Tobacco as a promising crop for low-carbon biorefinery.

Energy crops play a vital role in meeting future energy and chemical demands while addressing climate change. However, the idealization of low-carbon workflows and careful consideration of cost-benefit equations are crucial for their more sustainable implementation. Here, we propose tobacco as a promising energy crop because of its exceptional water solubility, mainly attributed to a high proportion of water-soluble carbohydrates and nitrogen, less lignocellulose, and the presence of acids. We then designed a strategy that maximizes biomass conversion into bio-based products while minimizing energy and material inputs. By autoclaving tobacco leaves in water, we obtained a nutrient-rich medium capable of supporting the growth of microorganisms and the production of bioproducts without the need for extensive pretreatment, hydrolysis, or additional supplements. Additionally, cultivating tobacco on barren lands can generate sufficient biomass to produce approximately 573 billion gallons of ethanol per year. This approach also leads to a reduction of greenhouse gas emissions by approximately 76% compared to traditional corn stover during biorefinery processes. Therefore, our study presents a novel and direct strategy that could significantly contribute to the goal of reducing carbon emissions and global sustainable development compared to traditional methods.

Metabolically activated energetic materials mediate cellular anabolism for bone regeneration.

The understanding of cellular energy metabolism activation by engineered scaffolds remains limited, posing challenges for therapeutic applications in tissue regeneration. This study presents biosynthesized poly(3-hydroxybutyrate-co-4-hydroxybutyrate) [P(3HB-co-4HB)] and its major degradation product, 3-hydroxybutyrate (3HB), as endogenous bioenergetic fuels that augment cellular anabolism, thereby facilitating the progression of human bone marrow-derived mesenchymal stem cells (hBMSCs) towards osteoblastogenesis. Our research demonstrated that 3HB markedly boosts in vitro ATP production, elevating mitochondrial membrane potential and capillary-like tube formation. Additionally, it raises citrate levels in the tricarboxylic acid (TCA) cycle, facilitating the synthesis of citrate-containing apatite during hBMSCs osteogenesis. Furthermore, 3HB administration significantly increased bone mass in rats with osteoporosis induced by ovariectomy. The findings also showed that P(3HB-co-4HB) scaffold substantially enhances long-term vascularized bone regeneration in rat cranial defect models. These findings reveal a previously unknown role of 3HB in promoting osteogenesis of hBMSCs and highlight the metabolic activation of P(3HB-co-4HB) scaffold for bone regeneration.

Engineered Halomonas for production of gamma-Aminobutyric acid and 2-Pyrrolidone.

Gamma-Aminobutyric acid (GABA) is a derivative of L-glutamate, also a precursor for the synthesis of 2-pyrrolidone, which is a monomer of nylon-4. This study achieved a one-step biosynthesis of GABA and 2-pyrrolidone by Halomonas bluephagenesis overexpressing key genes involved in GABA and 2-pyrrolidone synthesis and deleting GABA degradation genes combined with reducing the degradation of 2-pyrrolidone precursor. The resulting H. bluephagenesis strain WLp07 was employed in whole-cell catalysis, producing 357 g/L of GABA and 72 wt% of PHA. Furthermore, a self-flocculating H. bluephagenesis allowed rapid, convenient recycling of the cells, achieving 880 g/L of GABA over three cycles. Shake flask studies showed that engineered H. bluephagenesis harboring ß-alanine CoA transferase was able to synthesized 2-pyrrolidone from GABA. H. bluephagenesis as a chassis of next generation industrial biotechnology (NGIB), demonstrated its diverse ability to produce GABA and 2-pyrrolidone in addition to intracellular PHA.

Comparison of percutaneous nephrolithotripsy combined with retrograde intrarenal surgery and multi-tract percutaneous nephrolithotripsy for octopus stone: A propensity score-matching study.

