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Akt2 influences the expression of HIF-1α/VEGF through mTOR. Protein measurement of mTOR and p-mTOR by western blotting after transfecting pcDNA-Akt2 and sh-Akt2 (A); mRNA measurement of VEGF and HIF-1α by qPCR after treatment with shAkt2, pcDNA-Akt2 + Rapamycin, or sh-Akt2 + MHY1485 (B); Protein measurement of VEGF and HIF-1α by western blotting after treatment with sh-Akt2, pcDNA-Akt2 + Rapamycin, or sh-Akt2 + MHY1485 (C). Values are displayed as the mean ± SD from 3 independent experiments. *P<0.05 or **P<0.01, ***P<0.001 compared with the blank control and NC.
Source publication
Background:
Bladder cancer is one of the most frequent urologic tumours in the world. MicroRNA-200c (miR-200c) has been considered a regulator of tumour angiogenesis. Akt2/mTOR was considered a regulator of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1α (HIF-1α). However, the mechanism by which miR-200c regulates bladder...
Contexts in source publication
Context 1
... we further investigated if Akt2 could influence HIF-1α/VEGF through mTOR. First, we transfected pcDNA-Akt2 and sh-Akt2 in both the 5627 and T24 cell lines and proved that overexpression of Akt2 significantly increased the expression of mTOR and p-mTOR, but shAkt2 exerted the opposite effect ( Figure 4A). Therefore, Akt2 could influence the expression of mTOR. ...
Context 2
... is the specific inhibitor of mTOR, and MHY1485 is the activator of mTOR. The expression of mTOR was markedly decreased after treatment with sh-Akt2 ( Figure 4A). Compared with group NC, the protein and mRNA expression of HIF-1α/VEGF were remarkably decreased in sh-Akt2 and pcDNA-Akt2 + Rapamycin. ...
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Objective:
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Purpose:
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Citations
... Thus, we wondered whether miR-200c-3p could target ECs to down-regulate Flt1 and thereby promote ATII cell transdifferentiation in a paracrine manner. This idea is consistent with recent studies describing a role for miR-200c in cancerassociated angiogenesis [26][27][28], and with other studies highlighting the role of angiogenesis during alveolar regeneration [8,9,29]. ...
Pulmonary fibrosis is a devastating disease, in which fibrotic tissue progressively replaces lung alveolar structure, resulting in chronic respiratory failure. Alveolar type II cells act as epithelial stem cells, being able to transdifferentiate into alveolar type I cells, which mediate gas exchange, thus contributing to lung homeostasis and repair after damage. Impaired epithelial transdifferentiation is emerging as a major pathogenetic mechanism driving both onset and progression of fibrosis in the lung. Here, we show that lung endothelial cells secrete angiocrine factors that regulate alveolar cell differentiation. Specifically, we build on our previous data on the anti-fibrotic microRNA-200c and identify the Vascular Endothelial Growth Factor receptor 1, also named Flt1 , as its main functional target in endothelial cells. Endothelial-specific knockout of Flt1 reproduces the anti-fibrotic effect of microRNA-200c against pulmonary fibrosis and results in the secretion of a pool of soluble factors and matrix components able to promote epithelial transdifferentiation in a paracrine manner. Collectively, these data indicate the existence of a complex endothelial-epithelial paracrine crosstalk in vitro and in vivo and position lung endothelial cells as a relevant therapeutic target in the fight against pulmonary fibrosis.
... Instantly, the TS miRNAs such as miR-381, miR-101, miR-22, and miR-200c were founded to have lower expression in BC, and their down expression is associated with the advancement of BC due to the promotion of invasion and migration and also angiogenesis. The artificially induced overexpression of these miRNAs suppressed BC progression via targeting BMI1/Rho/ROCK1 (Rho-associated protein kinase) signaling pathway by miR-381 [61], Frizzled class receptor 4 (FZD4) by miR-101 [85], VEGF and HIF-1α through the Akt2/mTOR signaling pathway by miR-200c [86], and MAPK1 (mitogen-activated protein kinase 1)/Slug/vimentin by miR-22 [87]. ...
