism studies on the toxic effect of various MPs on crops and their future risk assessment.

Three typical microplastics affect the germination and growth of amaranth (Amaranthus mangostanus L.) seedlings.

Microplastics (MPs) have been a global emerging contaminant and have aroused wide public concern. Currently, it is still unknown the phytotoxicity effect of MPs on amaranth (Amaranthus mangostanus L.). This study investigated the early responses of amaranth by exposing its seeds to suspensions of polystyrene (PS), polyethylene (PE), and polypropylene (PP) MPs. We observed the effects of MPs on seed germination and growth of amaranth, especially on the oxidative damage in amaranth roots. Impacts of MPs on the germination and growth of amaranth varied with the type, concentration, and particle size of MPs. PE MPs and PP MPs inhibited the shoot extension of amaranth, while the root length under PP MPs treatment was generally shorter than that under PS MPs and PE MPs. The accumulation of H2O2 in amaranth roots increased with the rising of MPs concentration. Compared with the control, a little number of dead cells were found in the roots of amaranth under high MPs treatment. It is noteworthy that only under 100 mg/L PP treatment, the amaranthus seedlings root cells were disorganized, due to the reactive oxygen species (ROS) damage in the roots. These findings provide essential information to assess the phytotoxicity of MPs in agricultural products, and provide insights into the underlying mechanisms of the observed phytotoxicity.

The Interaction between DNMT1 and High-Mannose CD133 Maintains the Slow-Cycling State and Tumorigenic Potential of Glioma Stem Cell.

The quiescent/slow-cycling state preserves the self-renewal capacity of cancer stem cells (CSCs) and leads to the therapy resistance of CSCs. The mechanisms maintaining CSCs quiescence remain largely unknown. Here, it is demonstrated that lower expression of MAN1A1 in glioma stem cell (GSC) resulted in the formation of high-mannose type N-glycan on CD133. Furthermore, the high-mannose type N-glycan of CD133 is necessary for its interaction with DNMT1. Activation of p21 and p27 by the CD133-DNMT1 interaction maintains the slow-cycling state of GSC, and promotes chemotherapy resistance and tumorigenesis of GSCs. Elimination of the CD133-DNMT1 interaction by a cell-penetrating peptide or MAN1A1 overexpression inhibits the tumorigenesis of GSCs and increases the sensitivity of GSCs to temozolomide. Analysis of glioma samples reveals that the levels of high-mannose type N-glycan are correlated with glioma recurrence. Collectively, the high mannose CD133-DNMT1 interaction maintains the slow-cycling state and tumorigenic potential of GSC, providing a potential strategy to eliminate quiescent GSCs.

Phytotoxicity of polystyrene, polyethylene and polypropylene microplastics on tomato (Lycopersicon esculentum L.).

Despite the fact that microplastic pollution in terrestrial ecosystems has received increasing attention, there are few studies on the potential effects of different microplastics on terrestrial plants. In this study, the toxicity of polystyrene (PS), polyethylene (PE) and polypropylene (PP) microplastics with different concentrations (0, 10, 100, 500 and 1000 mg/L) to tomato (Lycopersicon esculentum L.) were studied by a hydroponic experiment. The results showed that the three microplastics had inhibitory effects on seed germination when the concentration was less than or equal to 500 mg/L, and the inhibition rate ranged from 10.1% to 23.6%. Interestingly, the inhibition effect was alleviated under 1000 mg/L microplastic treatment. Generally, PE was more toxic to seedling growth than PS and PP. Additionally, it was confirmed that microplastics could cause oxidative stress in plants, and PP was relatively less toxic to antioxidant enzymes than PS and PE. These results can provide a theoretical basis and data support for further investigation on the toxicity of microplastics to tomatoes, and contribute to understanding the type specificity of microplastics' toxic effects on plants.

Kochia scoparia L., a newfound candidate halophyte, for phytoremediation of cadmium-contaminated saline soils.