To compared the effectiveness and safety of single standard mini percutaneous nephrolithotripsy (SM-PCNL) combined with retrograde intrarenal surgery (RIRS) and multiple standard mini percutaneous nephrolithotomy (MSM-PCNL) in the treatment of octopus stone of 2 to 4 cm. The clinical data of SM-PCNL combined with RIRS and MSM-PCNL for octopus stone with a 2 to 4 cm diameter from October 2019 to December 2022 were analyzed retrospectively, and propensity score matching was used to screen patients. The matched patients were paired, and the operation time, complications, postoperative pain, tubeless rate, stone-free rate (SFR), and postoperative hospital stay were further compared between the 2 groups. 88 patients underwent SM-PCNL combined with RIRS (combined group), and 143 patients underwent MSM-PCNL (multiple channel group). After matching analysis, there were 49 patients in each group, and there was no significant difference in the general preoperative data between the 2 groups. The perioperative complications and stone-free rate were no statistical difference. In postoperative pain (4.00 ±â€…0.74 vs 5.00 ±â€…0.74, P = .00), tubeless rate (44.90% vs 20.41%, P = .01), hemoglobin drop (9.38 ±â€…7.48 vs 14.22 ±â€…7.69, P = .01), postoperative hospital stay (3.37 ±â€…1.09 vs 5.08 ±â€…1.29, P = .00), the combined group was significantly better than the multiple channel group. Regarding operation time, the combined group was more than the multiple channel group (103.27 ±â€…27.61 vs 78.39 ±â€…19.31, P = .000). For octopus stone with a diameter of 2 to 4 cm, the effectiveness and safety of SM-PCNL combined with RIRS were similar to those of MSM-PCNL The surgeon should carefully evaluate the patient's physical condition, stone characteristics, and expectations before the operation and assist the patient in choosing an appropriate plan.

Secreted PTEN binds PLXDC2 on macrophages to drive antitumor immunity and tumor suppression.

Loss of phosphatase and tensin homolog (PTEN) has been linked to an immunosuppressive tumor microenvironment, but its underlying mechanisms remain largely enigmatic. Here, we report that PTEN can be secreted by the transmembrane emp24 domain-containing protein 10 (TMED10)-channeled protein secretion pathway. Inhibiting PTEN secretion from tumor cells contributes to immunosuppression and impairs the tumor-suppressive role of PTEN, while intratumoral injection of PTEN protein promotes antitumor immunity and suppresses tumor growth in mice. Mechanistically, extracellular PTEN binds to the plexin domain-containing protein 2 (PLXDC2) on macrophages, triggering subsequent activation of JAK2-STAT1 signaling, which switches tumor-associated macrophages (TAMs) from the immunosuppressive to inflammatory phenotype, leading to enhanced activation of CD8+ T and natural killer cells. Importantly, PTEN treatment also enhances the therapeutic efficacy of anti-PD-1 treatment in mice and reverses the immune-suppressive phenotype of patient-derived primary TAMs. These data identify a cytokine-like role of PTEN in immune activation and tumor suppression and demonstrate the therapeutic potential for extracellular administration of PTEN in cancer immunotherapy.

ß-resorcylic acid released by Limosilactobacillus reuteri protects against cisplatin-induced ovarian toxicity and infertility.

Chemotherapy-induced premature ovarian insufficiency (CIPOI) triggers gonadotoxicity in women undergoing cancer treatment, leading to loss of ovarian reserves and subfertility, with no effective therapies available. In our study, fecal microbiota transplantation in a cisplatin-induced POI mouse model reveals that a dysbiotic gut microbiome negatively impacts ovarian health in CIPOI. Multi-omics analyses show a significant decrease in Limosilactobacillus reuteri and its catabolite, ß-resorcylic acid , in the CIPOI group in comparison to healthy controls. Supplementation with L. reuteri or ß-RA mitigates cisplatin-induced hormonal disruptions, morphological damages, and reductions in follicular reserve. Most importantly, ß-RA pre-treatment effectively preserves oocyte function, embryonic development, and fetus health, thereby protecting against chemotherapy-induced subfertility. Our results provide evidence that ß-RA suppresses the nuclear accumulation of sex-determining region Y-box 7, which in turn reduces Bcl-2-associated X activation and inhibits granulosa cell apoptosis. These findings highlight the therapeutic potential of targeting the gut-ovary axis for fertility preservation in CIPOI.

