Search

Expression of Concern: A. Iervolino, D. Trisciuoglio, D. Ribatti, A. Candiloro, A. Biroccio, G. Zupi, D. Del Bufalo, "Bcl-2 Overexpression in Human Melanoma Cells Increases Angiogenesis Through VEGF mRNA Stabilization and HIF-1-mediated Transcriptional Activity," The FASEB Journal 16, no. 11 (2002): 1453-1455, https://doi.org/10.1096/fj.02-0122fje. This Expression of Concern is for the above article, published online on July 01, 2002, in Wiley Online Library (http://onlinelibrary.wiley.com/), and has been issued by agreement between the journal Editor-in-Chief, Loren E. Wold; the Federation of American Societies for Experimental Biology; and Wiley Periodicals LLC. A third party reported concerns of duplication and manipulation in Figure 1, and splicing and duplication in Figures 2B and 5A. These concerns were confirmed by the journal and publisher. Author D. Del Bufalo responded to an inquiry by the journal on behalf of the authors, but the authors were not able to supply original data due to the length of time that has elapsed since publication. The Expression of Concern has been agreed on because the evidence of image manipulation and duplication calls into question the validity of the data in Figures 1, 2, and 5, which cannot be confirmed due to the lack of original data. Author D. Del Bufalo disagrees with the Expression of Concern. All other authors did not respond to our notice regarding the Expression of Concern., (© 2025 Federation of American Societies for Experimental Biology.)

Objective: The aim of this research was to investigate the specific regulatory role of miR-6760-5p in angiogenesis in moyamoya disease., Methods: HUVECs were transfected with miR-6760-5p inhibitor and mimics fragments, then subjected to assays for cell proliferation, migration, and tube formation. Subsequently, downstream target genes of miR-6760-5p were predicted and the protein expression levels of these genes were evaluated. The presence of miR-6760-5p and YAP1 was verified by a dual luciferase reporter gene test, followed by an assessment of the effects of YAP1 and miR-6760-5p on the HUVECs., Results: Comparatively to the control group, increased expression of miR-6760-5p decreased cell growth, movement, and tube formation. YAP1 gene was discovered as a target controlled by miR-6760-5p, with subsequent investigation confirming YAP1 as a gene regulated by miR-6760-5p. Additionally, miR-6760-5p was found to counteract the angiogenesis-promoting effect of YAP1., Conclusion: The results of this research suggest a possible link between the miR-6760-5p gene found in the cerebrospinal fluid of individuals with moyamoya disease and the process of vascularization in this particular condition. The findings indicate that miR-6760-5p may be a new molecular indicator and potential target for the diagnosis of moyamoya disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Bladder cancer (BLCA) is one of the ten most common cancers worldwide. However, the deregulation of PROS1 and its specific function in BLCA is not well understood. By combining proteomic and transcriptomic datasets, we discovered PROS1 expression was significantly reduced in BLCA tissues and revealed the clinical relevance of PROS1 with BLCA. Analysis of multiple BLCA datasets consistently showed the group with reduced PROS1 expression was linked to cancer-promoting pathways, more aggressive characteristics, and a greater chance of responding positively to immunotherapy. Next, various functional experiments were performed and the results revealed PROS1 overexpression inhibited the proliferation, cell cycle progression, migration, invasion, and angiogenesis of BLCA. In recovery trials, the AKT activator SC79 offered additional proof that PROS1 may influence BLCA cells via the AKT/GSK3β/β-catenin pathway. In conclusion, as an angiogenesis-related gene, PROS1 may play an inhibitory role in the biological functions of bladder cancer., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: We confirmed that all experiments in this study were performed in accordance with the relevant guidelines and regulations. All the procedure of the study is followed by the ARRIVE guidelines., (© 2025. The Author(s).)

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with high morbidity and mortality worldwide. Angiogenesis is essential for HCC progression and metastasis. Some angiogenesis-related genes promote this process, whereas other antiangiogenic genes inhibit HCC growth and metastasis. Therefore, finding new potential biomarkers for HCC prognosis prediction and treatment is essential. Public RNAseq and clinical data from TCGA and GEO database, download angiogenesis-related genes from the GeneCards, MSigDB database, through the single factor analysis of Cox, LASSO build risk score-Cox regression analysis model and external validation verified from the GEO. Cox regression analysis, Kaplan Meier (KM) curve, ROC curve, and decision-curve analysis will be used to evaluate and examine the risk score prediction effect of the model. GSVA analysis was used to assess the variation of gene sets between groups, and ClBERSOFT, ESTIMATE, and TIMER databases were used to analyze the immune infiltration in the single-cell level analysis of gene expression differences between cells. Finally, in the three pairs of HCC tissues and tissue adjacent to carcinoma by real-time fluorescent quantitative PCR (qRT_PCR) and western blotting (WB) to evaluate angiogenesis-related genes (ATP2A3 AEBP1 PNMA1, PLAT) expression level in HCC, and AEBP1 was knocked out in HCCLM3 cells, which is to study AEBP1 biological function in HCC. We established a prognostic risk assessment model based on 13 significant genes associated with HCC prognosis by Cox analysis and LASSO-Cox regression analysis. The median was used to divide these patients into high-risk and low-risk groups, and the prognosis of the high-risk group was worse than that of the low-risk group. Through the multivariate Cox regression analysis, it was found that the risk score was an independent predictor of overall survival (OS). The GSVA analysis suggested that the predicted high-risk population showed higher activity in the purine, pyrimidine, and riboflavin metabolic pathways. Compared with the low-risk group, the tumor microenvironment in the high-risk group showed a reduction in the number of cells promoting anti-tumor immunity and an increase in the number of cells inhibiting anti-tumor immunity, as well as a reduction in overall immune infiltration and matrix components. On the single-cell level, it was confirmed that the key genes (AEBP1, ATP2A3, PLAT, and PNMA1) expressed differently between liver cancer and adjacent tissue cell groups. Finally, qRT_PCR and WB results showed that ATP2A3, AEBP1, PNMA1, and PLAT were highly expressed in liver cancer tissue compared to adjacent tissue, and the proliferation, migration, and invasion of HCCLM3 cells were inhibited after knocking out AEBP1. We constructed novel risk score models as prognostic biomarkers for HCC, which has the potential to guide the development of more personalized treatment strategies for HCC patients. In addition, AEBP1 is a potential therapeutic target for HCC., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethical approval: The study involving human participants were approved by the Ethics Review Committee of Guizhou Medical University (NO.2022375). The all patients provided their written informed consent in accordance with the Declaration of Helsinki., (© 2025. The Author(s).)

