TWEAK increases angiogenesis to promote diabetic skin wound healing by regulating Fn14/EGFR signaling.

OBJECTIVE: Tumor necrosis factor-like weak inducer of apoptosis (TWEAK), a member of tumor necrosis factor superfamily, can bind to fibroblast growth factor-inducible 14 (Fn14) receptor and stimulate angiogenesis. The interaction between epidermal growth factor receptor (EGFR) and endothelial growth factor (EGF) leads to EGFR signal transduction and promotes angiogenesis. The objective of this study was to explore whether TWEAK participated in the diabetic skin wound healing by regulating Fn14/EGFR signaling. METHODS: Human umbilical vein endothelial cells (HUVECs) were treated with 35 mmol/L d-glucose and classified into the Control Group, High Glucose (HG) Group and HG + TWEAK Group. Then, the TWEAK expression and the proliferation, migration and tubule formation of HUVECs were detected, respectively. In vivo experiment, the diabetic model was established by injecting streptozotocin (STZ, 50 mg/kg) into male BALB/c mice. On the back of successfully modeled diabetic mice, a full-thickness skin wound of 6 mm diameter was formed. Then, the mice were randomly assigned into three groups: Blank Group, Phosphate Buffer Saline (PBS) Group, and TWEAK Group. Subsequently, expression levels of TWEAK, Fn14, EGFR and vascular endothelial growth factor (VEGF)-A were measured, and the CD31 expression in the wounded skin tissue of mice was checked by immunohistochemistry staining. RESULTS: The expression level of TWEAK in HUVECs of HG Group decreased significantly, as well as the viability, migration, and tubule formation of cells. After over-expression of TWEAK, the cell viability, migration, and tubule formation abilities of HUVECs recovered remarkably. In vivo, the wound healing rate of diabetic mice was raised, the neovascularization was increased, and the CD31 expression in the wounded tissue was obviously upregulated after injection with recombinant TWEAK antibody. CONCLUSION: TWEAK stimulates angiogenesis and accelerates the wound healing of diabetic skin by regulating Fn14/EGFR signaling.

Integrated ceRNAs regulating relationship and bioinformatics analysis to study the molecular mechanisms of the inhibition of puerarin on bladder cancer cell.

Based on previous experiments, we demonstrated puerarin inhibited the proliferation of BC T24 cells. To further explore the molecular mechanisms, whole transcriptome sequencing combined with bioinformatics analysis was performed. The results showed puerarin significantly inhibited T24 proliferation and pathway enrichment analysis of differentially expressed RNAs were mainly enriched in Cell cycle, PI3K/AKT, Ras family chromatin remodeling. lncRNAs and circRNAs may regulate miRNAs, thereby regulating the expression of ITGA1, PAK2 and UTRN. The predicted upstream transcription factor ERG and puerarin were well docked, which may be one of the underlying mechanisms by which puerarin inhibiting BC cells.

Shortened Cerebral Circulation Time Predicts Resistance to Obliteration in High-Flow Brain Arteriovenous Malformations After Stereotactic Radiosurgery.

BACKGROUND AND OBJECTIVES: Treatment selection for brain arteriovenous malformations (BAVMs) is complicated by BAVM size, location, and hemodynamics. Quantitative digital subtraction angiography is used to quantify the hemodynamic impact of BAVMs on cerebral circulation. This study investigated the association between cerebral circulation time and the complete obliteration (CO) rate of BAVMs after stereotactic radiosurgery (SRS). METHODS: We analyzed the data of 143 patients who underwent SRS for BAVMs between January 2011 and December 2019 in our institute. Their pre-SRS magnetic resonance imaging and angiography images were analyzed to acquire BAVM characteristics and quantitative digital subtraction angiography parameters. Modified cerebral circulation time (mCCT) was defined as the time difference between the bolus arrival time of the ipsilateral cavernous internal carotid artery and that of the parietal vein, as determined from the lateral view of images obtained using digital subtraction angiography. Cox regression with hazard ratios and Kaplan-Meier analyses were conducted to determine the associations between the parameters and BAVM CO after SRS. RESULTS: Of the 143 patients, 101 (70.6%) achieved BAVM CO. According to the multivariate analyses, an increased mCCT (hazard ratio: 1.24, P = .041) was the independent factor associated with BAVM CO after adjustment for age, sex, hemorrhagic presentation, a BAVM volume of >5 cm3, and a margin dose of >18 Gy. Individuals with an mCCT of ≤2.32 s had a lower 36-month probability of BAVM CO than did those with an mCCT of >2.32 s (44.1% ± 6.8% vs 63.3% ± 5.6%, P = .034). CONCLUSION: The hemodynamic impact of high-flow BAVM demonstrated by a shortened mCCT is associated with a lower BAVM CO rate after SRS.