In-situ polymerization of phosphorus/nitrogen flame-retardant coating for polyester/cotton blend fabrics with superior durability.

The durable flame-retardant functional coating of polyester/cotton (T/C) blend fabrics is both interesting and challenging. In this study, a novel in-situ polymerization strategy for phosphorus/nitrogen-based flame-retardant on T/C blend samples was developed through the polycondensation of tetramethylolphosphonium sulfate, dicyandiamide, and anionic cyclic phosphate ester. The chemical structure of the polycondensation compounds, as well as the surface morphology, combustion behavior, flame-retardant capacity, washing durability and flame-retardant mechanism of the coated T/C blend fabrics, were investigated. The coated T/C blend fabrics demonstrated excellent self-extinguishing performance, with the damaged length decreasing to as low as 8.0 cm and the LOI reaching 28 %. Moreover, the peak heat release rate of the coated T/C blend fabrics decreased by 39.7 %. The superior flame retardancy can be attributed to the enhanced dehydration and carbonization by phosphate groups in the condensed phase, as well as the quenching effect and diluting effect in the gas phase. Additionally, the coated T/C blend fabrics exhibited remarkable washing durability and still achieved self-extinguishing after 65 washing cycles, and the in-situ deposition of insoluble three-dimensional polycondensation compounds onto the T/C blend fabrics was beneficial. The flame-retardant coating had a minor impact on the whiteness, tensile strength and breathability of the T/C blend fabrics.

Predictive value of gradient boosting decision trees for postoperative atelectasis complications in patients with pulmonary destruction.

OBJECTIVE: To explore the application value of a gradient boosting decision tree (GBDT) in predicting postoperative atelectasis in patients with destroyed lungs. METHODS: A total of 170 patients with damaged lungs who underwent surgical treatment in Chest Hospital of Guangxi Zhuang Autonomous Region from January 2021 to May 2023 were retrospectively selected. The patients were divided into a training set (n = 119) and a validation set (n = 51). Both GBDT algorithm model and Logistic regression model for predicting postoperative atelectasis in patients were constructed. The receiver operating characteristic (ROC) curve, calibration curve and decision curve were used to evaluate the prediction efficiency of the model. RESULTS: The GBDT model indicated that the relative importance scores of the four influencing factors were operation time (51.037), intraoperative blood loss (38.657), presence of lung function (9.126) and sputum obstruction (1.180). Multivariate Logistic regression analysis revealed that operation duration and sputum obstruction were significant predictors of postoperative atelectasis among patients with destroyed lungs within the training set (P = 0.048, P = 0.002). The ROC curve analysis showed that the area under the curve (AUC) for GBDT and Logistic model in the training set was 0.795 and 0.763, and their AUCs in the validation set were 0.776 and 0.811. The GBDT model's predictions closely matched the ideal curve, showing a higher net benefit than the reference line. CONCLUSIONS: GBDT model is suitable for predicting the incidence of complications in small samples.

Exosomal miRNA-21 derived from umbilical cord mesenchymal stem cells inhibits microglial overactivation to counteract nerve damage.

