Identification of a vascular invasion-related signature based on lncRNA pairs for predicting prognosis in hepatocellular carcinoma.

OBJECTIVES: Most signatures are constructed on the basis of RNA or protein expression levels. The value of vascular invasion-related signatures based on lncRNA pairs, regardless of their specific expression level in hepatocellular carcinoma (HCC), is not yet clear. METHODS: Vascular invasion-related differentially expressed lncRNA (DElncRNA) pairs were identified with a two-lncRNA combination strategy by using a novel modeling algorithm. Based on the optimal cutoff value of the ROC curve, patients with HCC were classified into high- and low-risk subgroups. We used KM survival analysis to evaluate the overall survival rate of patients in the high- and low-risk subgroups. The independent indicators of survival were identified using univariate and multivariate Cox analyses. RESULTS: Five pairs of vascular invasion-related DElncRNAs were selected to develop a predictive model for HCC. High-risk subgroups were closely associated with aggressive clinicopathological characteristics and genes, chemotherapeutic sensitivity, and highly expressed immune checkpoint inhibitors. CONCLUSIONS: We identified a signature composed of 5 pairs of vascular invasion-related lncRNAs that does not require absolute expression levels of lncRNAs and shows promising clinical predictive value for HCC prognosis. This predictive model provides deep insight into the value of vascular invasion-related lncRNAs in prognosis.

A case of atypical reninoma with mild hypertension and normal plasma renin activity but elevated plasma renin concentration.

BACKGROUND: Reninoma is a rare, benign renal neoplasm. Typical clinical features include severe hypertension, secondary hyperaldosteronism, hypokalaemia and metabolic alkalosis caused by the overproduction of renin. CASE PRESENTATION: A 25-year-old lean Chinese woman with no family history of hypertension was hospitalized for stage 1 hypertension that gradually developed over two years. Endocrine investigation showed hyperreninemia without hyperaldosteronism and hypokalaemia. Interestingly, although the patient had an elevated plasma renin concentration (PRC), her plasma renin activity (PRA) was in the normal range. Abdominal contrast-enhanced computed tomography (CT) scanning revealed a solid, low-density, renal cortical mass with delayed enhancement. Selective renal vein sampling (SRVS) was performed, and a lateralization of the renin secretion from the left kidney was found. Enucleation of the tumour led to a rapid remission of hypertension and hyperreninemia. Based on pathological findings, the patient was diagnosed with reninoma. Immunohistochemical staining of the tumour was positive for Renin, CD34, Vimentin, and synaptophysin (Syn) and negative for somatostatin receptor 2 (SSTR2) and chromogranin A (CgA). CONCLUSIONS: Reninoma can present as mild hypertension without hyperaldosteronism and hypokalaemia. The clinical features of reninoma may depend on the degree of activation of the renin-angiotensin-aldosterone system (RAAS). PRC should be incorporated in the differential diagnosis of secondary hypertension.

The role of different PI3K protein subtypes in the metastasis, angiogenesis and clinical prognosis of hepatocellular carcinoma.

BACKGROUND AND OBJECTIVES: Abnormal activation of the PI3K/AKT pathway is closely related to tumor occurrence, development and angiogenesis. PI3K, as a key protein in the PI3K/Akt pathway, has different subtypes that play diverse roles in various tumors. The aim of this study was to examine the roles of different PI3K protein subtypes (PI3Kp110α, PI3Kp110ß, and PI3Kp110δ) in the metastasis, angiogenesis and prognosis of hepatocellular carcinoma (HCC). METHODS: The roles of different PI3K protein subtypes in the metastasis, angiogenesis and prognosis of HCC were assessed by immunohistochemical staining of 97 HCC tissues and the STRING database. RESULTS: Our results showed that PI3Kp110α and PI3Kp110δ were associated with HCC metastasis and angiogenesis. Patients with high expression of PI3Kp110α and PI3Kp110δ had a worse prognosis and shorter survival time, respectively, than those with low expression, whereas these effects were not observed for PI3Kp110ß. Cox regression analysis showed that PI3Kp110α and clinical stage were independent risk factors for the overall survival of HCC patients. CONCLUSIONS: PI3Kp110α and PI3Kp110δ promoted HCC metastasis and angiogenesis via the PI3K/AKT pathway, and PI3Kp110α was an independent risk factor for HCC patients. These findings provide valuable insights for the prognosis evaluation and the selection of subtype inhibitors of HCC patients.