In recent years, heavy metal pollution in saline soil is increasingly severe due to the rapid development of industry and agriculture. Halophytes can survive at higher concentrations of salt and heavy metal, which make them suitable candidates for the phytoremediation of heavy metals in saline soils. In the present study, the halophyte plant Kochia scoparia (L.) Schrad. seedlings were exposed to different doses of Cd (0, 5, 10, 30 mg/kg) and NaCl (0, 200, 400, 800 mM) to explore its tolerance and phytoremediation ability for Cd. There was no significant toxic effect of Cd on the K. scoparia seedlings. NaCl reduced the biomass of K. scoparia compared with the control, but did not show any visible toxic symptom. Furthermore, Cd accumulation in K. scoparia is mainly distributed in the shoot; especially when exposed to low-Cd (5 mg/kg) treatment, the accumulation of Cd in the shoots was up to 5.42-22.25 mg/kg, which was 3.18-53.4 times of that in the roots. Moreover, the contents of glutathione and oxalate in plants increased gradually with the increase of NaCl concentration. Under the treatment of 800 mM NaCl without Cd, the content of glutathione reached the highest 51.21 µg/g, and the proportion of oxalate reached the highest 28.76% under the treatment of 30 mg/kg Cd with 400 Mm NaCl. Finally, we also found the significant alterations of cadmium chemical forms in rhizosphere soil with the addition of NaCl. Overall, K. scoparia could be an efficient and valuable candidate for the phytoextraction of low-Cd (5 mg/kg)-contaminated saline soil.

Effects of polyester microfibers (PMFs) and cadmium on lettuce (Lactuca sativa) and the rhizospheric microbial communities: A study involving physio-biochemical properties and metabolomic profiles.

Microfibers (MFs) and cadmium (Cd) are widely distributed in soil ecosystems, posing a potential threat to soil biota. To explore potential risks of single MFs and in combination with Cd (co-PMFs/Cd) to soil environment, we systematically investigated the effects of PMFs and co-PMFs/Cd treatments on physio-biochemical performance and metabolomic profile of lettuce (Lactuca sativa), as well as the rhizospheric bacterial communities. Our results showed that both PMFs and co-PMFs/Cd treatments adversely disturbed the plant shoot length, photosynthetic, and chlorophyll content. Co-PMFs/Cd specifically increased the activities of antioxidant enzymes. The metabolites in lettuce leaf were significantly altered by PMFs and co-PMFs/Cd treatments. A significant reduction in the relative abundance of amino acids sugar and sugar alcohols indicated the altered nitrogen and carbohydrates related metabolic pathways. Additionally, PMFs and co-PMFs/Cd treatments altered the structure of rhizospheric bacterial communities and caused significant changes in some key beneficial/functional bacteria involved in the C, and N cycles. The present study provides a novel insight into the potential effects of PMFs on plant and rhizosphere bacterial communities and highlights that PMFs can threaten the terrestrial ecosystem and should be further explored in future research.

Siglec-15 promotes the migration of liver cancer cells by repressing lysosomal degradation of CD44.

Sialic acid-binding immunoglobulin-like lectin-15 (Siglec-15) has been identified as a novel potential target for cancer immunotherapy. Here, we explored the role of Siglec-15 in human hepatoma cells. In this study, we found that the expression of Siglec-15 is substantially upregulated in liver cancer tissues in comparison with the nontumor tissues. Functionally, in vitro experiments show that Siglec-15 promotes the migration of hepatoma cells. Furthermore, the data demonstrated an interaction between Siglec-15 and CD44, a transmembrane glycoprotein that mediates tumor progression and metastasis. In addition, we show that CD44 is modified by α2,6-linked sialic acids on N-glycans in hepatoma cells and that CD44 sialylation affects its interaction with Siglec-15. Removal of the sialic acid residues from CD44 resulted in suppressed interaction between Siglec-15 and CD44. We further demonstrate that Siglec-15 interacts and promotes the stability of CD44 by preventing its lysosomal-mediated degradation. Taken together, our findings demonstrate that Siglec-15 promotes the migration of hepatoma cells by regulating the CD44 protein stability.

The binding of LDN193189 to CD133 C-terminus suppresses the tumorigenesis and immune escape of liver tumor-initiating cells.