Research Advances in Stem Cell Therapy for Erectile Dysfunction.

Erectile dysfunction (ED) is a common clinical condition that mainly affects men aged over 40 years. Various causes contribute to the progression of ED, including pelvic nerve injury, diabetes, metabolic syndrome, age, Peyronie's disease, smoking, and psychological disorders. Current treatments for ED are limited to symptom relief and do not address the root cause. Stem cells, with their powerful ability to proliferate and differentiate, are a promising approach for the treatment of male ED and are gradually gaining widespread attention. Current uses for treating ED have been studied primarily in experimental animals, with most studies observing improvements in erectile quality as well as improvements in erectile tissue. However, research on stem cell therapy for human ED is still limited. This article summarizes the recent literature on basic stem cell research on ED, including cavernous nerve injury, aging, diabetes, and sclerosing penile disease, and describes mechanisms of action and therapeutic effects of various stem cell therapies in experimental animals. Stem cells are also believed to interact with host tissue in a paracrine manner, and improved function can be supported through both implantation and paracrine factors. To date, stem cells have shown some preliminary promising results in animal and human models of ED.

Comprehensive genomic analysis of puerarin in inhibiting bladder urothelial carcinoma cell proliferation and migration.

BACKGROUND: Bladder urothelial carcinoma (BUC) ranks second in the incidence of urogenital system tumors, and the treatment of BUC needs to be improved. Puerarin, a traditional Chinese medicine (TCM), has been shown to have various effects such as anti-cancer effects, the promotion of angiogenesis, and anti-inflammation. This study investigates the effects of puerarin on BUC and its molecular mechanisms. METHODS: Through GeneChip experiments, we obtained differentially expressed genes (DEGs) and analyzed these DEGs using the Ingenuity® Pathway Analysis (IPA®), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) pathway enrichment analyses. The Cell Counting Kit 8 (CCK8) assay was used to verify the inhibitory effect of puerarin on the proliferation of BUC T24 cells. String combined with Cytoscape® was used to create the Protein-Protein Interaction (PPI) network, and the MCC algorithm in cytoHubba plugin was used to screen key genes. Gene Set Enrichment Analysis (GSEA®) was used to verify the correlation between key genes and cell proliferation. RESULTS: A total of 1617 DEGs were obtained by GeneChip. Based on the DEGs, the IPA® and pathway enrichment analysis showed they were mainly enriched in cancer cell proliferation and migration. CCK8 experiments proved that puerarin inhibited the proliferation of BUC T24 cells, and its IC50 at 48 hours was 218µmol/L. Through PPI and related algorithms, 7 key genes were obtained: ITGA1, LAMA3, LAMB3, LAMA4, PAK2, DMD, and UTRN. GSEA showed that these key genes were highly correlated with BUC cell proliferation. Survival curves showed that ITGA1 upregulation was associated with poor prognosis of BUC patients. CONCLUSION: Our findings support the potential antitumor activity of puerarin in BUC. To the best of our knowledge, bioinformatics investigation suggests that puerarin demonstrates anticancer mechanisms via the upregulation of ITGA1, LAMA3 and 4, LAMB3, PAK2, DMD, and UTRN, all of which are involved in the proliferation and migration of bladder urothelial cancer cells.

Upregulation of Parkinson's disease-associated protein alpha-synuclein suppresses tumorigenesis via interaction with mGluR5 and gamma-synuclein in liver cancer.