TP53INP1 inhibits hypoxia-induced vasculogenic mimicry formation via the ROS/snail signalling axis in breast cancer.

Tumour protein p53-inducible nuclear protein 1 (TP53INP1) is a tumour suppressor associated with malignant tumour metastasis. Vasculogenic mimicry (VM) is a new tumour vascular supply pattern that significantly influences tumour metastasis and contributes to a poor prognosis. However, the molecular mechanism of the relationship between TP53INP1 and breast cancer VM formation is unknown. Here, we explored the underlying mechanism by which TP53INP1 regulates VM formation in vitro and in vivo. High TP53INP1 expression was not only negatively correlated with a poor prognosis but also had a negative relationship with VE-cadherin, HIF-1α and Snail expression. TP53INP1 overexpression inhibited breast cancer invasion, migration, epithelial-mesenchymal transition (EMT) and VM formation; conversely, TP53INP1 down-regulation promoted these processes in vitro by functional experiments and Western blot analysis. We established a hypoxia model induced by CoCl2 and assessed the effects of TP53INP1 on hypoxia-induced EMT and VM formation. In addition, we confirmed that a reactive oxygen species (ROS)-mediated signalling pathway participated in TP53INP1-mediated VM formation. Together, our results show that TP53INP1 inhibits hypoxia-induced EMT and VM formation via the ROS/GSK-3ß/Snail pathway in breast cancer, which offers new insights into breast cancer clinical therapy.

UTP23 Functions in Breast Cancer Progression and Predicts Poor Prognosis of Luminal a Breast Cancer.

BACKGROUND: Luminal A breast cancer is the most common molecular subtype of breast cancer. Exploring biomarkers to identify luminal A breast cancer patients at high risk of recurrence and metastasis has important clinical significance. UTP23 is a component of ribosomal small-subunit processome, which is involved in ribosome synthesis and RNA maturation. The role of UTP23 in breast cancer has not been reported. METHODS: TCGA-BRCA data, LinkedOmics, STRING, Metascape and ssGSEA were used to analyze UTP23 expression in breast cancer and evaluate prognosis. Quantitative real-time PCR, western blot and in vitro cell experiment were used to demonstrate the role of UTP23 in breast cancer. RESULTS: UTP23 showed abnormally high expression in multiple cancers and was associated with poor prognosis. UTP23 was associated with T stage, lymph node metastasis, race, histological type, molecular subtypes and survival status in breast cancer. Importantly, UTP23 was significantly associated with poor OS in luminal A or early breast cancer, not in non-luminal A or advanced breast cancer. UTP23 expression was significantly correlated with immune cells infiltration. Enrichment analysis suggested that UTP23 might regulate cell cycle and cell division. Bioinformatics analysis showed DCAF13 might be downstream factor of UTP23. UTP23 expression promoted MCF-7 cells proliferation, migration and invasion possibly through regulating DCAF13 expression. CONCLUSIONS: UTP23 may function in breast cancer progression. The elevated UTP23 may be a potential prognostic biomarker for luminal A or early breast cancer.

Tuning the Electronic Structure of a Novel 3D Architectured Co-N-C Aerogel to Enhance Oxygen Evolution Reaction Activity.

Hydrogen generation through water electrolysis is an efficient technique for hydrogen production, but the expensive price and scarcity of noble metal electrocatalysts hinder its large-scale application. Herein, cobalt-anchored nitrogen-doped graphene aerogel electrocatalysts (Co-N-C) for oxygen evolution reaction (OER) are prepared by simple chemical reduction and vacuum freeze-drying. The Co (0.5 wt%)-N (1 wt%)-C aerogel electrocatalyst has an optimal overpotential (0.383 V at 10 mA/cm2), which is significantly superior to that of a series of M-N-C aerogel electrocatalysts prepared by a similar route (M = Mn, Fe, Ni, Pt, Au, etc.) and other Co-N-C electrocatalysts that have been reported. In addition, the Co-N-C aerogel electrocatalyst has a small Tafel slope (95 mV/dec), a large electrochemical surface area (9.52 cm2), and excellent stability. Notably, the overpotential of Co-N-C aerogel electrocatalyst at a current density of 20 mA/cm2 is even superior to that of the commercial RuO2. In addition, density functional theory (DFT) confirms that the metal activity trend is Co-N-C > Fe-N-C > Ni-N-C, which is consistent with the OER activity results. The resulting Co-N-C aerogels can be considered one of the most promising electrocatalysts for energy storage and energy saving due to their simple preparation route, abundant raw materials, and superior electrocatalytic performance.