The tumor-initiating cell (TIC) marker CD133 promotes TIC self-renewal and tumorigenesis through the tyrosine phosphorylation of its c-terminal domain. Therefore, finding compounds that target the phosphorylation of CD133 will provide an effective method for inhibiting TICs characteristics. Here, through small molecule microarray screening, compound LDN193189 was found to bind to the c-terminus of CD133 and influenced its tyrosine phosphorylation. LDN193189 inhibited the interaction between CD133 and p85, accompanied by a reduction in the self-renewal and tumorigenicity of liver TIC. In addition, LDN193189 inhibited the expression and transcription of Galectin-3 by reducing the tyrosine phosphorylation of CD133. Galectin-3 secreted by liver TICs inhibited the proliferation of activated CD8+ T cells by binding to PD-1. LDN193189 suppressed the immune escape ability of liver TICs by downregulating Galectin-3. Taken together, LDN193189 suppressed the tumorigenesis and immune escape of liver CSCs by targeting the CD133-Galectin-3 axis.

KLF5-Modulated lncRNA NEAT1 Contributes to Tumorigenesis by Acting as a Scaffold for BRG1 to Silence GADD45A in Gastric Cancer.

Long noncoding RNAs (lncRNAs), genomic "dark matter," are deeply involved in diverse biological processes. The lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) is a highly participatory lncRNA; however, its roles in gastric cancer (GC) remain largely unexplored. Here, we demonstrated that the expression of NEAT1 was significantly increased and negatively correlated with prognosis in GC. Subsequent experiments confirmed that KLF5 can induce NEAT1 expression by binding to the NEAT1 promoter region. Further experiments revealed that NEAT1 silencing significantly suppressed cell proliferation both in vitro and in vivo and induced apoptosis. We used mRNA sequencing (mRNA-seq) to identify the preferentially affected genes linked to cell proliferation in cells with NEAT1 knockdown. Mechanistically, NEAT1 bound BRG1 (SMARCA4) directly, modulating H3K27me3 and H3K4me3 in the GADD45A promoter to regulate GADD45A-dependent G2/M cell cycle progression. In addition, BRG1 was significantly upregulated and correlated with outcomes in GC; moreover, it promoted cell proliferation both in vitro and in vivo. Taken together, our data support the importance of NEAT1 in promoting GC tumorigenesis and indicate that NEAT1 might be a diagnostic and therapeutic target in GC.

HB-EGF Activates the EGFR/HIF-1α Pathway to Induce Proliferation of Arsenic-Transformed Cells and Tumor Growth.

Arsenic was recently identified as a pollutant that is a major cause of lung cancer. Since heparin-binding EGF-like growth factor (HB-EGF) was reported to be a promising therapeutic target for lung cancer, we investigated the role and mechanism of HB-EGF during arsenic-induced carcinogenesis and development of lung cancer. HB-EGF expression were upregulated in As-T cells, lung cancer cell lines, and in most lung cancer tissue samples; and HB-EGF activated the EGFR/p-ERK/HIF-1α pathway and induced VEGF by regulating HIF-1α transcription. HIF-1α transcriptional stimulation by HB-EGF was facilitated by PKM2 and played an important role in HB-EGF's effect on cells. An HB-EGF inhibitor(CRM197, cross-reacting material 197) slowed cell proliferation and inhibited migration of As-T and A549 cells, and inhibited tumor growth. PKM2 also played an important role in the proliferation and migration in As-T cells. The positive staining ratios of EGFR phosphorylation (Y1068) and PKM2 were significantly higher in most cases of lung cancer than in paired normal tumor-adjacent lung tissues; and HB-EGF expression levels strongly correlated with p-EGFR expression levels. Thus, HB-EGF drives arsenic-induced carcinogenesis, tumor growth, and lung cancer development via the EGFR/PKM2/HIF-1α pathway.

TEAD4 modulated LncRNA MNX1-AS1 contributes to gastric cancer progression partly through suppressing BTG2 and activating BCL2.