Numerous epidemiological studies suggest a link between Parkinson's disease (PD) and cancer, indicating that PD-associated proteins may mediate the development of cancer. Here, we investigated a potential role of PD-associated protein α-synuclein in regulating liver cancer progression in vivo and in vitro. We found the negative correlation of α-synuclein with metabotropic glutamate receptor 5 (mGluR5) and γ-synuclein by analyzing the data from The Cancer Genome Atlas database, liver cancer patients and hepatoma cells with overexpressed α-synuclein. Moreover, upregulated α-synuclein suppressed the growth, migration, and invasion. α-synuclein was found to associate with mGluR5 and γ-synuclein, and the truncated N-terminal of α-synuclein was essential for the interaction. Furthermore, overexpressed α-synuclein exerted the inhibitory effect on hepatoma cells through the degradation of mGluR5 and γ-synuclein via α-synuclein-dependent autophagy-lysosomal pathway (ALP). Consistently, in vivo experiments with rotenone-induced rat model of PD also confirmed that, upregulated α-synuclein in liver cancer tissues through targeting on mGluR5/α-synuclein/γ-synuclein complex inhibited tumorigenesis involving in ALP-dependent degradation of mGluR5 and γ-synuclein. These findings give an insight into an important role of PD-associated protein α-synuclein accompanied by the complex of mGluR5/α-synuclein/γ-synuclein in distant communications between PD and liver cancer, and provide a new strategy in therapeutics for the treatment of liver cancer.

IL-4 modified expanded polytetrafluoroethylene (e-PTFE) surgical patch promotes angiogenesis in transplanted flap and inhibits inflammatory response.

Skin flap transplantation is one of the most common tissue transplantation methods for wound repair and organ reconstruction in plastic surgery. During the transplantation process, the inflammatory response of transplanted flap and angiogenesis are critical to the successful rate of skin flap transplantation. In recent years, to improve the biocompatibility and cell affinity of biomedical materials, the modified biomaterials have gradually become a popular subject in scientific researches. In our study, the IL-4 modified expanded polytetrafluoroethylene (e-PTFE) surgical patch IL4-e-PTFE was prepared, and the rat skin flap transplantation model was constructed. The results of cell experiment prove that IL-4 has potentiation in the angiogenesis of human umbilical vein endothelial cell (HUVEC) induced by monocyte, and IL-4 can also promote angiogenesis by inducing the M2 macrophages. According to the results of in vivo experiment, the apoptosis level of transplanted flap cells of rats in the IL4-e-PTFE group was lower than that in the e-PTFE group, and in the IL4-e-PTFE group, the expression levels of pro-inflammatory cytokines IL-1ß, IL-6 and TNF-α showed significantly decline compared to the e-PTFE group, while the expression levels of anti-inflammatory cytokines IL-1Ra, IL-10 and TGF-ß presented significant increase compared to the e-PTFE group; the immunofluorescence staining results show that the number of M2 macrophages in transplanted flap area of rats in the IL4-e-PTFE group was significantly higher than that in the e-PTFE group, and the angiogenesis level was remarkably improved. In this study, by preparing IL4-e-PTFE and carrying out the cell and in vivo experiments, a reference method is proposed, which can reduce the inflammatory response during skin transplantation process using e-PTFE and optimize the long-term effects of flap blood vessels, hoping to provide a broader space for the applications of e-PTFE in medicine.

An esterase-responsive ibuprofen nano-micelle pre-modified embryo derived nucleus pulposus progenitor cells promote the regeneration of intervertebral disc degeneration.

Stem cell-based transplantation is a promising therapeutic approach for intervertebral disc degeneration (IDD). Current limitations of stem cells include with their insufficient cell source, poor proliferation capacity, low nucleus pulposus (NP)-specific differentiation potential, and inability to avoid pyroptosis caused by the acidic IDD microenvironment after transplantation. To address these challenges, embryo-derived long-term expandable nucleus pulposus progenitor cells (NPPCs) and esterase-responsive ibuprofen nano-micelles (PEG-PIB) were prepared for synergistic transplantation. In this study, we propose a biomaterial pre-modification cell strategy; the PEG-PIB were endocytosed to pre-modify the NPPCs with adaptability in harsh IDD microenvironment through inhibiting pyroptosis. The results indicated that the PEG-PIB pre-modified NPPCs exhibited inhibition of pyroptosis in vitro; their further synergistic transplantation yielded effective functional recovery, histological regeneration, and inhibition of pyroptosis during IDD regeneration. Herein, we offer a novel biomaterial pre-modification cell strategy for synergistic transplantation with promising therapeutic effects in IDD regeneration.