Bladder cancer (BC) is the 11th most popular cancer in females and 4th in males. A lot of efforts have been exerted to improve BC patients' care. Besides, new approaches have been developed to enhance the efficiency of BC diagnosis, prognosis, therapeutics, and monitoring. MicroRNAs (miRNAs, miRs) are small chain nucleic acids that can regulate wide networks of cellular events. They can inhibit or degrade their target protein-encoding genes. The miRNAs are either downregulated or upregulated in BC due to epigenetic alterations or biogenesis machinery abnormalities. In BC, dysregulation of miRNAs is associated with cell cycle arrest, apoptosis, proliferation, metastasis, treatment resistance, and other activities. A variety of miRNAs have been related to tumor kind, stage, or patient survival. Besides, although new approaches for using miRNAs in the diagnosis, prognosis, and treatment of BC have been developed, it still needs further investigations. In the next words, we illustrate the recent advances in the role of miRNAs in BC aspects. They include the role of miRNAs in BC pathogenesis and therapy. Besides, the clinical applications of miRNAs in BC diagnosis, prognosis, and treatment are also discussed.
... Additionally, miR-200c has been considered as a regulator of tumor angiogenesis, while AKT2/mTOR is considered a regulator of VEGF and HIF1α. miR-200c was able to negatively regulate the expression of angiogenesis related proteins HIF1α/VEGF expression in BLCA via targeting AKT2/mTOR as did miR-27a, inhibiting angiogenesis and affecting the process of tubule formation [75]. ...
Simple Summary
In cells possessing invasive or metastatic capabilities, several classes of proteins that are involved in the tethering of cells to their surroundings are altered. Loss of cell–cell and cell–matrix adhesions, proteolysis, and induction of angiogenesis are all processes that allow the development of cancer invasion and metastasis. Additionally, epithelial mesenchymal transition (EMT) is a major contributor to the aggressive behavior of cells responsible for invasive growth and metastasis. Here we cover the roles of a few microRNAs (miRNAs) on the molecules that have been shown to play a significant role in bladder cancer metastasis and angiogenesis. These miRNAs could be considered as therapeutic modalities or as diagnostic biomarkers in future research.
Abstract
Angiogenesis is the process of generating new capillaries from pre-existing blood vessels with a vital role in tumor growth and metastasis. MicroRNAs (miRNAs) are noncoding RNAs that exert post-transcriptional control of protein regulation. They participate in the development and progression of several cancers including bladder cancer (BLCA). In cancer tissue, changes in microRNA expression exhibit tissue specificity with high levels of stability and detectability. miRNAs are less vulnerable to degradation, making them novel targets for therapeutic approaches. A suitable means of targeting aberrant activated signal transduction pathways in carcinogenesis of BLCA is possibly through altering the expression of key miRNAs that regulate them, exerting a strong effect on signal transduction. Precaution must be taken, as the complexity of miRNA regulation might result in targeting several downstream tumor suppressors or oncogenes, enhancing the effect further. Since exosomes contain both mRNA and miRNA, they could therefore possibly be more effective in targeting a recipient cell if they deliver a specific miRNA to modify the recipient cell protein production and gene expression. In this review, we discuss the molecules that have been shown to play a significant role in BLCA tumor development. We also discuss the roles of various miRNAs in BLCA angiogenesis and metastasis. Advances in the management of metastatic BLCA have been limited; miRNA mimics and molecules targeted at miRNAs (anti-miRs) as well as exosomes could serve as therapeutic modalities or as diagnostic biomarkers.
... With high rates of metastasis and recurrence and a poor prognosis, discovering effective molecular markers for predicting the prognosis of GC patients is crucial. Studies have reported abnormal expressions of SOX9, Tiam1, and PTEN are present in GC tissues (2)(3)(4)(5), which may bear significance for early diagnosis and predicting prognosis in GC. Neovascularization is an essential process in tumor growth, invasion, and metastasis. ...
Background:
With a high rate of metastasis and recurrence, gastric cancer (GC), a common malignant tumor, often has a poor prognosis. GC tissues have abnormal expressions of the Sry-related HMG-box family of transcription factors (SOX9), T-lymphoma invasion and metastasis-inducing factor 1 (Tiam1), and phosphatase and tensin homolog deleted on chromosome ten (PTEN). Meanwhile, vascular endothelial growth factor (VEGF) have been reported to play an important role in tumor angiogenesis. This study aimed to analyze the correlation of SOX9, Tiam1, and PTEN with angiogenesis and prognosis in GC.