Abnormal angiogenesis is a key process associated with ischaemic retinopathies such as diabetic retinopathy, for which the underlying pathological mechanisms are still poorly understood. Here, we confirm that angiogenic factor 1 with a G patch and FHA domain (AGGF1) is elevated in the diabetics and induces retinal angiogenesis. Mechanistic investigations demonstrate that HIF-1α directly regulates AGGF1 expression. AGGF1 upregulates the expression of cell cycle proteins by increasing the binding of tumour necrosis factor ligand superfamily member 12 (TNFSF12) to fibroblast -growth -factor-inducible 14 (FN14, TNFRSF12A). Furthermore, targeting AGGF1 attenuates pathological neovascularisation in ischaemic retinopathy. Additionally, we discover that sodium-glucose cotransporter 2 inhibitors (SGLT2i) could inhibit the AGGF1 signalling pathway early to achieve therapeutic effects. Overall, we elucidate the mechanism underlying pathological retinal angiogenesis involved in endothelial AGGF1-dependent events and highlight a therapy for the effective treatment of ischaemic retinopathy., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background/aim: Hypoxia-inducible factor-1 alpha (HIF-1α) plays a key role in the cellular response to hypoxia, which plays a crucial role in the induction of abnormal angiogenesis and metastasis. Understanding the mechanism for the regulation of angiogenesis by HIF-1α-regulating miRNA will contribute to developing the strategy to prevent metastasis., Materials and Methods: We conducted a functional screening for HIF-1α-inhibiting miRNAs by evaluating the effects of miRNA mimics on HIF-1α expression and identified miR-5586-5p as an angiogenesis inhibitor through a mechanistic study. Angiogenic activity was assessed by tube formation assays using HUVEC cells exposed to conditioned media from miRNA-transfected breast cancer cells. In vivo activity of miR-5586-5p was examined through intratumoral injection of miRNA in orthotopic xenograft mice established by injecting MDA-MB-231 cells into the mammary fat pads of BALB/c nu/nu mice., Results: The expression of the critical proangiogenic factors vascular endothelial growth factor A (VEGFA) and angiopoietin-like protein 4 (ANGPTL4) was inhibited by miR-5586-5p. Migration and tube formation of human umbilical vein endothelial cells were reduced in the conditioned medium prepared from miR-5586-5p-transfected cells. miR-5586-5p also suppressed the expression of heparin-binding EGF-like growth factor (HBEGF) and a disintegrin and metalloprotease 17 (ADAM17), which play a role in hypoxic signaling to induce the expression of VEGFA and ANGPTL4. HIF-1α, HBEGF, and ADAM17 were verified as the direct targets of miR-5586-5p responsible for the angiogenesis-suppressing function of miR-5586-5p. Expression levels of miR-5586-5p were lower in tumor tissues than in neighboring normal tissues of breast cancer patients. The expression of miR-5586-5p was inversely correlated to those of HIF-1α, HBEGF, ADAM17, VEGFA, and ANGPTL4. Angiogenesis and subsequent tumor growth were suppressed by intratumoral injection of miR-5586-5p in orthotopic MDA-MB-231 xenografts in mice., Conclusion: A potent tumor-suppressive function of miR-5586-5p applicable for the development of a novel cancer treatment strategy is herein described., (Copyright © 2025 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Metastasis is the major cause of breast cancer mortality, with angiogenesis and tumor-released exosomes playing key roles. However, the communication between breast cancer cells and endothelial cells and its role in tumor metastasis remains unclear. Here, we characterize a long noncoding RNA, RPPH1, which is upregulated in breast cancer tissues and positively associated with poor prognosis. Hypoxia microenvironment upregulates the expression of RPPH1 in breast cancer cells, and promotes its packaging into exosomes through hnRNPA1, leading to the maintenance of stemness and aggressive traits in cancer cells and angiogenesis in endothelial cells. The function of cellular and exosomal RPPH1 was confirmed in the MMTV-PyMT mouse model, in which ASO-RPPH1 therapy effectively inhibited tumor progression and metastasis. Mechanistically, RPPH1 protects IGF2BP2 from ubiquitination-induced degradation, stabilizes N6-methyladenosine (m6A)-modified FGFR2 mRNA, and activates the PI3K/AKT pathway. Our research unveils the role of RPPH1 in breast cancer metastasis and highlights its potential as a therapeutic target., Competing Interests: Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: Ethical approval was given by the Medical Research Ethics Committee of Nanjing Drum Tower Hospital (Nanjing, China, ethics approval number: 2023-354-01) and written informed consent was obtained from each patient. Animal studies were approved by the animal ethics committee of China Pharmaceutical University (Permit Number: 2162326) and were in accordance with the international laws and policies (EEC Council Directive 86/609,1987)., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Thrombomodulin is predominantly expressed on vascular endothelial cells and modulates endothelial cell functions by interacting with multiple ligands. The specific thrombomodulin receptor or cofactor active on the endothelial cell surface remains elusive. This study aims to identify interacting partners of thrombomodulin on endothelial cells. Here, using a liquid chromatograph-tandem mass spectrometer, hornerin was identified as a candidate protein. We then investigated hornerin protein and mRNA expression in endothelial cells. Hornerin protein was detected in the mouse endothelium of the aorta and lung. Both human- and mouse-cultured endothelial cells expressed hornerin mRNA and protein. Moreover, immunoprecipitation analysis suggested the direct protein interaction between thrombomodulin and hornerin. Lipopolysaccharides administration increased serum hornerin concentrations in mice and reduced hornerin protein levels on the surface of cultured endothelial cells as same as thrombomodulin protein. Thrombomodulin-targeting siRNA decreased not only thrombomodulin protein levels but also hornerin protein levels in cultured endothelial cells. Thrombomodulin- or hornerin-targeting siRNA impaired tube formation and leukocyte adhesion to endothelial cells. Our findings reveal that hornerin is located on vascular endothelial cells in the presence of thrombomodulin and suggest that endothelial thrombomodulin and hornerin may interact, which may play an important role in endothelial cell functions such as vascular inflammation and angiogenesis., Competing Interests: Declaration of competing interest Takayuki Okamoto and Koji Suzuki have received research grants from the Asahi Kasei Pharma Corporation. The funder had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. The other authors report no other conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Proline/arginine-rich end and leucine-rich protein (PRELP) is identified as a small proteoglycan in the extracellular matrix that has been tightly associated with cell adhesion. At present, the role of PRELP in colorectal cancer (CRC) remains largely unknown. PRELP expression in human CRC tissue samples was analyzed by qRT-PCR and immunochemistry. CCK-8, colony formation, transwell, and tube formation assays were utilized to determine the influences of PRELP on the malignant phenotypes of CRC cells. Mouse xenograft and tumor metastasis models were constructed to further validate the function of PRELP. Furthermore, we investigated the efficacy of PRELP combined with bevacizumab treatment in a mouse xenograft model of CRC. Additionally, RNA-seq was performed to analyze the potential signaling pathways regulated by PRELP. Immunofluorescence staining and coimmunoprecipitation were conducted to confirm the interaction between PRELP and fibroblast growth factor 1 (FGF1). In this study, we found that PRELP exerted a tumor-suppressive effect on CRC. The expression level of PRELP was significantly reduced in CRC tissues and cell lines. Both in vivo and in vitro experiments confirmed that PRELP inhibited CRC cell proliferation, promoted apoptosis, and suppressed migration and invasion via a reduction in the epithelial-mesenchymal transition and attenuated angiogenesis, thereby dampening tumor progression. In addition, PRELP markedly potentiated the efficacy of bevacizumab in a mouse xenograft model. Mechanistically, PRELP bound to FGF1 and reduced the stability of the FGF1 protein, accompanied by an increase in its degradation, which subsequently inactivated the PI3K/AKT/mTOR pathway, thereby leading to reduction in tumor angiogenesis and metastasis. Our study for the first time unveiled the tumor-suppressive role of PRELP in CRC and provided a potential effective strategy for the treatment of CRC., Competing Interests: Declarations. Competing interests: We declare that we do not have any commercial or affiliate interests that conflict with the submitted work. Ethical approval: The Experimental Animal Management and Use Committee of Chongqing Medical University approved the experiment (approval number: IACUC-CQMU-2024–0269). Consent for publication: Not applicable., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Angiopoietin‑like 4 (ANGPTL4), a member of the angiopoietin family, plays critical roles in angiogenesis, lipid metabolism and inflammation. It has been demonstrated that ANGPTL4 has significant influence on various diseases. Accumulating evidence has highlighted the impacts of ANGPTL4 on human malignancies. ANGPTL4 is commonly overexpressed in various types of cancer, such as breast, non‑small cell lung, gastric and colorectal cancer. Its upregulation promotes tumor growth, invasion, metastasis and angiogenesis, as well as metabolic reprogramming and resistance to programmed cell death, radiotherapy and chemotherapy. However, ANGPTL4 has also exhibited antitumor effects under certain conditions, indicating its complex roles in tumor biology. The transcriptional regulation of ANGPTL4 is influenced by multiple factors, such as HIF‑1, PPARs, TGF‑β and long non‑coding RNAs. In terms of signaling pathways, STATs, PI3K/AKT and COX-2/PGE2 are important in regulating cellular processes. The present review summarizes the biological functions of ANGPTL4 in tumors and its association with patient prognosis. Furthermore, the key molecular mechanisms and potential reasons for its dual roles in cancer are also discussed. In conclusion, ANGPTL4 is a valuable diagnostic biomarker and a potential therapeutic target for human cancers.

Insufficient trophoblast cell infiltration is implicated in the progression of preeclampsia (PE). The immunoglobulin superfamily member 8 (IGSF8) has been shown to promote cell migration, invasion, and epithelial mesenchymal transition (EMT). However, the specific impact of IGSF8 on trophoblast cells in PE has not been definitively demonstrated. To address this, placental tissues from PE patients and normal subjects was collected. A PE-like rat model was established by administering L-NAME (60 mg/kg) intragastrically to pregnant rats from the 10th to the 19th day of gestation. Knockdown and overexpression plasmids of IGSF8 were transfected into JEG-3 cells for further experiments. Clinical samples indicated impaired spiral artery remodeling, and high IGSF8 expression in the placental tissues of PE patients. PE rats exhibited increased mean arterial pressure, elevated 24-h urine protein levels, higher abortion rates, and decreased placental and fetal weight compared to rats of sham group. Failure of physiological transformation of spiral arteries was observed in PE rats, along with increased IGSF8 expression. IGSF8 overexpression inhibited JEG-3 cell migration, invasion and EMT, as well as reduced release of VEGF in JEG-3 cells, impairing HUVEC tube formation. mRNA-sequencing analysis of JEG-3 cells transfected with shIGSF8 showed differentially expressed genes related to angiogenesis, and mesenchymal cell differentiation, with IGSF8 knockdown being associated with the activation of pathways involved in blood vessel development and cell migration. Overall, this study suggests that IGSF8 plays a role in the development of PE and provides new insights for potential treatments., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Inc. All rights reserved.)

Considering the high degree of malignancy, recurrence rate and poor prognosis, exploring promising targets is an imperious strategy for colorectal carcinoma therapy. Recent studies have indicated that GABPα plays a role in cancer aggressiveness, but its exact function and regulatory mechanisms in colorectal cancer progression remain unclear. This study aims to explore the biological role of GABPα and its upstream regulator, miR-378a-5p, in modulating cancer progression. The expression levels of GABPα and miR-378a-5p were analyzed through comprehensive data mining and qPCR assays. The functional effects of GABPα were assessed using CCK-8, wound healing, transwell invasion assay, tube formation and xenograft model in nude mice. A co-transfection assay was also performed to investigate the regulatory relationship between miR-378a-5p and GABPα. We found that GABPα expression was significantly downregulated in human colorectal cancer tissues and cell lines. Functional assays revealed that GABPα overexpression suppressed the proliferation, migration, invasion and angiogenesis of colorectal cancer cells, and in vivo experiments further confirmed the inhibitory role of GABPα. Additionally, miR-378a-5p was upregulated in colorectal cancer, and GABPα was identified as a direct target of miR-378a-5p, as confirmed by luciferase reporter assays. Furthermore, overexpression of GABPα partially counteracted the enhanced malignant behaviors of cancer cells induced by miR-378a-5p. Our findings suggest that miR-378a-5p promotes the aggressive progression of colorectal cancer by directly targeting GABPα, highlighting this regulatory axis as a potential therapeutic target for colorectal carcinoma., Competing Interests: Declaration of Competing Interest I have nothing to declare., (Copyright © 2024. Published by Elsevier Ltd.)