Construction and validation of postoperative hypothermia prediction model for patients undergoing joint replacement surgery.

AIM: To construct and validate a postoperative hypothermia prediction model for patients undergoing joint replacement surgery. BACKGROUND: Postoperative hypothermia is one of the harmful perioperative complications in patients undergoing joint replacement surgery. The previous studies mainly focused on intraoperative hypothermia prediction models. The prediction model for postoperative hypothermia in patients with joint replacement surgery was understudied. DESIGN: Cohort study. METHODS: We collected data from 503 participants undergoing joint replacement surgery in a tertiary hospital from January 2019 to December 2021. Of those, 404 cases were assigned to the modelling and 99 to the validation groups. Logistic regression was used to construct the model. The AUC was used to test the predictive effect of the model. Finally, 99 cases were used to verify the application effect of the model. A TRIPOD checklist was used to guide the reporting of this study. RESULTS: The factors entered into the prediction model were age, intraoperative hypothermia, BMI, heat preservation measures and platelet (PLT). The model was constructed as follows: Logit (P) = .537 + 3.669 × 1 (intraoperative hypothermia) + .030 × age - .289 × BMI + 2.857 × 1 (intraoperative insulation measures) + .003 × PLT. Hosmer-Lemeshow test, p = .608, the area under the receiver operating characteristic curve (AUC) was .861. The Youden index was .530, the sensitivity was .599 and the specificity was .93. The incidence of postoperative hypothermia in the modelling group was 42.93% (173/404), and that in the verification group was 43.43% (43/99), χ2 = .012, p = .912. The correct practical application rate was 87.88%. This model has a good application effect. CONCLUSION: The current prediction model provided a reference for clinical screening of patients with high-risk hypothermia after joint replacement surgery. RELEVANCE TO CLINICAL PRACTICE: Clinical nurses can use the developed prediction model to predict the occurrence of postoperative hypothermia and provide a reference for the preventive measure.

Hub genes for early diagnosis and therapy of adamantinomatous craniopharyngioma.

BACKGROUND: Adamantinomatous craniopharyngioma (ACP) is a subtype of craniopharyngioma, a neoplastic disease with a benign pathological phenotype but a poor prognosis in the sellar region. The disease has been considered the most common congenital tumor in the skull. Therefore, this article aims to identify hub genes that might serve as genetic markers of diagnosis, treatment, and prognosis of ACP. METHODS: The procedure of this research includes the acquisition of public data, identification and functional annotation of differentially expressed genes (DEGs), construction and analysis of protein-protein interaction network, and the mining and analysis of hub genes by Spearman-rho test, multivariable linear regression, and receiver operator characteristic curve analysis. Quantitative real-time polymerase chain reaction was used to detect the level of mRNA of relative genes. RESULTS: Among 2 datasets, a total of 703 DEGs were identified, mainly enriched in chemical synaptic transmission, cell adhesion, odontogenesis of the dentin-containing tooth, cell junction, extracellular region, extracellular space, structural molecule activity, and structural constituent of cytoskeleton. The protein-protein interaction network was composed of 4379 edges and 589 nodes. Its significant module had 10 hub genes, and SYN1, SYP, and GRIA2 were significantly down-regulated with ACP. CONCLUSION: In a word, we find out the DEGs between ACP patients and standard samples, which are likely to play an essential role in the development of ACP. At the same time, these DEGs are of great value in tumors' diagnosis and targeted therapy and could even be mined as biological molecular targets for diagnosing and treating ACP patients.

Evaluating the Coronary Artery Disease Consortium Model and the Coronary Artery Calcium Score in Predicting Obstructive Coronary Artery Disease in a Symptomatic Mixed Asian Cohort.