RSRC2 Expression Inhibits Malignant Progression of Triple-Negative Breast Cancer by Transcriptionally Regulating SCIN Expression.

Triple-negative breast cancer (TNBC) has a shorter survival time and higher mortality rate than other molecular subtypes. RSRC2 is a newly discovered tumor suppressor gene. However, the potential functional mechanism of RSRC2 in TNBC remains unknown so far. Multiple bioinformatics databases were used. A Human Transcriptome Array 2.0 analysis, ChIP-seq analysis, ChIP-qPCR, RT-qPCR, Western blot, cell function assays in vitro and a metastatic mouse model in vivo were performed to demonstrate the role of RSRC2 in TNBC. Through the analysis of various databases, RSRC2 expression was the lowest in TNBC tissues compared to other molecular subtypes. The low expression of RSRC2 was associated with a worse prognosis for patients with breast cancer. The transcriptome array, ChIP-seq and bioinformatics analysis identified that GRHL2 and SCIN might have a close relationship with RSRC2. The functional bioinformatics enrichment analysis and functional cell experiments showed that RSRC2 was involved in cell adhesion, cell proliferation, cell migration and invasion. Furthermore, RSRC2 expression suppressed SCIN expression but not GRHL2 expression. SCIN re-expression in the RSRC2 overexpression cells or SCIN knockdown in the RSRC2 knockdown cells reversed the cellular function caused by RSRC2. Mechanistically, RSRC2 transcriptionally inhibited SCIN expression. In summary, our study reveals that RSRC2 acts as a tumor suppressor in TNBC development and progression through negatively regulating SCIN-mediated cell function, thus providing a potential target for TNBC treatment.

Promoting melanoma growth and metastasis by enhancing VEGF expression.

Angiogenesis plays an essential role in tumor growth and metastasis and is a promising target for cancer therapy. Vascular endothelial growth factor (VEGF) is a key regulator of angiogenesis. The present study was designed to determine the role of VEGF in tumor growth and metastasis. The sequences for the VEGF gene were cloned into expression plasmids and then transfected into melanoma B16 cells. Overexpression of VEGF transfected with expression plasmids or given exogenous VEGF and epidermal growth factor (EGF) significantly enhanced tumor cell proliferation, migration, and invasion. Tumor growth and metastasis of melanoma B16 cells transfected with VEGF plasmid were significantly promoted compared with those of cells administered with exogenous VEGF or EGF. These results indicated that VEGF can be an effective antiangiogenic strategy for melanoma.

GRHL2 Expression Functions in Breast Cancer Aggressiveness and Could Serve as Prognostic and Diagnostic Biomarker for Breast Cancer.

Background: Breast cancer (BC) is the most frequent malignancy in women worldwide and the leading cause of female cancer-associated death in the world. Grainyhead-like 2 (GRHL2) is an important gene involved in human cancer progression. However, the role of GRHL2 in BC is unknown. Methods: In this study, we used in vitro experiments to verify the role of GRHL2 expression in BC progression. We used 14 databases to analyse the expression level of GRHL2 in BC and its prognostic and diagnostic value. In addition, the correlation between GRHL2 expression and immune cell infiltration and DNA methylation was also analysed. Results: At the cellular level, overexpression of GRHL2 induced E-cadherin expression in BC cells with a mesenchymal phenotype and resulted in a hybrid epithelial/mesenchymal (E/M) phenotype, which is more strongly correlated with tumour aggressiveness than a pure mesenchymal phenotype. Through analysis of various databases, we found that tumour tissue had a higher expression level of GRHL2. High expression of GRHL2 was associated with worse prognosis of BC patients and indicated that GRHL2 had significant diagnostic value. Grainyhead-like 2 is also related to immune infiltration and regulated by DNA methylation. Furthermore, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses showed that GRHL2-related signalling pathways in BC were related to tumour cell proliferation, invasion, and angiogenesis. Conclusions: In summary, evidence indicates that GRHL2 can be used as a prognostic and diagnostic biomarker for BC.