Lung cancer stands prominently among the foremost contributors to human mortality, distinguished by its elevated fatality rate and the second-highest incidence rate among malignancies. The metastatic dissemination of lung cancer stands as a primary determinant of its elevated mortality and recurrence rates, underscoring the imperative for comprehensive investigation into its metastatic pathways. Circular RNAs (circRNAs), a subclass of non-coding RNA (ncRNA) molecules, have garnered attention for their pivotal involvement in the genesis and advancement of lung cancer. Emerging evidence highlights the indispensable functions of circRNAs in orchestrating the metastatic cascade of lung cancer. This review primarily discusses the mechanisms by which circRNAs act as competitive endogenous RNAs (ceRNAs) and modulate various signaling pathways to regulate lung cancer metastasis. CircRNAs influence critical cellular processes including angiogenesis, autophagy, and glycolysis, thereby exerting influence over the metastatic cascade in lung cancer. These discoveries offer innovative perspectives and therapeutic avenues for the diagnosis and management of lung cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Breast cancer is the leading cause of cancer-related mortality in women. Deregulation of miRNAs is frequently observed in breast cancer and affects tumor biology. A pre-miRNA, such as pre-miR-1307, gives rise to several mature miRNA molecules with distinct functions. However, the impact of global deregulation of pre-miR-1307 and its individual mature miRNAs in breast cancer has not been investigated in breast cancer, yet., Results: Here, we found significant upregulation of three mature miRNA species derived from pre-miR-1307 in human breast cancer tissue. Surprisingly, the overexpression of pre-miR-1307 in breast cancer cell lines resulted in reduced xenograft growth and impaired angiogenesis. Mechanistically, overexpression of miR-1307-5p altered the secretome of breast cancer cells and reduced endothelial cell sprouting. Consistently, expression of miR-1307-5p was inversely correlated with endothelial cell fractions in human breast tumors pointing at an anti-angiogenic role of miR-1307-5p. Importantly, the arm usage of miR-1307 and other miRNAs was highly correlated, which suggests an undefined common regulatory mechanism., Conclusions: In summary, miR-1307-5p reduces angiogenesis in breast cancer, thereby antagonizing the oncogenic effects of miR-1307-3p. Our results emphasize the importance of future research on the regulation of miRNA arm selection in cancer. The underlying mechanisms might inspire new therapeutic strategies aimed at shifting the balance towards tumor-suppressive miRNA species., Competing Interests: Declarations. Ethics approval and consent to participate: The animal study protocol was approved by the Institutional Review Board (or Ethics Committee) of the Weizmann Institute of Science (experiments with NOG mice) and by the local regulatory authorities (regional council, Karlsruhe, Germany under reference code G288/14; experiments with NSG mice). No human subjects were involved in the study. Consent for publication: Not applicable. Competing interests: The authors declare that they have no competing interests. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results., (© 2025. The Author(s).)

Pathological neovascularization is a hallmark of many vision-threatening diseases. However, some patients exhibit poor responses to current anti-VEGF therapies due to resistance and limited efficacy. Recent studies have highlighted the roles of noncoding RNAs in various biological processes, paving the way for RNA-based therapeutics. In this study, we report a marked down-regulation of miR-205 under pathological conditions. miR-205 potently inhibits endothelial cell functions critical for pathological neovascularization, including proliferation, migration, and tube formation. Furthermore, miR-205 strengthens the endothelial barrier, thereby reducing vascular leakage. In mouse models of retinal and choroidal neovascularization, miR-205 administration effectively suppresses abnormal blood vessel formation and leakage. Mechanistically, miR-205 directly targets VEGFA and ANGPT2, which are key drivers of pathological neovascularization. To improve delivery, we successfully loaded miR-205 into exosomes derived from mesenchymal stem cells. This innovative approach avoids cytotoxicity while preserving therapeutic efficacy in both cellular and animal models. Collectively, our findings highlight miR-205 as a promising therapeutic for ocular neovascularization, with exosome delivery offering a novel and efficient strategy for treating vision-threatening vascular diseases., Competing Interests: Declarations. Ethics approval and consent to participate: All animal experiments were conducted according to the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research and approved by the Experimental Animal Center of Nanjing Medical University. Consent for publication: All authors agree to be published. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Objectives: Melanoma is a highly aggressive and metastatic form of cancer, and the role of exosomal microRNAs (miRNAs) in its progression remains largely unexplored. This study aimed to investigate the effects of melanoma cell-derived exosomal miR-424-5p on angiogenesis and its underlying mechanisms., Methods: Exosomes were isolated from melanoma cell lines A375 and A2058, and their effects on the proliferation, migration, and angiogenesis of human umbilical vein endothelial cells (HUVECs) were examined. The interaction between miR-424-5p and its target gene, large tumor suppressor kinase 2 (LATS2), was analyzed using luciferase reporter assays and functional experiments. In vivo , tumor growth and angiogenesis were studied in a xenograft model using nude mice., Results: Melanoma cell-derived exosomes could be internalized by HUVECs, which promoted proliferation, migration, and angiogenesis. miR-424-5p was highly expressed in melanoma cells and their exosomes, and its inhibition in exosomes suppressed HUVEC proliferation, migration, and angiogenesis. LATS2 was identified as a direct target of miR-424-5p, and its silencing reversed the inhibitory effects of miR-424-5p inhibition on HUVEC functions. In vivo , exosomes derived from miR-424-5p-inhibited melanoma cells suppressed tumor growth and angiogenesis in xenograft models., Conclusions: Melanoma cell-derived exosomal miR-424-5p promotes angiogenesis by targeting LATS2, contributing to melanoma progression. Targeting the exosomal miR-424-5p/LATS2 axis could be a potential therapeutic strategy for melanoma., Competing Interests: The authors declare no conflicts of interest to report regarding the present study., (© 2025 The Authors.)

Cancer-associated fibroblasts (CAFs) contribute to the progression of lung cancer. Four and a half LIM domain protein-2 (FHL2) is a component of focal adhesion structures. We analyzed the function of FHL2 expressed by CAFs in lung adenocarcinoma. Expression of FHL2 in fibroblast subtypes was investigated using database of single-cell RNA-sequencing of lung cancer tissue. The role of FHL2 in the proliferation and migration of CAFs was assessed. The effects of FHL2 knockout on the migration and invasion of human lung adenocarcinoma cells and tube formation of endothelial cells induced by CAF-conditioned medium (CM) were evaluated. The effect of FHL2 knockout in CAFs on metastasis was determined using a murine orthotopic lung cancer model. The prognostic significance of stromal FHL2 was assessed by immunohistochemistry in human adenocarcinoma specimens. FHL2 is highly expressed in myofibroblasts in cancer tissue. TGF-β1 upregulated FHL2 expression in CAFs and FHL2 knockdown attenuated CAF proliferation. FHL2 knockout reduced CAF induced migration of A110L and H23 human lung adenocarcinoma cell lines, and the induction of tube formation of endothelial cells. FHL2 knockout reduced CAF-induced metastasis of lung adenocarcinomas in an orthotopic model in vivo. The concentration of Osteopontin (OPN) in CM from CAF was downregulated by FHL2 knockout. siRNA silencing and antibody blocking of OPN reduced the pro-migratory effect of CM from CAF on lung cancer cells. In resected lung adenocarcinoma specimens, positive stromal FHL2 expression was significantly associated with higher microvascular density and worse prognosis. In conclusion, FHL2 expression by CAFs enhances the progression of lung adenocarcinoma by promoting angiogenesis and metastasis., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Introduction: Recent epidemiological data suggests a rising incidence of breast angiosarcoma (AS-B) in the Western population, with over two-thirds related to irradiation or chronic lymphedema. However, unlike head and neck angiosarcoma (AS-HN), AS-B disease characteristics in Asia remain unclear., Methods: We examined clinical patterns of angiosarcoma patients (n = 176) seen in an Asiantertiary cancer center from 1999 to 2021, and specifically investigated the molecular and immune features of AS-B in comparison to AS-HN. Data from whole genome sequencing (WGS), NanoString gene expression profiling and 10x Genomics Visium spatial transcriptomics were analyzed., Results: Majority of cases were AS-HN (n = 104; 59.1%), while AS-B (n = 16, all females) accounted for 9.1% of the cases. The median age at diagnosis was 43 years (range, 26 to 74). Based on WGS, 4 of the 7 AS-B had non-synonymous somatic variants in 47 genes (range, 2 to 28 per case). These genes were functionally annotated and were enriched in cancer-related pathways such as regulation of cell differentiation, VEGFR and receptor tyrosine kinases signaling pathways. By NanoString gene expression profiling, ASB, compared to AS-HN, were enriched for angiogenesis, notch signaling and metastasis-associated matrix remodeling pathways. Additionally, AS-B were enriched for macrophages and CD8+ T cells expression signatures. Similarly, Visium spatial transcriptomics showed that AS-B were enriched for macrophages and T-cells., Discussion: In conclusion, in our AS-B cases, we observed a convergence of both mutational and expression signatures on angiogenic-related pathways. Thus, anti-angiogenic therapy could be an option to treat AS-B., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2025 Ko, Guo, Kannan, Lim, Lee, Li, Lee, Teh and Chan.)