BACKGROUND: Gastric cancer (GC) is the third leading cause of cancer-related mortality globally. Long noncoding RNAs (lncRNAs) are dysregulated in obvious malignancies including GC and exploring the regulatory mechanisms underlying their expression is an attractive research area. However, these molecular mechanisms require further clarification, especially upstream mechanisms. METHODS: LncRNA MNX1-AS1 expression in GC tissue samples was investigated via microarray analysis and further determined in a cohort of GC tissues via quantitative reverse transcription polymerase chain reaction (qRT-PCR) assays. Cell proliferation and flow cytometry assays were performed to confirm the roles of MNX1-AS1 in GC proliferation, cell cycle regulation, and apoptosis. The influence of MNX1-AS1 on GC cell migration and invasion was explored with Transwell assays. A xenograft tumour model was established to verify the effects of MNX1-AS1 on in vivo tumourigenesis. The TEAD4-involved upstream regulatory mechanism of MNX1-AS1 was explored through ChIP and luciferase reporter assays. The mechanistic model of MNX1-AS1 in regulating gene expression was further detected by subcellular fractionation, FISH, RIP, ChIP and luciferase reporter assays. RESULTS: It was found that MNX1-AS1 displayed obvious upregulation in GC tissue samples and cell lines, and ectopic expression of MNX1-AS1 predicted poor clinical outcomes for patients with GC. Overexpressed MNX1-AS1 expression promoted proliferation, migration and invasion of GC cells markedly, whereas decreased MNX1-AS1 expression elicited the opposite effects. Consistent with the in vitro results, MNX1-AS1 depletion effectively inhibited the growth of xenograft tumour in vivo. Mechanistically, TEAD4 directly bound the promoter region of MNX1-AS1 and stimulated the transcription of MNX1-AS1. Furthermore, MNX1-AS1 can sponge miR-6785-5p to upregulate the expression of BCL2 in GC cells. Meanwhile, MNX1-AS1 suppressed the transcription of BTG2 by recruiting polycomb repressive complex 2 to BTG2 promoter regions. CONCLUSIONS: Our findings demonstrate that MNX1-AS1 may be able to serve as a prognostic indicator in GC patients and that TEAD4-activatd MNX1-AS1 can promote GC progression through EZH2/BTG2 and miR-6785-5p/BCL2 axes, implicating it as a novel and potent target for the treatment of GC.

Do polystyrene nanoplastics affect the toxicity of cadmium to wheat (Triticum aestivum L.)?

There has been an increase on the research of microplastics (<5 mm in diameter) as carriers for toxic chemicals to evaluate their risks for human health and environment, but only few works focused on nanoplastics (1 nm-1000 nm in diameter) interacting with pre-existing contaminants such as heavy metals. It is still unclear whether polystyrene nanoplastics (PSNPs) could affect the toxicity of cadmium to wheat (Triticum aestivum L.). Here, we assessed the impact of polystyrene nanoplastics (0, 10 mg/L) on the Cd (0, 20 µM) toxicity to wheat grown in 25% Hoagland solution for three weeks. We found that the presence of PSNPs could partially reduce Cd contents in leaves and alleviate Cd toxicity to wheat, which might be due to weakened adsorption capacity of PSNPs affected by ionic strength. In addition, PSNPs have little effect on catalase (CAT), peroxidase (POD) activities, except for decreasing superoxide dismutase (SOD) activity, which suggested that antioxidant defense systems might not be the main mechanism to reduce the oxidative damage induced by Cd in wheat. Electron paramagnetic resonance (EPR) analysis showed that PSNPs could accelerate the formation of long-lived radicals in leaves after exposure to Cd. Notably, our metabolomics profiling further indicated that the simultaneously elevated carbohydrate and amino acid metabolisms induced by PSNPs could partly alleviate Cd toxicity to wheat. Nevertheless, the present study provides important implications for the toxicological interaction and future risk assessment of co-contamination of nanoplastics and heavy metals in the environment.

MiR-199a Inhibits Tumor Growth and Attenuates Chemoresistance by Targeting K-RAS via AKT and ERK Signalings.