ITGA3 Is Associated With Immune Cell Infiltration and Serves as a Favorable Prognostic Biomarker for Breast Cancer.

BACKGROUND: ITGA3 is a member of the integrin family, a cell surface adhesion molecule that can interact with extracellular matrix (ECM) proteins. The purpose of this study was to explore the significance of ITGA3 expression in the prognosis and clinical diagnosis of breast cancer patients. METHODS: Oncomine, the Human Protein Atlas (HPA) and UALCAN were used to analyze the expression of ITGA3 in various cancers. PrognoScan, GEPIA, Kaplan-Meier plotter and Easysurv were utilized to analyze the prognosis of ITGA3 in certain cancers. Based on TCGA data, a receiver operating characteristic (ROC) curve was used to evaluate the diagnostic performance of ITGA3 expression. cBio-Portal and MethSurv were used to evaluate the genomic mechanism. LinkedOmics, NetworkAnalyst and Metascape were used to build the signaling network. TIMER is a web server for comprehensive analysis of tumor infiltrating immune cells and tumor infiltrating lymphocytes (TILs). RESULTS: The expression of ITGA3 in normal breast tissues was greater than that in breast cancer tissues at both the mRNA and protein levels. High expression of ITGA3 was associated with better prognosis of breast cancer patients. ROC analysis indicated that ITGA3 had significant diagnostic value. Genomic analysis revealed that promoter methylation of ITGA3 leads to transcriptional silencing, which may be one of the mechanisms underlying ITGA3 downregulation in BRCA. Immune infiltration analysis showed that ITGA3 may be involved in the recruitment of immune cells. CONCLUSIONS: This study identified ITGA3 as a novel biomarker to estimate the diagnosis and prognosis of breast cancer. In addition, ITGA3 is involved in ECM regulation and immune cell infiltration.

An autopsy case of unexpected death due to Addison's disease caused by adrenal tuberculosis.

BACKGROUND: Adrenal tuberculosis is difficult to diagnose due to non-specific symptom. Unexpected death due to adrenal insufficiency after trauma surgery is rare. CASE PRESENTATION: A 45-year-old man, who was admitted to hospital because of trauma to the right hand, died unexpectedly on the 13th day after replantation of amputated fingers. He was diagnosed with brain edema and diluted hyponatremia. Autopsy and histopathologic examination revealed severe brain edema combined with cerebellar tonsillar hernia, extensive destruction of adrenal gland caused by bilateral adrenal tuberculosis and right lung invasive pulmonary tuberculosis. CONCLUSIONS: Trauma and pulmonary tuberculosis complicated with adrenal tuberculosis induced the adrenal crisis, which eventually lead to severe cerebral edema and hernia, and finally death from respiratory and circulatory failure. This autopsy and histopathologic examination suggested a possible pathophysiologic mechanism of sudden death due to diluted hyponatremia after trauma surgery.

TCDD-induced antagonism of MEHP-mediated migration and invasion partly involves aryl hydrocarbon receptor in MCF7 breast cancer cells.

Evidence has shown that the activation of AhR (aryl hydrocarbon receptor) can promote cancer cell metastasis. However, limited studies have been carried out on mixed exposure to endocrine-disrupting chemicals (EDCs), especially in human breast cancer. Therefore, using MCF7 human breast cancer cells, we investigated the effects of coexposure to MEHP (mono 2-ethylhexyl phthalate) and TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) on cell migration and invasion, as well as the roles of AhR and the MMP/slug pathway. Our data suggest that MEHP or TCDD can induce migration and invasion in MCF7 cells, and the promotion is partly AhR dependent. We also observed that MEHP antagonized TCDD to reduce AhR-mediated CYP1A1 expression. Subsequently, we revealed that MEHP recruited AhR to dioxin response element (DRE) sequences and decreased TCDD-induced AhR-DRE binding in CYP1A1 genes. Overall, MEHP is a potential AHR agonist, capable of decreasing TCDD-induced AhR-DRE binding in CYP1A1 genes. The antagonizing effect of coexposure led to the inhibition of the epithelial-mesenchymal transition (EMT) in MCF7 cells. Our study provides new evidence for the potential mechanisms involved in EDCs exposure and their interactions in EMT.