Preeclampsia is characterized by insufficient invasion of extravillous trophoblasts and is a consequence of failed adaption of extravillous trophoblasts to changes in the intrauterine environment developing embryo. Specific miRNAs are implicated in the development of preeclampsia (PE). miR-455-5p is present at low levels in PE but its role is not known. Combining cell and molecular biology methods, we provide evidence of the function and mechanism of miR-455-5p action, and identify its potential target, Shc3, in PE. In vitro, when miR-455-5p was overexpressed in HTR-8/SVneo cells they migrated and invaded more rapidly under hypoxia/reoxygenation (H/R) than in either hypoxic or normoxic conditions. In contrast, apoptosis of HTR-8/SVneo was reduced in H/R. Shc3 was identified as a direct downstream target gene of miR-455-5p. Overexpression of Shc3 reversed the effect of miR-455-5p, promoting apoptosis and suppressing invasion and migration of HTR-8/SVneo under H/R. Shc3 was highly expressed in H/R, but its level was reduced in isolated hypoxic or normoxic environments. Furthermore, we showed Shc3 overexpression is involved in placental inflammation and angiogenesis inhibition. Finally, we showed that the downregulation of miR-455-5p in PE contributes to increased Shc3 in extravillous trophoblasts, thereby limiting extravillous trophoblast cell invasion. Elevated Shc3 is associated with placental inflammation and angiogenesis inhibition. Thus Shc3 serves as a potential biomarker for PE diagnosis and treatment., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2025 Gong et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Angiogenesis is a significant character of lung adenocarcinoma (LUAD) and is an important reason leading to high mortality rates of LUAD patients. However, the molecular mechanisms of lncRNAs regulating the angiogenesis in LUAD have not been fully elucidated. Here we show lncRNA chromatin-associated RNA 10 (CAR10) was upregulated in the tumor tissue of patients with LUAD and enhanced tumor metastasis. Mechanistically, CAR10 could bind to Lactate Dehydrogenase A (LDHA) protein to regulate the phosphorylation and acetylation of LDHA and increase the dimerization of LDHA to promote its nuclear translocation, which increased the H3K79 methylation in Vascular Endothelial Growth Factor A (VEGFA) and Vascular Endothelial Growth Factor C (VEGFC) gene interval. CAR10 induced microvascular formation in vivo and in vitro by regulating LDHA-VEGFA/C axis. In addition, MYC and TP53 bonded to the promotor of CAR10 and reverse regulated its expression in LUAD cells. CAR10 regulates post-translational modification of LDHA and increases the H3K79 methylation of VEGFA/VEGFC to promote angiogenesis of LUAD, which is a potential therapeutic target for LUAD., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Patients with estrogen receptor (ER)-positive breast cancer (BC) can be treated with endocrine therapy targeting ER, however, metastatic recurrence occurs in 25% of the patients who have initially been treated. Secreted proteins from tumors play important roles in cancer metastasis but previous methods for isolating secretory proteins had limitations in identifying novel targets., Methods: We applied an in situ secretory protein labeling technique using TurboID to analyze secretome from tamoxifen-resistant (TAMR) BC. The increased expression of LGALS3BP was validated using western blotting, qPCR, ELISA, and IF. Chromatin immunoprecipitation was applied to analyze estrogen-dependent regulation of LGALS3BP transcription. The adhesive and angiogenic functions of LGALS3BP were evaluated by abrogating LGALS3BP expression using either shRNA-mediated knockdown or a neutralizing antibody. Xenograft mouse experiments were employed to assess the in vivo metastatic potential of TAMR cells and the LGALS3BP protein. Clinical evaluation of LGALS3BP risk was carried out with refractory clinical specimens from tamoxifen-treated ER-positive BC patients and publicly available databases., Results: TAMR secretome analysis revealed that 176 proteins were secreted at least 2-fold more from MCF7/TAMR cells than from sensitive cells, and biological processes such as cell adhesion and angiogenesis were associated with the TAMR secretome. Galectin-3 binding protein (LGALS3BP) was one of the top 10 most highly secreted proteins in the TAMR secretome. The expression level of LGALS3BP was suppressed by estrogen signaling, which involves direct ERα binding to its promoter region. Secreted LGALS3BP in the TAMR secretome helped BC cells adhere to the extracellular matrix and promoted the tube formation of human umbilical vein endothelial cells. Compared with sensitive cells, xenograft animal experiments with MCF7/TAMR cells showed increased pulmonary metastasis, which completely disappeared in LGALS3BP-knockdown TAMR cells. Finally, higher levels of LGALS3BP were associated with poor prognosis in ER-positive BC patients treated with adjuvant tamoxifen in the clinic., Conclusion: TAMR secretome analysis identified secretory proteins, such as LGALS3BP, that are involved in biological processes closely related to metastasis. Secreted LGALS3BP from the TAMR cells promoted adhesion of the cells to the extracellular matrix and vasculature formation, which may support metastasis of TAMR cells., Competing Interests: Declarations. Ethics approval: The animal experiments were performed in accordance with the guidelines of the Seoul National University Animal Care and Use Committee (SNU-210906-2-3 and SNU-240124-3). Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Extensive neovascularization is a hallmark of glioblastoma (GBM). In addition to supplying oxygen and nutrients, vascular endothelial cells provide trophic support to GBM cells via paracrine signaling. Here we report that Endocan (ESM1), an endothelial-secreted proteoglycan, confers enhanced proliferative, migratory, and angiogenic properties to GBM cells and regulates their spatial identity. Mechanistically, Endocan exerts at least part of its functions via direct binding and activation of the PDGFRA receptor. Subsequent downstream signaling enhances chromatin accessibility of the Myc promoter and upregulates Myc expression inducing stable phenotypic changes in GBM cells. Furthermore, Endocan confers radioprotection on GBM cells in vitro and in vivo. Inhibition of Endocan-PDGFRA signaling with ponatinib increases survival in the Esm1 wild-type but not in the Esm1 knock-out mouse GBM model. Our findings identify Endocan and its downstream signaling axis as a potential target to subdue GBM recurrence and highlight the importance of vascular-tumor interactions for GBM development., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Emerging evidence suggests that TGFβ1 can inhibit angiogenesis, contradicting the coexistence of active angiogenesis and high abundance of TGFβ1 in the tumor microenvironment. Here, we investigated how tumors overcome the antiangiogenic effect of TGFβ1. TGFβ1 treatment suppressed physiologic angiogenesis in chick chorioallantoic membrane and zebrafish models but did not affect angiogenesis in mouse hepatoma xenografts. The suppressive effect of TGFβ1 on angiogenesis was recovered in mouse xenografts by a hypoxia-inducible factor 1α (HIF1α) inhibitor. In contrast, a HIF1α stabilizer abrogated angiogenesis in zebrafish, indicating that hypoxia may attenuate the antiangiogenic role of TGFβ1. Under normoxic conditions, TGFβ1 inhibited angiogenesis by upregulating antiangiogenic factor thrombospondin 1 (TSP1) in endothelial cells (EC) via TGFβ type I receptor (TGFβR1)-SMAD2/3 signaling. In a hypoxic microenvironment, HIF1α induced miR145 expression; miR145 abolished the inhibitory effect of TGFβ1 on angiogenesis by binding and repressing SMAD2/3 expression and subsequently reducing TSP1 levels in ECs. Primary ECs isolated from human hepatocellular carcinoma displayed increased miR145 and decreased SMAD3 and TSP1 compared with ECs from adjacent nontumor livers. The reduced SMAD3 or TSP1 in ECs was associated with increased angiogenesis in hepatocellular carcinoma tissues. Collectively, this study identified that TGFβ1-TGFβR1-SMAD2/3-TSP1 signaling in ECs inhibits angiogenesis. This inhibition can be circumvented by a hypoxia-HIF1α-miR145 axis, elucidating a mechanism by which hypoxia promotes angiogenesis. Significance: Suppression of angiogenesis by TGFβ1 is mediated by TSP1 upregulation in endothelial cells and abrogated by HIF1α-miR145 activity in the hypoxic tumor microenvironment, providing potential targets to remodel the tumor vasculature., (©2024 American Association for Cancer Research.)

As the most prevalent subtype of lung cancer, lung adenocarcinoma (LUAD) is closely associated with angiogenesis, which is fundamental to its progression. ADAM8 (A disintegrin and metalloproteinase 8) is an enzyme associated with tumor invasion, while its implications in LUAD angiogenesis are a field that awaits exploration. A thorough investigation into the impacts of ADAM8 on LUAD angiogenesis could contribute to the development of therapeutic drugs for LUAD. Bioinformatics delineated the expression profiles of TFAP2A and ADAM8 in LUAD tissues, focusing on ADAM8-enriched pathways. qRT-PCR confirmed their expression in LUAD cells. The CCK-8 assay was applied to gauge cell viability, and Western blot detected the presence of JAK2/STAT3 pathway proteins and VEGFR-2 and VEGF. Angiogenesis assays quantified the length of angiogenesis, and dual-luciferase and Chromatin immunoprecipitation assays verified the TFAP2A-ADAM8 binding. ADAM8 exhibited high expression in LUAD tissues and cells, with notable enrichment in the VEGF and JAK/STAT pathways. Cellular assays revealed that elevated ADAM8 expression enhanced cell viability, promoted the phosphorylation of JAK2 and STAT3, and boosted angiogenic capacity. The JAK inhibitor Peficitinib reversed the proangiogenic effects induced by ADAM8 overexpression. We also discovered overexpression of TFAP2A, an upstream transcription factor of ADAM8, in LUAD. Rescue experiments indicated that ADAM8 overexpression could counteract the inhibitory effects of TFAP2A knockdown on LUAD angiogenesis. This study reveals for the first time the critical role of ADAM8 in LUAD angiogenesis, demonstrating that TFAP2A promotes JAK/STAT pathway conduction by activating ADAM8. This finding not only provides a new perspective for understanding the pathogenesis of LUAD but also lays the foundation for the development of new therapies targeting ADAM8., (© 2025 Wiley Periodicals LLC.)