Background The utility of a given pretest probability score in predicting obstructive coronary artery disease (CAD) is population dependent. Previous studies investigating the additive value of coronary artery calcium (CAC) on pretest probability scores were predominantly limited to Western populations. This retrospective study seeks to evaluate the CAD Consortium (CAD2) model in a mixed Asian cohort within Singapore with stable chest pain and to evaluate the incremental value of CAC in predicting obstructive CAD. Methods and Results Patients who underwent cardiac computed tomography and had chest pain were included. The CAD2 clinical model comprised of age, sex, symptom typicality, diabetes, hypertension, hyperlipidemia, and smoking status and was compared with the CAD2 extended model that added CAC to assess the incremental value of CAC scoring, as well as to the corresponding locally calibrated local assessment of the heart models. A total of 522 patients were analyzed (mean age 54±11 years, 43.1% female). The CAD2 clinical model obtained an area under the curve of 0.718 (95% CI, 0.668-0.767). The inclusion of CAC score improved the area under the curve to 0.896 (95% CI, 0.867-0.925) in the CAD2 models and from 0.767 (95% CI, 0.721-0.814) to 0.926 (95% CI, 0.900-0.951) in the local assessment of the heart models. The locally calibrated local assessment of the heart models showed better discriminative performance than the corresponding CAD2 models (P<0.05 for all). Conclusions The CAD2 model was validated in a symptomatic mixed Asian cohort and local calibration further improved performance. CAC scoring provided significant incremental value in predicting obstructive CAD.

Changes in Schlemm's canal, trabecular meshwork, and relevant parameters in the early stage after SMILE of myopia patients.

AIM: To observe the changes in Schlemm's canal (SC), trabecular meshwork (TM), and anterior chamber relevant parameters after small incision lenticule extraction (SMILE) of myopia patients. METHODS: A total of 58 eyes from 30 patients who underwent SMILE were divided into a low and moderate myopia group (group A, 32 eyes) and a high myopia group (group B, 26 eyes). The diameter and area of the SC, the width and thickness of TM obtained by CIRRUS HD-OCT5000, and the related anterior chamber parameters obtained by Pentacam anterior segment analysis system, accommodation amplitude (AMP) were observed pre- and postoperatively. The preoperative intraocular pressure (IOP) and postoperative correction of intraocular pressure (IOPcc) were measured. RESULTS: The diameter and area of the SC in the two groups were significantly increased postoperatively (all P<0.01). The TM width of the patients in the two groups were increased at 1mo after surgery (both P<0.01), but the TM thickness did not change (P>0.05). The corneal curvature, central anterior chamber depth, and anterior chamber volume decreased after SMILE surgery (all P<0.01). There was a weak negative correlation between the SC area change and AMP change in group A (r=-0.362, P<0.01). The postoperative IOP decreased after correction by Shah formula (P<0.05). CONCLUSION: SC and TM in myopia patients change in the early postoperative stage of SMILE and the IOP is decline.

Autonomous sensing of the insulin peptide by an olfactory G protein-coupled receptor modulates glucose metabolism.

Along with functionally intact insulin, diabetes-associated insulin peptides are secreted by ß cells. By screening the expression and functional characterization of olfactory receptors (ORs) in pancreatic islets, we identified Olfr109 as the receptor that detects insulin peptides. The engagement of one insulin peptide, insB:9-23, with Olfr109 diminished insulin secretion through Gi-cAMP signaling and promoted islet-resident macrophage proliferation through a ß cell-macrophage circuit and a ß-arrestin-1-mediated CCL2 pathway, as evidenced by ß-arrestin-1-/- mouse models. Systemic Olfr109 deficiency or deficiency induced by Pdx1-Cre+/-Olfr109fl/fl specifically alleviated intra-islet inflammatory responses and improved glucose homeostasis in Akita- and high-fat diet (HFD)-fed mice. We further determined the binding mode between insB:9-23 and Olfr109. A pepducin-based Olfr109 antagonist improved glucose homeostasis in diabetic and obese mouse models. Collectively, we found that pancreatic ß cells use Olfr109 to autonomously detect self-secreted insulin peptides, and this detection arrests insulin secretion and crosstalks with macrophages to increase intra-islet inflammation.

Evaluation of non-contrast magnetic resonance imaging as an imaging surveillance tool for hepatocellular carcinoma in at-risk patients.