[Pilot study of differentiation of bone marrow derived mesenchymal stem cells into endothelial cells induced by B16 melanoma cells in vitro].

OBJECTIVE: Bone-marrow derived mesenchymal stem cells (BMSC) have the potential to differentiate into endothelial cells. The aim of the study was to investigate the induction process of BMSC by B16 melanoma cells in vitro and to analyze the role of VEGF-a in the process. METHODS: A co-culture system containing BMSC and B16 melanoma cells based on transwell indirect model was established, and the induction process of BMSC by B16 melanoma cells was studied in vitro. RESULTS: BMSC were isolated from the bone marrow of C57 mice. BMSC expressed CD105, CD90, CD73, CD44 and CD166, and acquired expressin of endothelial phenotype markers including VEGFR-1, VEGFR-2 and Factor VIII after co-culture with B16 melanoma cells for 48 hours. The expression level of VEGFR-2 would be double and Factor VIII threefold more by extending the co-culture time to 72 hours. In the co-culture system, B16 melanoma cells also up-regulated the expression of VEGF-a. CONCLUSIONS: VEGF-a plays a significant role in the differentiation of BMSC into cells of endothelial phenotype, therefore, is important to tumor angiogenesis.

S1PR1 regulates the switch of two angiogenic modes by VE-cadherin phosphorylation in breast cancer.

Angiogenesis in solid tumors is divided into two modes: endothelium-dependent vessel (EDV) and vasculogenic mimicry (VM). Sphingosine-1-phosphate receptor 1 (S1PR1) plays a vital role on EDV in a variety of human tumors. However, the relationship between S1PR1 and VM is not clear. The aim of this study is to investigate S1PR1 on the regulation of EDV and mimicry formation in breast cancer. Here we show that S1PR1 phosphorylates the complex of VE-cadherin to regulate the switch of EDV and mimicry formation. Suppression of S1PR1 impairs EDV, but contributes to the generation of VM, invasion, and metastasis in vivo and vitro. By inhibiting RhoA activation, the S1PR1/VE-cadherin signaling is blocked. S1PR1 controls VE-cadherin expression and EDV via RhoA activation. Moreover, the low expression of S1PR1 correlates with VM and poor prognosis in breast cancer patient. The results show that S1PR1 regulated RhoA activation to accelerate VE-cadherin phosphorylation (Y731), leading to increased EDV and reduced VM in breast cancer. S1PR1 may provide a new thinking direction for antiangiogenic therapy for patients with breast cancer.

Pilot study on the interaction between B16 melanoma cell-line and bone-marrow derived mesenchymal stem cells.

Bone-marrow derived mesenchymal stem cells (BMSCs) have the potential to differentiate into osteocytes, chondrocytes, adipocytes and endothelial cells. The interaction between BMSCs and epithelial tumor cell was enhanced on proliferation. Our previous study had shown that BMSCs maybe participate in angiogenesis in melanoma in vivo. The aim of this study was to investigate the interaction between B16 melanoma cells and BMSCs in vitro, the mechanism of BMSCs participating in melanoma angiogenesis in vivo is unclear, so a co-culture system containing BMSCs and B16 melanoma cells, based on transwell indirect model, was established, and the interaction between BMSCs and B16 melanoma cells was studied in vitro. In our study, BMSCs were generated out of bone marrow from C57 mouse, isolated BMSCs were positive for the markers CD105, CD90, CD73, CD44 and CD166 and negative for endothelial markers, which acquired endothelial phenotype (including the expression of VEGFR-1, VEGFR-2, Factor VIII) after co-culture with B16 melanoma cells; at the same time, B16 melanoma cells also up-regulated the expression of VEGF-a, VEGFR-1, VEGFR-2 and Factor VIII. The proliferation rate of B16 melanoma cells and BMSCs were also found to be increased. We could show the differentiation of BMSCs into cells with phenotypic features of endothelial cells. BMSCs promoted proliferation of tumor cells and improved the microenvironment in tumor. Our study suggests that the BMSCs may play an important role in tumor angiogenesis.