The tumor microenvironment, which is the tailored physiological milieu of heterogeneous cancer cell populations surrounded by stromal and immune cells as well as extracellular matrix components, is a leading modulator of critical cancer hallmarks and one of the most significant prognostic indicators in breast cancer. In the last few decades, with the discovery of the interactions of ncRNAs with diverse cellular molecules, considerable emphasis has been devoted to understanding their direct and indirect roles in specific functions in breast cancer. Collectively, all of these have revealed that the competitive action of protein-coding RNAs and ncRNAs such as circRNAs and lncRNAs, which have a shared affinity for miRNAs, play a vital role in the molecular regulation of breast cancer. This phenomenon, termed as competing endogenous RNAs (ceRNAs), facilitates modeling the microenvironment through intercellular shuttles. Microenvironment ceRNA interactions have emerged as a frontier in the deep understanding of the complex mechanisms of breast cancer. In this review, we first discuss cellular ceRNAs in four key biological processes critical for microenvironmental regulation in breast cancer tissues: hypoxia, angiogenesis, immune regulations, and ECM remodeling. Further, we draw a complete portrait of microenvironment regulation by cell-to-cell cross-talk of shuttled ceRNAs and offer a framework of potential applications and challenges in overcoming the aggressive phenotype of the breast cancer microenvironment., Competing Interests: Declarations. Conflict of Interest: The authors declare no competing interests. Ethics Approval and Consent to Participate: Not applicable., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Most epithelial cancers are infiltrated by prognostically relevant myelomonocytic cells. Immunosuppressive tumor associated macrophages (TAMs) and their precursor monocytic myeloid-derived suppressor cells (MDSCs) have previously been associated with worse outcomes in human breast cancer (BCa), yet the mechanism of immunosuppressive TAMs-polarization from myelomonocytic precursors is not completely understood. In this study, we show that persuaded AXL/GAS6 pathway alters macrophage phenotype from HLA-DR high CD206 low CD163 low classical phagocytic into HLA-DR low CD206 high CD163 high immunosuppressive ones with accelerated BCa progression, and increased angiogenesis signature and invasion ability of cancer cells at tumor beds. Notably, both AXL and GAS6 expressions are upregulated in human invasive breast carcinoma, with maximum expression in triple negative histology type. Mechanistically, we demonstrate that AXL/GAS6 signaling drives immunosuppression by governing increased immunosuppressive IL10 production while dampening IL-1β expression within the tumor microenvironment (TME) of BCa. Further, AXL/GAS6 signaling promotes angiogenesis through the activation of PI3K/AKT and NF-κB signaling pathways. Our results unveil role of AXL/GAS6 axis in the differentiation of TAMs, which governs malignant growth, and suggest that therapies that uncouple AXL/GAS6 axis may exhibit therapeutic opportunity for otherwise undruggable Triple Negative Breast Cancer (TNBC) patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Our objective was to elucidate the pivotal roles of BCAR1 in unfolded protein response (UPR), autophagy and vasculogenic mimicry (VM) formation, processes that essential for the metastasis of lung adenocarcinoma (LUAD) cells., Methods: The morphological assessment of endoplasmic reticulum (ER) status and autolysosomes in H1975 and H1299 LUAD cells following BCAR1 knockout (KO) was conducted using transmission electron microscope. The expression of markers and cellular functions related to the UPR, autophagy, and VM formation were examined in LUAD cells tissues. Additionally, proteomic analysis of LUAD cells was performed via mass spectrometry, and the pertinent signaling pathways were analyzed using bioinformatics tools., Results: BCAR1-KO inhibited autophagy and UPR induced triggered starvation in LUAD cells. Cleaved-ATF6a-mediated UPR and subsequent autophagy, enhanced by BCAR1, were confirmed using the UPR stimulator and blocker. High BCAR1 expression, along with elevated UPR and autophagy, predicts poor prognosis in LUAD patients. BCAR1-KO reduced tube formation and VM markers expressions in LUAD cells. Additionally, BCAR1 expression positively correlated with VM formation in BALB/c-nu mice xenografts and LUAD patient tissues., Conclusion: BCAR1 promotes LUAD metastasis by enhancing cancer cell survival in nutrient-poor environments through ATF6-mediated UPR activation and autophagy. As BCAR1 induces VM formation, metastatic lesions eventually colonize. Thus, BCAR1 is a promising anti-metastasis target., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Gliomas are common brain tumors. Despite extensive research, the 5-year survival rate of glioma remains low. Many studies have reported that circular RNAs (circRNAs) play a role in promoting the malignant progression of glioma; however, the role of circ_0059914 in this process remains unclear. In this study, we aimed to investigate the function and underlying mechanism of circ_0059914 in glioma. Western blotting and qRT-PCR were used to determine the levels of circ_0059914, miR-1249, VEGFA, N-cadherin, vimentin, Snail, and EIF4A3. EDU and colony formation assays were conducted to evaluate cell proliferation. Transwell assays were used to explore cell migration and invasion and tube formation assays were used to analyze angiogenesis. RNA immunoprecipitation (RIP) and dual-luciferase reporter assays were used to explore the relationship between EIF4A3, circ_0059914, miR-1249, and VEGFA. A xenograft tumor assay was performed to determine the role of circ_0059914 in vivo. Circ_0059914 expression was upregulated in gliomas. Knockdown of gliomal circ_0059914 expression reduced the proliferation, migration, invasion, epithelial-mesenchymal transition (EMT), angiogenesis, and growth of glioma cells in vivo. Circ_0059914 sponged miR-1249, and miR-1249 inhibition reversed the circ_0059914 knockdown-mediated effects in glioma cells. VEGFA was found to be a target gene of miR1249; overexpression of VEGFA reversed the effect of miR-1249 up-regulation in glioma. Finally, EIF4A3 increased the expression of circ_0059914. EIF4A3-induced circ_0059914 expression plays a role in promoting glioma via the miR-1249/VEGFA axis., Competing Interests: Declarations. Ethics Approval and Consent Participate: The present experiment was approved (approval no. 2022PS780K) by the Medical Ethics Committee of Shengjing Hospital (Shenyang, China). Consent for Publication: Not applicable. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: The overall prevalence of placenta accreta spectrum (PAS) is approximately 0.17 %, but it accounts for 7 % of maternal mortality and is associated with intraoperative and postoperative morbidity. The pathogenesis mechanisms of PAS include an imbalance between decidualization and trophoblast invasion. The aim of this study is to identify the pathogenesis roles of miR-34a in PAS., Methods: For this purpose, we collected 15 placenta tissues from pregnant subjects with PAS complications and another 15 placenta tissues from normal pregnancy (NP) cases. Then, we conducted in situ hybridization assay to compare miR-34a expression level, followed by in vitro simulations of NP and PAS with miR-34a and scrambled control (SC) mimic transfection in cells, respectively. Next, we conducted in vitro cellular assays to investigate the pathogenesis mechanisms of miR-34a in PAS., Results: We first confirmed significantly lower level of miR-34a in the trophoblast villous (TV) from PAS patients. By in vitro assays, lower miR-34a led to significantly higher cell proliferation and enhanced cell migration in TV epithelial cells. In addition, lower miR-34a resulted in elevated angiogenesis ability in vascular endothelial cells. Finally, to identify the pathway involved by miR-34a in PAS, we used microarray (raw data available via NCBI GEO database with accession number GSE279257) and flow cytometry to confirm that lower miR-34a significantly repressed the apoptosis activity in TV epithelial cells., Discussion: In this study, we not only confirmed miR-34a as a biomarker of PAS but also clarified the in vitro pathogenesis mechanism of miR-34a in PAS., Competing Interests: Declaration of Competing interest The authors declare no commercial or financial conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Rationale: The EGFR-driven angiogenesis is crucial in solid tumors, particularly through the delivery of biomolecules via extracellular vesicles (EVs), but the mechanism by which EGFR regulates EV cargo is still unclear. Methods: First, cell co-culture and murine tumor models were employed to examine the impact of EGFR overexpression on the pro-angiogenic properties of small EVs (sEVs) derived from oral squamous cell carcinoma (OSCC). Small RNA sequencing was then used to compare the miRNA profiles of OSCC-sEVs with and without EGFR overexpression, followed by functional enrichment and motif analyses of the differentially expressed miRNAs. Next, miRNA pull-down assays were conducted to identify potential molecules involved in sorting these miRNAs. Finally, the role of the candidate sorting protein was validated using existing public database, tissue samples, cell lines, and murine tumor models. Results: EGFR overexpression significantly enhances the pro-angiogenic effects of OSCC-sEVs, accompanied by a marked increase in the content of nucleic acid cargo carried in these sEVs. Small-RNA sequencing identified a group of miRNAs that were significantly enriched in OSCC-sEVs due to EGFR overexpression, which primarily functioned in angiogenesis and shared a characteristic "GGGU" motif. EGFR overexpression also strengthened the binding of PCBP2 with miRNAs containing this "GGGU" motif, thereby promoting their secretion through sEVs to support tumor angiogenesis. Mechanismly, EGFR overexpression upregulates PCBP2 protein content by activating its transcription rather than regulating the mRNA stability in OSCC cells. Additionally, depletion of PCBP2 impaired the EGFR-driven tumor angiogenesis by inhibiting the secretion of pro-angiogenic miRNAs through sEVs. Conclusions: EGFR boosts PCBP2 expression via transcriptional regulation, which then promotes the loading of specific miRNAs into sEVs by binding to the "GGGU" motif, thereby driving tumor angiogenesis., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Tumor angiogenesis and the presence of cancer stem cells (CSCs) are critical characteristics of tumors. Previous research has demonstrated that cancer stem cells promote tumor angiogenesis, while increased vascularity, in turn, fosters the growth of cancer stem cells. This creates a detrimental cycle that contributes to tumor progression. However, studies investigating the angiogenesis and stemness characteristics in ovarian cancer (OV) are limited. In this study, we employed cluster analysis and LASSO methods to assess the significance of angiogenesis- and stemness-related genes in the efficacy of OV immunotherapy. Through multivariate Cox regression analysis and Friends analysis, we identified TNFSF11 as the most significant prognostic gene associated with angiogenesis and stemness. Additionally, molecular docking results confirmed that TNFSF11 exhibits a high affinity for sorafenib and sunitinib. In summary, for the first time, we conducted a comprehensive analysis of the roles of angiogenesis and stemness-related genes in the prognosis and immunotherapy of OV patients, revealing TNFSF11 as a novel therapeutic target., (© 2024 The Author(s). BioFactors published by Wiley Periodicals LLC on behalf of International Union of Biochemistry and Molecular Biology.)