BACKGROUND: Traumatic brain injury (TBI) is a major cause of neurological disability, and current treatments have limited effectiveness. Recent studies have emphasized the potential of exosomes derived from umbilical cord mesenchymal stem cells (UC-MSCs-Exo) in TBI treatment, but the molecular mechanisms underlying their therapeutic effects are not fully understood. METHODS AND RESULTS: In this study, UC-MSCs-Exo was isolated using ultracentrifugation and intraventricularly injected to TBI rat model. The neurofunctional motor function of the rats was evaluated using the modified neurological severity score (mNSS), and the activation of microglia was assessed through immunofluorescence detection of IBA1 expression levels. Additionally, we established an in vitro neuroinflammatory model using BV2 microglia to investigate the effects of UC-MSCs-Exo and miRNA-21. Our findings indicate that UC-MSCs-Exo promote neurological recovery in TBI rats and inhibit excessive microglia activation. Furthermore, UC-MSCs-Exo highly expresses miRNA-21 and inhibited the proliferation, migration, and release of inflammatory mediators of BV2 microglia by transporting miRNA-21. CONCLUSIONS: The present study suggests that the promotion of neurological recovery in TBI rats by UC-MSCs-Exo may be attributed to the inhibition of excessive microglia activation through miRNA-21.

Trafficking circuit of CD8+ T cells between the intestine and bone marrow governs antitumour immunity.

Immunotherapy elicits a systemic antitumour immune response in peripheral circulating T cells. However, the T cell trafficking circuit between organs and their contributions to antitumour immunity remain largely unknown. Here we show in multiple mouse leukaemia models that high infiltration of leukaemic cells in bone marrow (BM) stimulates the transition of CD8+CD44+CD62L+ central memory T cells into CD8+CD44-CD62L- T cells, designated as inter-organ migratory T cells (TIM cells). TIM cells move from the BM to the intestine by upregulating integrin ß7 and downregulating C-X-C motif chemokine receptor 3 during leukaemogenesis. Upon immunogenic chemotherapy, these BM-derived TIM cells return from the intestine to the BM through integrin α4-vascular cell adhesion molecule 1 interaction. Blocking C-X-C motif chemokine receptor 3 function boosts the immune response against leukaemia by enhancing T cell trafficking. This phenomenon can also be observed in patients with leukaemia. In summary, we identify an unrecognized intestine-BM trafficking circuit of T cells that contributes to the antitumour effects of immunogenic chemotherapy.

Flexible, breathable, and durable superhydrophobic cotton fabric modified by behenic acid, tung oil, and ZIF-8 with anti-icing and self-cleaning properties.

Textiles with self-cleaning and anti-icing capabilities in cold climates are essential for outdoor workers and enthusiasts. Superhydrophobic modification of textile surfaces is effective in imparting these characteristics. Although there are numerous methods available for manufacturing superhydrophobic textiles, careful consideration is warranted for environmental concerns over fluorochemicals, stability of superhydrophobic coatings, and fabric breathability. In this work, we utilized biomass resources such as tung oil and behenic acid, along with zeolitic imidazolate framework (ZIF-8), to modify cotton fabrics, thereby creating an innovative behenic acid/tung oil/ZIF-8 modified cotton (BTZC) fabric with anti-icing and self-cleaning features. This material manifests a unique nanoflower-shaped surface morphology, demonstrating exceptional superhydrophobicity with a static water contact angle (CA) of 162° and a sliding angle (SA) of 2°. Moreover, BTZC excels in its thermal stability, breathability, and resistance to icing. Equally impressive is its robust stability, as evidenced through rigorous testing under continuous washing and abrasion, sustained high and low temperatures, extreme pH environments, and immersion in various chemical solvents. BTZC presents as a fluorine-free, durable, economically viable alternative for outdoor textile applications, marking substantial progress in the utilization of biomass and metal-organic framework materials in the textile industry and promising implications for value enhancement.

Perineural Invasion in Cervical Cancer: A Hidden Trail for Metastasis.

Perineural invasion (PNI), the neoplastic invasion of nerves, is an often overlooked pathological phenomenon in cervical cancer that is associated with poor clinical outcomes. The occurrence of PNI in cervical cancer patients has limited the promotion of Type C1 surgery. Preoperative prediction of the PNI can help identify suitable patients for Type C1 surgery. However, there is a lack of appropriate preoperative diagnostic methods for PNI, and its pathogenesis remains largely unknown. Here, we dissect the neural innervation of the cervix, analyze the molecular mechanisms underlying the occurrence of PNI, and explore suitable preoperative diagnostic methods for PNI to advance the identification and treatment of this ominous cancer phenotype.