Methods:
A total of 90 patients who underwent GC surgery at our hospital between January 2017 and October 2018 were enrolled. The expressions of SOX9, Tiam1, PTEN, and VEGF in GC tissues and adjacent normal tissues were detected by immunohistochemistry and the differences were analyzed. Spearman's correlation coefficient was applied to analyze the relationship between the expression levels of SOX9, Tiam1, PTEN, and VEGF. The patients were followed-up.
Results:
The positive expression rates of SOX9, Tiam1, PTEN, and VEGF in GC tissues were 75.56%, 61.11%, 52.22%, and 48.89%, respectively, compared with 6.67%, 4.44%, 97.78%, and 2.22%, respectively, in the adjacent normal tissues (P<0.05). Spearman's correlation analysis showed that the expression of SOX9 (r=0.349, P=0.001) and Tiam1 (Tiam1: r=0.370, P=0.000) in GC tissues was positively correlated with VEGF expression; however, PTEN was negatively correlated with VEGF (r=-0.311, P=0.000). There were no significant differences in SOX9, Tiam1, or PTEN expression in GC tissues from patients of different genders or ages (P>0.05). When the tumor was low differentiated, with lymph node metastasis or high TNM staging, the positive expression rates of SOX9 and Tiam1 were significantly increased (P<0.05), while the positive expression rate of PTEN was significantly decreased (P<0.05). The log-rank test results showed that the three-year survival rates of the groups with positive SOX9 (54.41%) and Tiam1 expression (49.09%) were significantly lower than those of the groups with negative SOX9 and Tiam1 expression (77.27% and 77.13%, respectively; P<0.05). The 3-year survival rate in the PTEN positive expression group was significantly higher than that of the PTEN negative expression group (76.60% vs. 41.80%; P<0.05).
Conclusions:
SOX9 and Tiam1 are highly expressed, in GC tissues while there is a low expression of PTEN. The expression levels of SOX9, Tiam1, and PTEN are all linearly correlated with VEGF expression, and they have important effects on angiogenesis and is closely related to the three-year survival rate of patients with GC.
Pancreatic cancer (PC) cell immune escape is a crucial element in PC malignant development. Some previous studies have reported that LncRNA NNT-AS1 played a carcinogenic role in various tumors. However, the effect of lncRNA NNT-AS1 in PC cell immune escape remains unclear. To evaluate PC cell immune escape, PC cells were co-cultured with CD8+ T cells under a hypoxic condition. PC cell proliferation and migration were evaluated using the colony formation assay and transwell assay. CD8+ T cell proliferation and apoptosis were measured using the carboxy fluorescein diacetate succinimidyl ester (CFSE) assay and flow cytometry. The secretion of antitumor cytokines was assessed using enzyme-linked immunosorbent assay (ELISA). The molecular interactions were analyzed using chromatin immunoprecipitation (ChIP), RNA immunoprecipitation (RIP), or dual-luciferase reporter gene assays. A tumor xenograft model was established to evaluate the effects of lncRNA NNT-AS1 on PC in vivo. It was found that lncRNA NNT-AS1 was highly expressed in PC, and its silencing inhibited hypoxia-induced PC cell growth and immune escape in vivo and in vitro. Mechanically, HIF-1α transcriptionally activated NNT-AS1 expression and NNT-AS1 increased ITGB1 stability and expression in a METTL3-HuR dependent manner. ITGB1 overexpression reversed the inhibitory effects of NNT-AS1 knockdown on hypoxia-induced PC cell immune escape. In conclusion, Hypoxia promoted PC cell immune escape through lncRNA NNT-AS1/METTL3-HuR-mediated m6A modification to increase ITGB1 expression, which provided a theoretical foundation and a potential therapeutic target for PC.