Glioma is the most malignant brain tumors in the world, the function and molecular mechanism of microRNA-199a (miR-199a) in glioma is not fully understood. Our research aims to investigate miR-199a/K-RAS axis in regulation of glioma tumor growth and chemoresistance. The function of miR-199a in glioma was investigated through in vitro and in vivo assays. We found that miR-199a in tumor tissues of glioma patients was significantly downregulated in this study. Kinase suppressor of ras 1 (K-RAS), was indicated as a direct target of miR-199a, as well as expression levels of K-RAS were inversely correlated with expression levels of miR-199a in human glioma specimens. Forced expression of miR-199a suppressed AKT and ERK activation, decreased HIF-1α and VEGF expression, inhibited cell proliferation and cell migration, forced expression of K-RAS restored the inhibitory effect of miR-199a on cell proliferation and cell migration. Moreover, miR-199a renders tumor cells more sensitive to temozolomide (TMZ) via targeting K-RAS. In vivo experiment validated that miR-199a functioned as a tumor suppressor, inhibited tumor growth by targeting K-RAS and suppressed activation of AKT, ERK and HIF-1α expression. Taken together, these findings indicated that miR-199a inhibits tumor growth and chemoresistance by regulating K-RAS, and the miR-199a/K-RAS axis is a potential therapeutic target for clinical intervention in glioma.

IL-17A secreted from lymphatic endothelial cells promotes tumorigenesis by upregulation of PD-L1 in hepatoma stem cells.

BACKGROUND & AIMS: The microenvironment regulates hepatoma stem cell behavior. However, the contributions of lymphatic endothelial cells to the hepatoma stem cell niche remain largely unknown; we aimed to analyze this contribution and elucidate the mechanisms behind it. METHODS: Associations between lymphatic endothelial cells and CD133+ hepatoma stem cells were analyzed by immunofluorescence and adhesion assays; with the effects of their association on IL-17A expression examined using western blot, quantitative reverse transcription PCR and luciferase reporter assay. The effects of IL-17A on the self-renewal and tumorigenesis of hepatoma stem cells were examined using sphere and tumor formation assays. The role of IL-17A in immune escape by hepatoma stem cells was examined using flow cytometry. The expression of IL-17A in hepatoma tissues was examined using immunohistochemistry. RESULTS: CD133+ hepatoma stem cells preferentially interact with lymphatic endothelial cells. The interaction between the mannose receptor and high-mannose type N-glycans mediates the interaction between CD133+ hepatoma stem cells and lymphatic endothelial cells. This interaction activates cytokine IL-17A expression in lymphatic endothelial cells. IL-17A promotes the self-renewal of hepatoma stem cells. It also promotes their immune escape, partly through upregulation of PD-L1. CONCLUSION: Interactions between lymphatic endothelial cells and hepatoma stem cells promote the self-renewal and immune escape of hepatoma stem cells, by activating IL-17A signaling. Thus, inhibiting IL-17A signaling may be a promising approach for hepatoma treatment. LAY SUMMARY: The microenvironment is crucial for the self-renewal and development of hepatoma stem cells, which lead to the development of liver cancer. Lymphatic endothelial cells are an important component of this niche microenvironment, helping hepatoma stem cells to self-renew and escape immune attack, by upregulating IL-17A signaling. Thus, targeting IL-17A signaling is a potential strategy for the treatment of hepatoma.

Down-regulation of lncRNA MALAT1 alleviates vascular lesion and vascular remodeling of rats with hypertension.

OBJECTIVE: Recently, the effect of long non-coding RNAs (lncRNAs) in hypertension (HTN) has been identified. This study aims to explore the expression of lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in HTN and its role in vascular lesion and remodeling of HTN rats. RESULTS: LncRNA MALAT1 expression was up-regulated in HTN patients, and lncRNA MALAT1 could be an effective index of HTN diagnosis. Down-regulated MALAT1 and inhibited Notch-1 could reduce relative factor expression, including inflammation-related factors, endothelial function-related factors and oxidative stress-related factors, and inhibit apoptosis of aortic endothelial cells of HTN rats. METHODS: LncRNA MALAT1 expression in HTN patients and healthy controls was detected by reverse transcription quantitative polymerase chain reaction (RT-qPCR). Angiotensin II (Ang II)-induced HTN rat models were injected with MALAT1-siRNA, empty lentivirus vector, Notch pathway inhibitor (DAPT) and dimethyl sulphoxide (DMSO) via caudal vein. After three-week treatment, changes of blood pressure, inflammatory factor levels, endothelial function-related factors, oxidative stress indices and apoptosis of vascular endothelial cells were determined by a series of assays. CONCLUSION: This study revealed that down-regulated lncRNA MALAT1 could alleviate the vascular lesion and remodeling of HTN rats, the mechanism may be related to the inhibited activation of Notch signaling pathway.