Integration of single-cell and bulk RNA sequencing revealed immune heterogeneity and its association with disease activity in rheumatoid arthritis patients.

Rheumatoid arthritis (RA) is a chronic, inflammatory, systemic autoimmune disease characterized by cartilage, bone damage, synovial inflammation, hyperplasia, autoantibody production, and systemic features. To obtain an overall profile of the immune environment in RA patients and its association with clinical features, we performed single-cell transcriptome and T-cell receptor sequencing of mononuclear cells from peripheral blood (PBMC) and synovial fluid (SF) from RA patients, integrated with two large cohorts with bulk RNA sequencing for further validation and investigation. Dendritic cells (DCs) exhibited relatively high functional heterogeneity and tissue specificity in relation to both antigen presentation and proinflammatory functions. Peripheral helper T cells (TPHs) are likely to originate from synovial tissue, undergo activation and exhaustion, and are subsequently released into the peripheral blood. Notably, among all immune cell types, TPHs were found to have the most intense associations with disease activity. In addition, CD8 effector T cells could be clustered into two groups with different cytokine expressions and play distinct roles in RA development. By integrating single-cell data with bulk sequencing from two large cohorts, we identified interactions among TPHs, CD8 cells, CD16 monocytes, and DCs that strongly contribute to the proinflammatory local environment in RA joints. Of note, the swollen 28-joint counts exhibited a more pronounced association with this immune environment compared to other disease activity indexes. The immune environment alternated significantly from PBMCs to SF, which indicated that a series of immune cells was involved in proinflammatory responses in the local joints of RA patients. By integrating single-cell data with two large cohorts, we have uncovered associations between specific immune cell populations and clinical features. This integration provides a rapid and precise methodology for assessing local immune activation, offering valuable insights into the pathophysiological mechanisms at play in RA.

A long-term growth stable Halomonas sp. deleted with multiple transposases guided by its metabolic network model Halo-ecGEM.

Microbial instability is a common problem during bio-production based on microbial hosts. Halomonas bluephagenesis has been developed as a chassis for next generation industrial biotechnology (NGIB) under open and unsterile conditions. However, the hidden genomic information and peculiar metabolism have significantly hampered its deep exploitation for cell-factory engineering. Based on the freshly completed genome sequence of H. bluephagenesis TD01, which reveals 1889 biological process-associated genes grouped into 84 GO-slim terms. An enzyme constrained genome-scale metabolic model Halo-ecGEM was constructed, which showed strong ability to simulate fed-batch fermentations. A visible salt-stress responsive landscape was achieved by combining GO-slim term enrichment and CVT-based omics profiling, demonstrating that cells deploy most of the protein resources by force to support the essential activity of translation and protein metabolism when exposed to salt stress. Under the guidance of Halo-ecGEM, eight transposases were deleted, leading to a significantly enhanced stability for its growth and bioproduction of various polyhydroxyalkanoates (PHA) including 3-hydroxybutyrate (3HB) homopolymer PHB, 3HB and 3-hydroxyvalerate (3HV) copolymer PHBV, as well as 3HB and 4-hydroxyvalerate (4HB) copolymer P34HB. This study sheds new light on the metabolic characteristics and stress-response landscape of H. bluephagenesis, achieving for the first time to construct a long-term growth stable chassis for industrial applications. For the first time, it was demonstrated that genome encoded transposons are the reason for microbial instability during growth in flasks and fermentors.

Reducing noise in polarization-sensitive optical coherence tomography for high-quality local phase retardation imaging.