Angiogenesis significantly drives tumor progression, and the functions of vascular endothelial cells are influenced by various factors. Tumor cells are characterized by abnormal sialylation, and their dynamic balance depends on sialyltransferases and sialidases. NEU3 is a plasma membrane-associated sialidase, vital for the regulation of cell surface sialylation. Our study revealed that, NEU3 is the most abundantly expressed among the four sialidase subtypes in EA.hy926 cells. Silencing NEU3 expression resulted in cell apoptosis and reduced proliferation, highlighting its crucial function in the regulation of cell activity. Subsequent experiments using transwell and tube formation assays demonstrated that the inhibition of NEU3 expression suppressed cell migration and angiogenesis. RNA sequencing analysis further elucidated that altering NEU3 expression in EA.hy926 cells impacts the Wnt/β-Catenin signaling pathway and c-Myc levels, thereby modulating cellular survival and migration capacity and exerting a regulatory effect on angiogenesis. These findings suggest that targeting NEU3 in the vascular endothelium may represent a promising strategy for anti-angiogenic therapy in tumors., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Xue Ma reports financial support was provided by Science and Technology Department of Sichuan Province. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Hepatocellular carcinoma (HCC) remains a lethal malignancy with limited treatment options. Recent discoveries have highlighted the pivotal role of miRNAs in HCC progression. We previously reported that the expression of miR-200b-3p was decreased in HCC cells and exosomal miR-200b-3p from hepatocytes inhibited angiogenesis by suppressing the expression of the endothelial transcription factor ERG (erythroblast transformation-specific (ETS)-related gene), leading to the hypothesis that the delivery of this miRNA may inhibit angiogenesis and suppress HCC growth in vivo. Here, we tested this hypothesis by using human HCC inoculation models. First, we transfected the human HepG2 HCC cells and established a stable cell line that overexpressed a high level of miR-200b-3p. When miR-200b-3p-overexpressing cells were injected into severe combined immunedeficiency (SCID)-beige mice, tumor growth was significantly reduced compared to tumors of control cells, with a reduction in the expression of ERG and vascular endothelial growth factor (VEGF) and subsequent angiogenesis. Intra-tumoral injection of exosomes containing high levels of miR-200b-3p also reduced the growth of parental HepG2 tumors with reduced ERG and VEGF expression and angiogenesis. These results validate the inhibitory role of miR-200b-3p in tumor angiogenesis, thereby suppressing HCC tumor growth, and provide a novel insight into its potential therapeutic application., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Promoting vascular endothelial cell regeneration can enhance recovery from cerebral ischemia reperfusion injury (CIRI), but there is a lack of bioinformatic studies on angiogenesis-related biomarkers in CIRI. In this study, we utilized the GSE97537 and GSE61616 datasets from GEO to identify 181 angiogenesis-related genes (ARGs) and analyzed differentially expressed genes (DEGs) between CIRI and control groups. We converted ARGs to 169 rat homologues and intersected them with DEGs to find DE-ARGs. RF and XGBoost models were employed to identify five biomarkers (Stat3, Hmox1, Egfr, Col18a1, Ptgs2) and conducted GSEA on these biomarkers, revealing their enrichment in pathways such as ECM-receptor interaction and hematopoietic cell lineage. We also analyzed the immune microenvironment, finding significant differences in 21 immune cells between CIRI and control groups. Furthermore, we constructed lncRNA-miRNA-mRNA networks and drug-gene networks. Finally, biomarker expression was compared between the CIRI and control groups by qRT-PCR in tissue and blood samples. Overall, our bioinformatic exploration of angiogenesis-related biomarkers in CIRI provides new insights for the diagnosis and treatment of CIRI., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Up to 50% of individuals with uveal melanoma (UM), a frequent cancer of the eye, pass away from metastases. One of the major challenges in treating UM is the role of receptor tyrosine kinases (RTKs), which mediate the epithelial-mesenchymal transition (EMT) of tumors. RTKs are involved in binding multiple growth factors, leading to angiogenesis and vasculogenic mimicry (VM) phenomena. Currently, most anti-angiogenic drugs have shown a tendency to increase the VM of tumors in clinical trials, resulting in limited efficacy. The existing gap in UM treatment lies in the lack of effective strategies to target RTK-mediated EMT and VM. While some approaches have been attempted, there is still a need for novel therapeutic interventions that can specifically interfere with these processes. This research employed the gene vector PEI-g-PEG to interfere with the platelet derived growth factor-alpha receptor (PDGFR-α)-mediated EMT process, thereby retarding the growth of UM. The cell experiments demonstrated that the gene polyplex exhibited favorable cell uptake and lysosome escape properties, effectively suppressing the expression of PDGFR-α protein and EMT marker proteins and the occurrence of VM phenomenon. In vivo animal studies also inhibited the growth of UM, and PAS assays showed that the treatment reduced the generation of VM in tumor tissue. This study broadens the application of PEI-g-PEG while interfering with the RTK-mediated tumor EMT process with the help of RNAi technology, providing a new idea for tumor reduction research., Competing Interests: Declarations. Ethics approval and consent to participate: The animal experiment was approved by the Experimental Animal Ethics Committee of Eye Hospital of Wenzhou Medical University. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Breast cancer is the most prevalent cancer among women worldwide. Most breast cancer-related deaths result from metastasis and drug resistance. Novel therapies are imperative for targeting metastatic and drug-resistant breast cancer cells. Accumulating evidence suggests that dysregulated microRNAs (miRNAs) promote breast cancer progression, metastasis, and drug resistance. Compared with healthy breast tissue, miR-660-5p is notably overexpressed in breast cancer tumor tissues. However, the downstream effectors of miR-660-5p in breast cancer cells have not been fully elucidated. Our aim was to investigate the role of miR-660-5p in breast cancer cell proliferation, migration, invasion, and angiogenesis and to identify its potential targets., Results: Our findings revealed significant upregulation of miR-660-5p in MDA-MB-231 and MCF-7 cells compared with MCF-10 A cells. Furthermore, inhibiting miR-660-5p led to notable decreases in the proliferation, migration, and invasion of breast cancer cells, as well as angiogenesis, in HUVEC cells. Through bioinformatics analysis, we identified 15 potential targets of miR-660-5p. We validated TMEM41B as a direct target of miR-660-5p via Western blot and dual-luciferase reporter assays., Conclusions: Our study highlights the upregulation and involvement of miR-660-5p in breast cancer cell proliferation, migration, invasion, and angiogenesis. Additionally, we identified TMEM41B as a direct target of miR-660-5p in breast cancer cells., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Functional cell death pathways are essential for normal ocular vascular development and tissue homeostasis. As our understanding of necrosis-based cell death pathways has expanded, the inclusion of regulated forms, including necroptosis, ferroptosis, and oxytosis, has occurred. Although the existence of these pathways is well described, our understanding of their role during vascular development and pathological neovascularization is very limited. Here, we examined the role of receptor-interacting protein kinase-3 (Ripk3), a key regulator of necroptosis, in postnatal retinal vascularization and retinal and choroidal neovascularization under pathological conditions. Postnatal vascularization of the retinal superficial layer in the absence of Ripk3 ( Ripk3 -/- ) was not significantly different from wild-type mice. However, we noted decreased retinal endothelial cells and pericyte numbers at 3 weeks of age when the formation of the retinal primary vascular plexus was complete. In contrast, choroidal and retinal neovascularization following laser treatment and oxygen-induced ischemic retinopathy increased in the absence of Ripk3 expression, respectively. In addition, the inhibition of RIPK1/3 activity suppressed choroidal neovascularization. Thus, Ripk3 expression and/or activity may have unique roles during normal and pathological ocular vascularization through its interactions with Caspase 8 and modulation of cell death processes.

Background: Krüppel-like factor 5 (KLF5) is recognized as a tumor mediator in multiple types of tumors. Nevertheless, whether KLF5 plays a role in gallbladder cancer (GBC) remains to be elucidated. This study aims to clarify the role of KLF5 in the proliferation, migration and angiogenesis in GBC cells., Methods: The expressions of KLF5 and platelet-derived growth factor subunit A (PDGFA) in GBC cell lines were analyzed by qRT-PCR and western blot assay. Cell proliferation was assessed utilizing the Cell Counting Kit-8 assay and EDU staining. Cell apoptosis was evaluated using flow cytometry, and apoptosis-related proteins was examined by western blotting. The migratory and invasive capabilities were evaluated utilizing wound healing and Transwell. Angiogenesis was assessed by ELISA, tube formation assay and western blot. The interaction between KLF5 and PDGFA was confirmed by ChIP assay, as well as luciferase reporter assay., Results: In this study, we discovered that the levels of KLF5 and PDGFA were upregulated in GBC cells. Silencing of KLF5 reduced the viability and suppressed the proliferation of GBC cells, as well as promoting the apoptosis. In addition, KLF5 silencing restrained the invasion and migration and angiogenesis in NOZ and GBC-SD cells. KLF5 transcription activated PDGFA expression and KLF5 was proved to bind to PDGFA promoter in NOZ cells. Following the silencing of PDGFA, the proliferation, invasion, migration, angiogenesis and apoptosis exhibited similar changes to KLF5 silencing. Additionally, PDGFA overexpression reversed the effects of KLF5 silencing on NOZ cells., Conclusion: Collectively, our results suggest that KLF5 regulates GBC cell proliferation, invasion, migration, angiogenesis, as well as apoptosis, via mediating PDGFA transcriptionally, which might provide a novel therapeutic strategy for treatment of human GBC., Competing Interests: Declarations. Conflict of interest: The authors declare no competing financial interests. Ethical approval: Not applicable., (© 2024. The Author(s).)