MicroRNAs are small non-coding RNAs that epigenetically regulate gene expression. MiR-200c is a known tumor suppressive microRNA found in many types of cancer, and its high expression has been associated with improved prognosis. However, the association between miR-200c expression and its clinical relevance in gastric cancer (GC) patients remains controversial. Here, we hypothesized that gastric cancer patients with high miR-200c gene expression translated to better overall survival. A total of 372 GC patients from the Cancer Genome Atlas (TCGA) were analyzed. The top three quartiles were defined as a high miR-200c expression group. High miR-200c expression was associated with decreased invasion, favorable histological type, and improved overall survival in gastric cancer patients. Unexpectedly, high miR-200c expression GC was also associated with enhanced cell proliferation, shown by MKi67 expression, proliferation score, and enrichment of Hallmark cell proliferation-related gene sets (E2F targets, G2M checkpoints, MYC targets v1 and v2) by gene set enrichment assay (GSEA). High miR-200c GC was also associated with a high mutation rate and homologous recombination deficiency. Despite the association with elevated neoantigens, high miR-200c GC was associated with significantly low infiltration of anti-cancer immune cells, decreased immune response, and with suppressed IL2, TNF-α, and IFN-γ pathways. On the other hand, GC with low miR-200c expression significantly enriched hypoxia, angiogenesis, epithelial-mesenchymal transition (EMT), and TGF-β signaling gene sets, all of which promote cancer progression and metastasis in GSEA. In conclusion, patients with high miR-200c expression GC had better survival despite association with aggressive tumor biology, such as high mutation rates, cell proliferation, and low cancer immunity. Given that low miR-200c GC was associated with hypoxia, angiogenesis, EMT and TGF-β signaling, we cannot help but speculate that the difference in survival by miR-200c expression may be at least partly due to the association between low miR-200c expression and aggressive biology.
Bladder cancer (BC) is one of the most common malignant tumors worldwide and poses a significant hazard to human health. During the development of BC, hypoxia plays a crucial role. Hypoxia-inducible factor (HIF) is a key transcription factor for hypoxic adaptation, which regulates the transcription of various genes, including inflammation, angiogenesis, and glycolytic metabolism. Recent studies have shown the precise role of HIF in various biological behaviors of BC. More importantly, a new antitumor medication targeting HIF-2 has been used to treat renal cancer. However, therapies targeting HIF-1 in BC have not yet been developed. In this review, we discussed how HIF-1 is expressed and affects the growth, metastasis, and angiogenesis of BC. At the same time, we investigated several HIF-1 inhibitors that provide new perspectives for targeting HIF-1.
Purpose of the Review
Angiogenesis plays a key role in bladder cancer (BC) pathogenesis. In the last two decades, an increasing number of publications depicting a multitude of novel angiogenic molecules and pathways have emerged. The growing complexity necessitates an evaluation of the breadth of current knowledge to highlight key findings and guide future research.
Recent Findings
Angiogenesis is a dynamic biologic process that is inherently difficult to assess. Clinical assessment of angiogenesis in BCs is advancing with the integration of image analysis systems and dynamic contrast-enhanced and magnetic resonance imaging (DCE-MRI). Tumour-associated macrophages (TAMs) significantly influence the angiogenic process, and further research is needed to assess their potential as therapeutic targets. A rapidly growing list of non-coding RNAs affect angiogenesis in BCs, partly through modulation of vascular endothelial growth factor (VEGF) activity. Vascular mimicry (VM) has been repeatedly associated with increased tumour aggressiveness in BCs. Standardised assays are needed for appropriate identification and quantification of VM channels.
Summary
This article demonstrates the dynamic and complex nature of the angiogenic process and asserts the need for further studies to deepen our understanding.
Background
Cancer-associated angiogenesis is a fundamental process in tumor growth and metastasis. A variety of signaling regulators and pathways contribute to establish neovascularization, among them as small endogenous non-coding RNAs, microRNAs (miRNAs) play prominent dual regulatory function in breast cancer (BC) angiogenesis.
Aim
This review aims at describing the current state-of-the-art in BC angiogenesis-mediated by angioregulatory miRNAs, and an overview of miRNAs dysregulation association with the anti-angiogenic response in addition to potential clinical application of miRNAs-based therapeutics.
Key scientific concepts
Angioregulatory miRNA–target gene interaction is not only involved in sprouting vessels of breast tumors but also, trans-differentiation of BC cells to endothelial cells (ECs) in a process termed vasculogenic mimicry. Using canonical and non-canonical angiogenesis pathways, the tumor cell employs the oncogenic characteristics such as miRNAs dysregulation to increase survival, proliferation, oxygen and nutrient supply, and treatment resistance. Angioregulatory miRNAs in BC cells and their microenvironment have therapeutic potential in cancer treatment. Although, miRNAs dysregulation can serve as tumor biomarker nevertheless, due to the association of miRNAs dysregulation with anti-angiogenic resistant phenotype, clinical benefits of anti-angiogenic therapy might be challenging in BC. Hence, unveiling the molecular mechanism underlying angioregulatory miRNAs sparked a booming interest in finding new treatment strategies such as miRNA-based therapies in BC.