Local phase retardation (LPR) is increasingly recognized as a crucial biomarker for assessing disease progression. However, the presence of speckle noise significantly challenges its accuracy and polarization contrast. To address this challenge, we propose a signal-processing strategy aimed at reducing the impact of noise on LPR measurements. In this approach, the LPR is reconstructed by polar decomposition after averaging multiple Mueller matrices from different overlapping sub-spectra. To optimize measurement accuracy, we systematically combined and traversed different sub-spectral numbers and bandwidths. By examining the quarter-wave plate and glass slide, high-accuracy phase retardation measurements were successfully verified, and the maximum polarization contrast was improved by 23%. Moreover, experimental results from multi-tissue imaging vividly illustrate that the equivalent number of looks (ENL) and polarization contrast were improved by 18% and 19%, respectively. This outcome indicates that our proposed strategy can effectively reduce the noise spikes, enhancing tissue discrimination capabilities.

A comprehensive scoring system for the better prediction of bowel resection in pediatric intussusception.

BACKGROUND: Intussusception presents a significant emergency that often necessitates bowel resection, leading to severe complications and management challenges. This study aims to investigate and establish a scoring system to enhance the prediction of bowel resection necessity in pediatric intussusception patients. METHODS: This retrospective study analyzed 660 hospitalized patients with intussusception who underwent surgical management at a pediatric hospital in Southwest China from April 2008 to December 2020. The necessity of bowel resection was assessed and categorized in this cohort. Variables associated with bowel resection were examined using univariate and multivariate logistic regression analyses. Based on these analyses, a scoring system was developed, grounded on the summation of the coefficients (ß). RESULTS: Among the 660 patients meeting the inclusion criteria, 218 required bowel resection during surgery. Bowel resection occurrence was linked to an extended duration of symptoms (Odds Ratio [OR] = 2.14; 95% Confidence Interval [CI], 1.03-5.23; P = 0.0015), the presence of gross bloody stool (OR = 8.98; 95% CI, 1.76-48.75, P < 0.001), elevated C-reactive protein levels (OR = 4.79; 95% CI, 1.12-28.31, P = 0.0072), lactate clearance rate (LCR) (OR = 17.25; 95% CI, 2.36-80.35; P < 0.001), and the intussusception location (OR = 12.65; 95% CI, 1.46-62.67, P < 0.001), as determined by multivariate logistic regression analysis. A scoring system (totaling 14.02 points) was developed from the cumulative ß coefficients, with a threshold of 5.22 effectively differentiating infants requiring surgical intervention from others with necrotizing enterocolitis (NEC), exhibiting a sensitivity of 78.3% and a specificity of 71.9%. CONCLUSIONS: This study successfully identified multiple risk factors for bowel resection and effectively used a scoring system to identify patients for optimal clinical management.

Harnessing TME depicted by histological images to improve cancer prognosis through a deep learning system.

Spatial transcriptomics (ST) provides insights into the tumor microenvironment (TME), which is closely associated with cancer prognosis, but ST has limited clinical availability. In this study, we provide a powerful deep learning system to augment TME information based on histological images for patients without ST data, thereby empowering precise cancer prognosis. The system provides two connections to bridge existing gaps. The first is the integrated graph and image deep learning (IGI-DL) model, which predicts ST expression based on histological images with a 0.171 increase in mean correlation across three cancer types compared with five existing methods. The second connection is the cancer prognosis prediction model, based on TME depicted by spatial gene expression. Our survival model, using graphs with predicted ST features, achieves superior accuracy with a concordance index of 0.747 and 0.725 for The Cancer Genome Atlas breast cancer and colorectal cancer cohorts, outperforming other survival models. For the external Molecular and Cellular Oncology colorectal cancer cohort, our survival model maintains a stable advantage.

Potential Benefits of Green Tea in Prostate Cancer Prevention and Treatment: A Comprehensive Review.