INTRODUCTION: This study aimed to evaluate the potential of non-contrast-enhanced magnetic resonance (MR) imaging as an imaging surveillance tool for detection of hepatocellular carcinoma (HCC) in at-risk patients and to compare the performance of non-contrast MR imaging with ultrasonography (US) as a screening modality for the same. METHODS: In this retrospective study, patients diagnosed with HCC between 1 January 2010 and 31 December 2015 were selected from our institution's cancer registry. Patients who underwent MR imaging and had US performed within three months of the MR imaging were included. For each MR imaging, two non-contrast MR imaging sequences - T2-weighted fat-saturated (T2-W FS) sequence and diffusion-weighted imaging (DWI) - were reviewed for the presence of suspicious lesions. A non-contrast MR image was considered positive if the lesion was seen on both sequences. The performance of non-contrast MR imaging was compared to that of hepatobiliary US for the detection of HCC. RESULTS: A total of 73 patients with 108 HCCs were evaluated. Sensitivity of non-contrast MR imaging for the detection of HCC using T2-W FS and DWI was 93.2%, which was significantly higher than that of US, which was 79.5% (p = 0.02). In a subgroup of 55 patients with imaging features of liver cirrhosis, the sensitivity of non-contrast MR imaging was 90.9%, which was also significantly higher than that of US, which was 74.5% (p = 0.02). CONCLUSION: Our pilot study showed that non-contrast MR imaging, using a combination of T2-W FS and DWI, is a potential alternative to US as a screening tool for surveillance of patients at risk for HCC.

Liver resection versus intensity-modulated radiation therapy for treatment of hepatocellular carcinoma with hepatic vein tumor thrombus: a propensity score matching analysis.

BACKGROUND: The presence of hepatic vein tumor thrombus (HVTT) is a major determinant of survival outcomes in hepatocellular carcinoma (HCC) patients. This study compared survival outcomes between liver resection (LR) and intensity-modulated radiation therapy (IMRT) in HCC patients with HVTT. METHODS: Data from patients who underwent LR or IMRT for HCC with HVTT at the Eastern Hepatobiliary Surgery Hospital were retrospectively analyzed. Their survival outcomes were compared before and after propensity score matching (PSM). RESULTS: Three hundred and seven HCC patients with HVTT who underwent either LR (n=140) or IMRT (n=167) were enrolled. PSM matched 82 pairs of patients. The overall survival (OS) and recurrence-free survival (RFS) rates were significantly higher for patients in the LR group than those in the IMRT group. On subgroup analysis, significantly better survival outcomes were obtained after LR than IMRT in patients with peripheral type of HVTT (pHVTT) and major type of HVTT (mHVTT). However, similar survival outcomes were obtained after LR and IMRT when the HVTT had developed into inferior vena cava tumor thrombus (IVCTT). CONCLUSIONS: LR resulted in significantly better survival outcomes in HCC patients with HVTT when compared to IMRT. Once the HVTT had developed IVCTT, LR and IMRT resulted in similarly bad survival outcomes.

Hub biomarkers for the diagnosis and treatment of glioblastoma based on microarray technology.

BACKGROUND: Glioblastoma (GBM) is the most common clinical intracranial malignancy worldwide, and the most common supratentorial tumor in adults. GBM mainly causes damage to the brain tissue, which can be fatal. This research explored potential gene targets for the diagnosis and treatment of GBM using bioinformatic technology. METHODS: Public data from patients with GBM and controls were downloaded from the Gene Expression Omnibus database, and differentially expressed genes (DEGs) were identified by Gene Expression Profiling Interactive Analysis (GEPIA) and Gene Expression Omnibus 2R (GEO2R). Construction of the protein-protein interaction network and the identification of a significant module were performed. Subsequently, hub genes were identified, and their expression was examined and compared by real-time quantitative (RT-q)PCR between patients with GBM and controls. RESULTS: GSE122498 (GPL570 platform), GSE104291 (GPL570 platform), GSE78703_DMSO (GPL15207 platform), and GSE78703_LXR (GPL15207 platform) datasets were obtained from the GEO. A total of 130 DEGs and 10 hub genes were identified by GEPIA and GEO2R between patients with GBM and controls. Of these, strong connections were identified in correlation analysis between CCNB1, CDC6, KIF23, and KIF20A. RT-qPCR showed that all 4 of these genes were expressed at significantly higher levels in patients with GBM compared with controls. CONCLUSIONS: The hub genes CCNB1, CDC6, KIF23, and KIF20A are potential biomarkers for the diagnosis and treatment of GBM.