Rheumatoid arthritis (RA) is a chronic autoimmune disorder marked by pain, inflammation, and discomfort in the synovial joints. It is critical to understand the pathological mechanisms of RA progression. MicroRNA-378 (miR-378) is highly expressed in the synovium of RA patients and positively correlated with disease severity, but its function and underlying mechanisms remain poorly understood. In this study, miR-378 transgenic (miR-378 high ) mice were used to construct the collagen-induced arthritis (CIA) model for exploring the role of miR-378 in RA development. miR-378 high CIA mice showed accelerated RA development, as evidenced by exaggerated joint swelling and bone structural deformities. More severe endoplasmic reticulum (ER) stress and the consequent angiogenesis and osteoclastogenesis were also activated in the synovial tissue and calcaneus, respectively, in the miR-378 high group, suggesting that ER plays a significant role in miR-378-mediated RA pathogenesis. Upon in vitro RA induction, fibroblast-like synoviocytes (FLSs) isolated from miR-378 high mice showed a higher expression level of ER stress markers. The conditioned medium (CM) from RA-FLSs of miR-378 high mice stimulated more intensive angiogenesis and osteoclastogenesis. The ER stress-related protein Crebrf was identified as a downstream target of miR-378. Crebrf knockdown diminished the promoting effect of miR-378 on ER stress, as well as its downstream angiogenesis and osteoclastogenesis activities. Tail vein injection of anti-miR-378 lentivirus in an established RA mouse model was shown to ameliorate RA progression. In conclusion, miR-378 amplified RA development by promoting ER stress and downstream angiogenesis and osteoclastogenesis, thus indicating that miR-378 may be a potential therapeutic target for RA treatment., Competing Interests: Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: This study was carried out in accordance with the principles outlined in the Declaration of Helsinki. The Laboratory Animal Ethics Committee at the Chinese University of Hong Kong reviewed and approved all experimental procedures involving these animals., (© 2024. The Author(s).)

Colorectal cancer is a common malignant tumor, whose growth and metastasis are influenced by numerous factors. MicroRNAs have garnered increasing attention in recent years due to their involvement in tumor development. Exosomes are involved in intercellular signaling and influence tumor development by promoting tumor cell proliferation and metastasis through activation of angiogenesis and other mechanisms. This study aimed to investigate how the exosomes containing miR-320d from colorectal cancer (CRC) cells promote colorectal cancer metastasis by regulating angiogenesis. CRC-derived exosomes containing miR-320d can be transferred to vascular endothelial cells, facilitating their proliferation, invasion, migration, and angiogenesis. By targeting GNAI1, miR-320d in these exosomes reduces GNAI1 levels in endothelial cells, causing more JAK2/STAT3 activation and VEGFA production. This ultimately enhances the migration and angiogenic capacity of vascular endothelial cells. Moreover, CRC patients with high levels of miR-320d in their blood respond better to treatment with bevacizumab. In vivo experiments further proved the role of miR-320d from CRC exosomes in increasing tumor size, blood vessel formation, and the spread of cancer to the liver. In this study, we have demonstrated that exosomal miR-320d promotes cancer cell metastasis and enhances angiogenesis by downregulating GNAI1 expression and enhancing JAK2/STAT3., Competing Interests: Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: The studies involving human participants (20171008) and animals (2024001004) were reviewed and approved by the Ethics Committee of Shandong Cancer Hospital and Institute. Informed consent was obtained from their families. All procedures were conducted in accordance with the Declaration of Helsinki., (© 2024. The Author(s).)

C-X-C motif chemokine ligand 12 (CXCL12; Stromal Cell-Derived Factor 1 [SDF-1]), most notably known for its role in embryogenesis and hematopoiesis, has been implicated in tumor pathophysiology and neovascularization. However, its cell-specific role and mechanism of action have not been well characterized. Previous work by our group has demonstrated that hypoxia-inducible factor (HIF)-1 modulates downstream CXCL12 expression following ischemic tissue injury. By utilizing a conditional CXCL12 knockout murine model, we demonstrate that endothelial-specific deletion of CXCL12 (eKO) modulates ischemic tissue survival, altering tissue repair and tumor progression without affecting embryogenesis and morphogenesis. Loss of endothelial-specific CXCL12 disrupts critical endothelial-fibroblast crosstalk necessary for stromal growth and vascularization. Using murine parabiosis with novel transcriptomic technologies, we demonstrate that endothelial-specific CXCL12 signaling results in downstream recruitment of non-inflammatory circulating cells, defined by neovascularization modulating genes. These findings indicate an essential role for endothelial-specific CXCL12 expression during the neovascular response in tissue injury and tumor progression., (© 2024 Federation of American Societies for Experimental Biology.)

Hepatocellular carcinoma (HCC) is a highly aggressive malignant tumor with a poor prognosis. This research aimed to investigate the role of F13B in HCC and its underlying mechanisms. Through comprehensive bioinformatics analysis of the GSE120123 and The Cancer Genome Atlas (TCGA)-Liver hepatocellular carcinoma (LIHC) datasets, we identified 220 overlapping prognosis-related genes. Eight key genes, including the previously unreported CCDC170 and F13B in HCC, were identified through Least Absolute Shrinkage and Selection Operator (LASSO)-Cox regression analysis. F13B emerged as a significant prognostic factor in HCC, warranting further investigation in subsequent analyses. In vitro experiments showed that F13B expression was notably reduced in HCC cell lines and tissues, particularly in Huh-7 and SMMC-7721 cells. Overexpression of F13B inhibited cell invasion, migration, and proliferation, while its knockdown produced the opposite effect. A lactate dehydrogenase (LDH) activity assay in human umbilical vein endothelial cells (HUVECs) demonstrated that F13B overexpression reduced vascular endothelial growth factor (VEGF)-induced cytotoxicity, whereas knockdown increased it. Further analysis revealed that F13B negatively regulates VEGFA expression, affecting HUVEC proliferation. In HUVECs, F13B overexpression reversed VEGF-induced upregulation of key angiogenesis markers, including phospho-VEGF receptor 2 (p-VEGFR2), matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), as well as AKT/mTOR signaling proteins, phospho-Akt (p-AKT), and phospho-mTOR (p-mTOR). Additionally, F13B negatively regulated VEGFA and hypoxia-inducible factor 1 A (HIF1A) under hypoxic conditions, counteracting the hypoxia-induced increase in cell viability. These findings suggest that F13B regulates angiogenesis through the HIF-1α/VEGF pathway and plays a crucial role in HCC progression. Our results highlight the potential of F13B as a therapeutic target in HCC, providing novel insights into the molecular mechanisms of HCC and its prognostic significance.

Glioblastoma is considered the most aggressive tumor of the central nervous system. The tumor microenvironment includes several components, such as endothelial cells, immune cells, and extracellular matrix components like matrix metalloproteinase-9 (MMP-9), which facilitates the proliferation of endothelial cells with pro-angiogenic roles. The MRI characteristics of glioblastomas can contribute to determining the prognosis. The aim of this study was to analyze the relationship between tumor angiogenesis in glioblastomas in association with MMP-9 immunoexpression. The results were correlated with the Ki-67 proliferation index, p53 immunoexpression, and the mutational status of IDH1 and ATRX , as well as MRI imaging data. This retrospective study included forty-four patients diagnosed with glioblastoma at the Department of Pathology, Târgu Mureș County Emergency Clinical Hospital. MMP-9 immunoexpression was observed in approximately half of the cases, more frequently in patients over 65 years old. Comparing the imaging data with the immunohistochemical results, we observed that the median tumor volume was higher in glioblastomas with IDH1 and p53 mutations, ATRX wild-type status, negative MMP-9 expression, and high Ki-67 proliferation indexes. The median values of MVD-CD34 and MVD-CD105 were higher in cases with extensive peritumoral edema in the contralateral hemisphere. Additionally, ATRX mutations were frequently associated with a more pronounced deviation of the median structures. To statistically validate the associations between MRI and the histopathological features of glioblastomas, further studies with larger cohorts are required.

Context: Pileostegia tomentella Hand. Mazz (Saxifragaceae) total coumarins (TCPT) show antitumour activity in colorectal cancer (CRC) with unknown mechanism of action. Tumour angiogenesis mediated by exosomes-derived miRNA exhibits the vital regulation of endothelial cell function in metastasis of CRC., Objective: To investigate the effect of TCPT on exosomal miRNA expression and angiogenesis of CRC cells., Materials and Methods: HT-29-derived exosomes were generated from human CRC cells (HT-29) or either treated with TCPT (100 μg/mL) for 24 h, followed by identification by transmission electron microscope, nanoparticle tracking analysis (NTA) and Western blot. Co-culture experiments for human umbilical vein endothelial cells (HUVECs) and exosomes were performed to detect the uptake of exosomes in HUVECs and its influence on HUVECs cells migration and lumen formation ability. Potential target miRNAs in exosomes were screened out by sequencing technology. Rescue assays of angiogenesis were performed by the transfecting mimics or inhibitors of targeted miRNA into HUVECs., Results: HT-29-derived exosomes, after TCPT treatment (Exo-TCPT), inhibited the migration and lumen formation of HUVECs, reduced the expression levels of vascular marker (FLT-1, VCAM-1 and VEGFR-2) in HUVECs. Furthermore, the level of miR-375-3p was significantly upregulated in Exo-TCPT. Rescue assays showed that high expression of miR-375-3p in HUVECs inhibited migration and lumen formation abilities, which was consistent with the effects of Exo-TCPT, whereas applying miR-375-3p inhibitors displayed opposite effects., Discussion and Conclusion: TCPT exhibits anti-angiogenesis in CRC, possibly through upregulating exosomal miR-375-3p. Our findings will shed light on new target exosomes miRNA-mediated tumour microenvironment and the therapeutic application of Pileostegia tomentella in CRC.