Role and mechanism of vasculogenic mimicry in gastrointestinal stromal tumors.

Vasculogenic mimicry (VM) is the formation of fluid-conducting channels by highly invasive and genetically dysregulated tumor cells. In this study, we collected specimens of 84 human gastrointestinal stromal tumors (GISTs) along with clinicopathologic data and another 42 GISTs with fresh tissue that was used for gelatin zymography. VM was found in 21 of the 84 GISTs using CD31/periodic acid-Schiff double staining and CD117 and CD31 immunohistochemical staining. There was a significant difference in the VM-positive rate between the lesions with a mitotic rate > or =5/50 high-power fields and those with a lower mitotic rate (P = .000) and between the cases with and without liver metastasis (P = .008). There was a significant difference in the VM-positive rate between the high-risk group (5.9%) and the very low/low-risk group (12.5%) (P = .010) or the intermediate-risk group (39.5%) (P = .020). Kaplan-Meier survival analysis showed VM indicated a poor prognosis (P = .0000). Cox proportional hazards model indicated that the presence of VM, tumor size 10 cm or greater, and hemorrhage were independent predictors of a poor prognosis (P = .000, .005, .032, respectively). The staining indexes of matrix metalloproteinase (MMP)-2 and MMP-9 were higher in the VM-positive than in the VM-negative group (P = .024 and .037, respectively). Gelatin zymography showed that the activity of MMP-2 and MMP-9 was significantly higher in the VM-positive lesions (P = .013 and .033, respectively). We conclude that VM in GISTs is an unfavorable prognostic sign and that patients with VM-positive tumors are prone to suffer liver metastasis. Both MMP-2 and MMP-9 play an important role in VM formation in GISTs.

[Genetic regulatory pathway of gene related breast cancer metastasis: primary study by linear differential model and k-means clustering].

OBJECTIVE: To investigate the potential genetic regulatory pathway of gene related breast cancer metastasis. METHODS: Microarray technique was used to identify the gene expression profile and to screen the differential expression genes in breast cancer with special emphasis on the metastasis factors. A gene chip was available, obtained from the surgical samples, including breast cancer primary tissues and metastasis tissues, of 30 female patients with breast cancer at different clinical stages. Then potential genetic regulatory pathway of gene related breast cancer metastasis was analyzed with a linear differential model and k-means clustering. RESULTS: Twenty-seven differential expression genes were identified. It was suggested that the potential regulatory pathway of gene related to breast cancer metastasis is made up of GRP, BPAG1, and SFRP2 genes. CONCLUSION: The metastasis of breast cancer is related to the cancerization caused by the abnormal expression of multiple genes. It is reliable to analyze the Genetic regulatory pathway of gene related breast cancer metastasis by using multiple bio-informatic measures.

Correlation between melanoma angiogenesis and the mesenchymal stem cells and endothelial progenitor cells derived from bone marrow.

Endothelial progenitor cells (EPC) reportedly differentiate into endothelial cells and participate in angiogenesis, including neovascularization at sites of neoplastic development. Recently, we reported that Flk+/CD31-/CD34- mesenchymal stem cells (MSC) possess the potential of differentiating into both endothelial and hematopoietic cells. We hypothesized that these MSC contribute to tumor angiogenesis. This concept is controversial and this study was undertaken to address this controversy. We show that progeny of human MSC as well as differentiated endothelial cells possess the ability to participate in tumor angiogenesis. When human marrow-derived MSC were injected into tail veins of severe combined immunodeficient (SCID) mice engrafted with human malignant melanoma, human cells incorporated into tumor vessels. Moreover, human-derived endothelial cells were identified in the walls of mouse tumor vessels by immunohistology. We report for the first time that similar results are obtained when mice carrying malignant melanoma are injected with differentiated human endothelial cells. Thus, we demonstrate that both differentiated endothelial cells from tissue peripheral to that of a tumor as well as progeny of human MSC have similar capacities to participate in angiogenesis.