Genome-wide long non-coding RNA association study on Han Chinese women identifies lncHSAT164 as a novel susceptibility gene for breast cancer.

BACKGROUND: Single-nucleotide polymorphisms (SNPs)-associated genes and long non-coding RNAs (lncRNAs) can contribute to human disease. To comprehensively investigate the contribution of lncRNAs to breast cancer, we performed the first genome-wide lncRNA association study on Han Chinese women. METHODS: We designed an lncRNA array containing >800,000 SNPs, which was incorporated into a 96-array plate by Affymetrix (CapitalBio Technology, China). Subsequently, we performed a two-stage genome-wide lncRNA association study on Han Chinese women covering 11,942 individuals (5634 breast cancer patients and 6308 healthy controls). Additionally, in vitro gain or loss of function strategies were performed to clarify the function of a novel SNP-associated gene. RESULTS: We identified a novel breast cancer-associated susceptibility SNP, rs11066150 (Pmeta = 2.34 × 10-8), and a previously reported SNP, rs9397435 (Pmeta = 4.32 × 10-38), in Han Chinese women. rs11066150 is located in NONHSAT164009.1 (lncHSAT164), which is highly expressed in breast cancer tissues and cell lines. lncHSAT164 overexpression promoted colony formation, whereas lncHSAT164 knockdown promoted cell apoptosis and reduced colony formation by regulating the cell cycle. CONCLUSIONS: Based on our lncRNA array, we identified a novel breast cancer-associated lncRNA and found that lncHSAT164 may contribute to breast cancer by regulating the cell cycle. These findings suggest a potential therapeutic target in breast cancer.

NET1 promotes HCC growth and metastasis in vitro and in vivo via activating the Akt signaling pathway.

Neuroepithelial cell transforming gene 1 (NET1), a member of the guanine nucleotide exchange factor family, is involved in various cancers, including gastric cancer, breast cancer and glioma. However, the role of NET1 in hepatocellular carcinoma (HCC) remains largely uncovered. In this study, we found that NET1 expression was upregulated in HCC, and that upregulated NET1 expression was closely associated with poor prognosis and some clinical characteristics in HCC patients. Whilst forced expression of NET1 in HCC cells was observed to significantly promote cell growth and metastasis in vitro and in vivo; downregulation of NET1 was shown to exhibit an opposite inhibitory effect. RNA-seq analysis and gene set enrichment analysis demonstrated that knockdown of NET1 significantly suppressed the level of Akt phosphorylation level and the expression of Akt downstream genes in HCC cells. Moreover, MK2206, a potent Akt inhibitor was shown to block the NET1-induced effects in HCC. Taken together, this study demonstrated that, through the Akt signaling pathway, NET1 plays an oncogenic role in HCC progression and metastasis. Hence, NET1 may potentially be used as a potential therapeutic target and prognostic marker of HCC.

A highly selective and potent CXCR4 antagonist for hepatocellular carcinoma treatment.

The CXC chemokine receptor type 4 (CXCR4) receptor and its ligand, CXCL12, are overexpressed in various cancers and mediate tumor progression and hypoxia-mediated resistance to cancer therapy. While CXCR4 antagonists have potential anticancer effects when combined with conventional anticancer drugs, their poor potency against CXCL12/CXCR4 downstream signaling pathways and systemic toxicity had precluded clinical application. Herein, BPRCX807, known as a safe, selective, and potent CXCR4 antagonist, has been designed and experimentally realized. In in vitro and in vivo hepatocellular carcinoma mouse models it can significantly suppress primary tumor growth, prevent distant metastasis/cell migration, reduce angiogenesis, and normalize the immunosuppressive tumor microenvironment by reducing tumor-associated macrophages (TAMs) infiltration, reprogramming TAMs toward an immunostimulatory phenotype and promoting cytotoxic T cell infiltration into tumor. Although BPRCX807 treatment alone prolongs overall survival as effectively as both marketed sorafenib and anti-PD-1, it could synergize with either of them in combination therapy to further extend life expectancy and suppress distant metastasis more significantly.