TGFβ-inhibited membrane associated protein (TIMAP), the endothelial cell-predominant protein phosphatase 1β regulatory subunit also known as PPP1R16B, promotes in vitro endothelial cell proliferation and angiogenic sprouting. TIMAP was first identified as a target of TGF-β1-mediated repression, but the molecular pathways regulating its expression in endothelial cells are not well-defined. This study examined the role of bone morphogenetic factor 9 (BMP9), hypoxia, and angiogenic growth factors in the regulation of TIMAP expression and determined whether TIMAP plays a role in tumor angiogenesis and growth in vivo. BMP9, which potently activated the SMAD1/5/8 pathway in endothelial cells, significantly reduced TIMAP mRNA and protein expression. Conversely, hypoxia and the prolyl hydroxylase inhibitor Roxadustat raised TIMAP mRNA and protein levels by inhibiting the SMAD1/5/8 pathway. Angiogenic growth factors, including VEGFA and IGF-I, raised endothelial TIMAP levels partly by attenuating SMAD1/5/8 pathway activation, but also through SMAD1/5/8-independent mechanisms. Cultured breast cancer E0771 cells released mediators that raised TIMAP expression in endothelial cells, effects that were inhibited by the VEGF inhibitor Sunitinib in conjunction with the IGF-1 inhibitor Picropodophyllin. In the mouse E0771 breast cancer model in vivo, tumor growth and tumor angiogenesis were markedly attenuated in TIMAP deficient, compared with wild-type littermates. These findings indicate that TIMAP plays a critical proangiogenic function during tumor angiogenesis in vivo, likely through hypoxia-driven inhibition of the SMAD1/5/8 pathway and through the elaboration of angiogenic growth factors by tumor cells. NEW & NOTEWORTHY The protein phosphatase 1 regulatory subunit TGFβ-inhibited membrane associated protein (TIMAP), known to activate AKT in endothelial cells (EC), was shown here to be repressed by bone morphogenetic factor 9 (BMP9). Hypoxia and angiogenic growth factors induced TIMAP expression by inhibiting the BMP9 pathway. In a mouse breast cancer model, TIMAP deletion inhibited tumor angiogenesis and tumor growth. Therefore, the proangiogenic functions of TIMAP are induced by hypoxia and angiogenic growth factors.

Esophageal squamous cell carcinoma (ESCC) has high mortality. The role and regulatory mechanism of hsa_circ_0021727 (circ_0021727) in ESCC remain largely unknown. This study focused on the undiscovered impact of circ_0021727 on cell cycle progression, apoptosis, and angiogenesis of ESCC. We found that circ_0021727 levels were significantly upregulated in ESCC cells. TUNEL, flow cytometry, and tubule formation assay indicated that knockdown of circ_0021727 in ESCC induced cell arrest at the G0/G1 phase, promoted apoptosis, and inhibited angiogenesis, whereas overexpression of circ_0021727 produced the opposite effect. Gastrulation brain homeobox 2 (GBX2) GBX2 was a downstream target gene of circ_0021727, and overexpression of GBX2 reversed the effect of circ_0021727 knockdown in ESCC progression. The results of the RIP and RNA pull-down showed that circ_0021727 and GBX2 mRNA bound with eukaryotic translation initiation factor 4A3 (EIF4A3). Overexpression of circ_0021727 promoted GBX2 mRNA stability by binding with EIF4A3. In a tumor xenograft model, the knockdown of circ_0021727 inhibited tumor growth, which was reversed by further overexpression of GBX2. In conclusion, circ_0021727 increased GBX2 mRNA stability by recruiting EIF4A3, which promoted cell cycle progression and angiogenesis in ESCC.

Intracerebral hemorrhage (ICH) is a subtype of stroke with the highest fatality and disability rate. Up to now, commonly used first-line therapies have limited value in improving prognosis. Angiogenesis is essential to neurological recovery after ICH. Recent studies have shown that microRNA-451(miR-451) plays an important role in angiogenesis by regulating the function of vascular endothelial cells. We found miR-451 was significantly decreased in the peripheral blood of ICH patients in the acute stage. Based on the clinical findings, we conducted this study to investigate the potential regulatory effect of miR-451 on angiogenesis after ICH. The expression of miR-451 in ICH mouse model and in a hemin toxicity model of human brain microvascular endothelial cells (hBMECs) was decreased the same as in ICH patients. MiR-451 negatively regulated the proliferation, migration, and tube formation of hBMECs in vitro. MiR-451 negatively regulated the microvessel density in the perihematoma tissue and affected neural functional recovery of ICH mouse model. Knockdown of miR-451 could recovered tight junction and protect the integrity of blood-brain barrier after ICH. Based on bioinformatic programs, macrophage migration inhibitory factor (MIF) was predicted to be the target gene and identified to be regulated by miR-451 inhibiting the protein translation. And p-AKT and p-ERK were verified to be downstream of MIF in angiogenesis. These results all suggest that miR-451 will be a potential target for regulating angiogenesis in ICH., Competing Interests: Declarations. Ethics Approval and Consent to Participate: This study was approved by the Ethics Committee of the Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China (No. TJ-IRB20211270). All participants provided written informed consent for the study. This study was approved by the Institute of Animal Care Committee (IACUC; protocol 4000152) of Tongji Medical College, Huazhong University of Science and Technology, China. Consent for Publication: Not applicable. Conflict of Interest: The authors declare no competing interests., (© 2024. The Author(s).)

In gastric cancer (GC), tumor cell metastasis to lymph node may occur, and can be impacted by synaptojanin 2 (SYNJ2). Herein, we explored the mechanism of SYNJ2 in the progress of GC. SYNJ2 level in GC tissues was predicted by GEPIA database. After GC cells were transfected with short hairpin RNA against SYNJ2 (shSYNJ2), shGRB2, SYNJ2 overexpression plasmid and growth factor receptor-bound protein 2 (GRB2) overexpression plasmid, the mRNA levels of SYNJ2 and GRB2 in GC cells were quantified by qRT-PCR. CCK-8, flow cytometry, wound healing, transwell and tube formation assays were performed for detecting viability, apoptosis, migration, invasion and angiogenesis of GC cells. Protein levels of GRB2, vascular endothelial growth factor (VEGF), E-Cadherin, N-Cadherin and Vimentin in GC cells were measured by Western blot. The relationship between SYNJ2 and GRB2 was assessed by Co-immunoprecipitation (CO-IP) assay. SYNJ2 was highly expressed in GC tissues and cells. SYNJ2 overexpression promoted viability, migration, invasion, angiogenesis and GRB2 level, and inhibited apoptosis of GC cells, while shSYNJ2 exhibited opposite effects. GRB2 overexpression boosted yet shGRB2 suppressed cell migration, invasion and angiogenesis. Notably, SYNJ2 could interact with GRB2. GRB2 overexpression and shGRB2 reversed the effects of shSYNJ2 and overexpressed SYNJ2 on cell migration, invasion and angiogenesis and levels of metastasis-related proteins, respectively. In conclusion, SYNJ2 promotes GC cell metastasis and angiogenesis by up-regulating GRB2., Competing Interests: Conflict-of-interest The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Gestational diabetes mellitus (GDM) presents significant risks during pregnancy, including adverse perinatal outcomes and placental dysfunction. Impaired angiogenesis, involving crucial factors like Vascular Endothelial Growth Factor (VEGF), contributes to these complications. The Nrf2/Keap1 pathway, crucial for vascular redox homeostasis, has been linked to GDM-associated angiogenesis dysregulation., Methods: This study aimed to investigate the molecular mechanisms underlying placental Nrf2 regulation, focusing on angiomiRs, key regulators of angiogenesis in GDM. Computational analysis identified miR-142-5p targeting Nrf2 mRNA. Expression levels of miR-142-5p were assessed in GDM placenta and correlated with Nrf2 expression. Experimental validation utilized human trophoblastic cell lines (BeWo) exposed to hyperglycemic conditions, assessing the effects of anti-miR-142 transfection on Nrf2 expression and angiogenic marker levels., Results: miR-142-5p expression was significantly downregulated in GDM placenta, correlating positively with Nrf2 expression. In BeWo cells exposed to hyperglycemia, anti-miR-142 transfection notably increased Nrf2 expression alongside angiogenic marker levels, confirming the computational predictions., Discussion: Our findings highlight the pivotal role of miRNAs in GDM-associated impaired angiogenesis by modulating Nrf2 expression. Understanding these molecular mechanisms provides insights into potential therapeutic targets for improving pregnancy outcomes in GDM cases., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests Ramkumar KM reports was provided by SRM Institute of Science and Technology., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: To explore the role of miR-29 in bladder cancer, released by exosomes into brain microglia to influence its polarization and promote angiogenesis. This, in turn, would help design therapeutic strategies for brain metastasis caused by bladder cancer., Methods: The relative expression of miR-29 in normal bladder and bladder cancer cells was compared by qPCR technology, and the difference of specific binding between PI3K and has-miR-29a in the NC group and mimic group was verified by luciferase activity. Bladder cancer cells T24 were transfected with miR-29 NC, mimic, or neferine and divided into miR-29-NC group, miR-29-mimic group, miR-29-NC-neferine group, and miR-29-mimic-neferine group. Then they were co-cultured with microglia BV2 in a 1% hypoxia environment. The protein expressions of p-PI3K, p-AKT, p-AMPK, p-PGC-1α, p-PPARγ, CD206, and HIF1α in glial cells BV2 were detected by Western blot. The effect of each group on angiogenesis was observed by the tube formation experiment. A glioma mouse model was established, and the number of blood vessels and tumor proliferation were observed by pathological section H&E staining, to assess the effect of miR-29 on angiogenesis., Results: qPCR and dual-luciferase reporter assay showed that miR-29 was highly expressed in bladder cancer compared with normal bladder cells. The binding of miR-29 to PI3K led to the degradation of PI3K mRNA. Protein expression analysis showed that miR-29 inhibited PI3K and p-AKT in bladder cancer cells, and promoted the expression of p-AMPK, p-PGC-1α, p-PPARγ, CD206, and HIF1α. In vivo experiments demonstrated that miR-29 could promote the cell volume of bladder cancer cells and increase the number of blood vessels in bladder cancer cells, while neferine could inhibit the above effects., Conclusion: miR-29 can regulate PI3K/AMPK/PGC-1α/PPAR-γ signaling in microglial cells, promote their polarization to M2, and ultimately promote neovascularization in bladder cancer.