Prostate cancer is a prevalent and debilitating disease that necessitates effective prevention and treatment strategies. Green tea, a well-known beverage derived from the Camellia sinensis plant, contains bioactive compounds with potential health benefits, including catechins and polyphenols. This comprehensive review aims to explore the potential benefits of green tea in prostate cancer prevention and treatment by examining existing literature. Green tea possesses antioxidant, anti-inflammatory, and anti-carcinogenic properties attributed to its catechins, particularly epigallocatechin gallate. Epidemiological studies have reported an inverse association between green tea consumption and prostate cancer risk, with potential protection against aggressive forms of the disease. Laboratory studies demonstrate that green tea components inhibit tumor growth, induce apoptosis, and modulate signaling pathways critical to prostate cancer development and progression. Clinical trials and human studies further support the potential benefits of green tea. Green tea consumption has been found to be associated with a reduction in prostate-specific antigen levels, tumor markers, and played a potential role in slowing disease progression. However, challenges remain, including optimal dosage determination, formulation standardization, and conducting large-scale, long-term clinical trials. The review suggests future research should focus on combinatorial approaches with conventional therapies and personalized medicine strategies to identify patient subgroups most likely to benefit from green tea interventions.

Preparation of Flower-like Nanosilver Based on Bioderived Caffeic Acid for Raman Enhancement and Dye Degradation.

In this study, a simple, green, and low-cost room temperature synthesis of broccoli-like silver nanoflowers (AgNF) with a particle size of about 300-500 nm was developed using plant-derived caffeic acid as a reducing agent and polyvinylpyrrolidone as a dispersant under ultrasound assistance. The flower clusters covered by small nanocrystals of 20-50 nm significantly enhance the electromagnetic field signals. AgNF was deposited on the surface of silicon wafers as a surface-enhanced Raman spectroscopy sensor for the detection of probe molecules such as rhodamine 6G (R6G) and malachite green with high sensitivity, homogeneity, and reproducibility. AgNF was deposited on cotton fabrics in the form of composites to catalyze the degradation of dye pollutants such as R6G, MG, and methyl orange in the presence of sodium borohydride. 0.1 g of AgNF/cotton fabric could assist 15 mmol/L NaBH4 to achieve over 90% degradation of various dyes as well as a high concentration of dyes in 12 min with good reusability and recyclability. The AgNF synthesized in this work can not only monitor the type and amounts of pollutants (dyes) in wastewater but also catalyze the rapid degradation of dyes, which is expected to be valuable for industrial applications.

VEGF-induced Nrdp1 deficiency in vascular endothelial cells promotes cancer metastasis by degrading vascular basement membrane.

Vascular endothelial cells (VECs) are key players in the formation of neovessels and tumor metastasis, the ultimate cause of the majority of cancer-related human death. However, the crosstalk between VECs and metastasis remain greatly elusive. Based on our finding that tumor-associated VECs present significant decrease of Nrdp1 protein which is closely correlated with higher metastatic probability, herein we show that the conditional medium from hypoxia-incubated cancer cells induces extensive Nrdp1 downregulation in human and mouse VECs by vascular endothelial growth factor (VEGF), which activates CHIP, followed by Nrdp1 degradation in ubiquitin-proteasome-dependent way. More importantly, lung metastases of cancer cells significantly increase in conditional VECs Nrdp1 knockout mice. Mechanically, Nrdp1 promotes degradation of Fam20C, a secretory kinase involved in phosphorylating numerous secreted proteins. Reciprocally, deficiency of Nrdp1 in VECs (ecNrdp1) results in increased secretion of Fam20C, which induces degradation of extracellular matrix and disrupts integrity of vascular basement membrane, thus driving tumor metastatic dissemination. In addition, specific overexpression of ecNrdp1 by Nrdp1-carrying adeno-associated virus or chemical Nrdp1 activator ABPN efficiently mitigates tumor metastasis in mice. Collectively, we explore a new mechanism for VEGF to enhance metastasis and role of Nrdp1 in maintaining the integrity of vascular endothelium, suggesting that ecNrdp1-mediated signaling pathways might become potential target for anti-metastatic therapies.