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A hypothetical representation of the regulatory pathway underlying ANG-induced MMP2 expression. Based on this study, ANG has two different effects on the cells a) induces DNMT3a expression, b) represses DNMT3b expression. Reduced DNMT3b levels lead to hypomethylation of the MMP2 promoter, which induces MMP2 gene transcription. Thus, expression of MMP2 contributes to increase invasive potential of bladder cancer and reduced disease free survival.
Source publication
Epigenetic-mediated gene activation/silencing plays a crucial role in human tumorigenesis. Eliciting the underlying mechanism behind certain epigenetic changes is essential for understanding tumor biology. Previous studies in human cancers revealed an unrecognized interplay between Angiogenin (ANG) and matrix metalloproteinase-2 (MMP2) leading to p...
Context in source publication
Citations
... Consistently, ANG-MMP2 overexpression and DNMT3b knockdown correlated with a reduction in disease-free survival in patients with BC. Together, these results establish ANG as an oncoprotein and further reveal that ANG contributes to oncogenesis by activating MMP2 through the modulation of DNMT3b function [41]. ...
Angiogenin (ANG) is a specialised secreted ribonuclease, also known as RNase5, that is widely expressed in vertebrates. ANG dysregulation is closely associated with the development of breast, nasopharyngeal, and lung cancers. In recent years, studies have found that ANG not only induces neovascularisation by activating endothelial cells, but also plays a regulatory role in the plasticity of cancer cells. Cellular plasticity plays pivotal roles in cancer initiation, progression, migration, therapeutic resistance, and relapse. Therefore, it is a promising biomarker for cancer diagnosis, prognostic evaluation, and therapy. This review summarises the current knowledge regarding the roles and clinical applications of ANG in cancer development and progression.
... However, the results of DNMT3B expression in bladder cancer is controversial. Peres et al. found that DNMT3B under expression correlated with reduction in disease free survival of human bladder cancer patients [12]. On the other hand, Ying et al. reported that hypermethylation of E-cadherin promoters mediated by DNMT3B induced cell migration in bladder cancer cell lines [13]. ...
Background
Cancer bladder is the most common malignant tumor affecting the urinary tract. Genetic alterations are tightly associated with the development of cancer bladder. MicroRNAs (miRNA) are small, noncoding single-stranded RNA molecules that have been linked to bladder cancer. miR-124-3pa exhibits altered expression in various types of human malignancies. DNA methyltransferase 3B (DNMT3B) is responsible for de novo DNA methylation which is a fundamental epigenetic process in carcinogenesis. This work was performed to study the expression of DNMT3B and miR 124-3pa in bladder cancer tissues, and investigate their significance in the diagnosis and prognosis of the disease.
Subjects & methods
This case-control study included one hundred and six tissue samples of patients with primary urothelial bladder cancer. The tissues were separated into two parts. The first part was immediately frozen and kept at − 80 °C for total RNA extraction with subsequent detection of miR 124-3pa and DNMT3B expressions. The other part was preserved in formalin solution for histopathological examination.
Results
There was a highly statistically significant difference between the cancerous and the normal tissues as regarding miRNA-124-3pa and DNMT3B expression (P < 0.001) for each. Also, there was a highly statistically significant strong negative correlation between miRNA-124-3pa and DNMT3B expression (r=-0.750, P < 0.001). The combined performance of miR-124-3pa and DNMT3B revealed that the cutoff point of ≥ 3.3 can be used as a predictor of the presence of cancer bladder with sensitivity of 98.1% and specificity of 80%.
Conclusion
miR-124-3pa and DNMT3B can be used as predictors of the presence of cancer bladder.
... Angiogenin (ANG) has been extensively reported across a variety of malignant diseases, including gestational trophoblast neoplasia (5,6), prostate cancer (7,8), bladder cancer (9)(10)(11)(12)(13), nasopharyngeal carcinoma (14,15), colorectal cancer (16,17), hepatocellular carcinoma (18), pancreatic cancer (19), renal cell carcinoma (20), gastric and colon cancer (21), lung cancer (22,23), breast cancer (24,25), multiple myeloma (26), lymphoma (27,28), oral cancer (29), neuroblastoma (30), melanoma (31), cervical cancer (32), and laryngeal carcinoma (33). ANG, also termed RNase5, belongs to the RNase A superfamily, whose family members primarily play roles in ribonucleolytic activity. ...
Background
Angiogenin (ANG) has been widely reported as a crucial molecular regulator in multiple malignancies. However, its role in gliomagenesis remains unclear. This study aimed to investigate the molecular and clinical characterization of ANG expression at transcriptome level and the association with glioma-related immune response.
Methods
A total of 301 glioma samples with mRNA microarray data (CGGA301) was obtained from the official website of CGGA project for yielding preliminary results, followed by validation in two independent RNAseq datasets, including TCGA with 697 samples and CGGA325 with 325 patients. Moreover, CGGA single-cell RNAseq (scRNAseq) data were analyzed to identify differential and dynamic ANG expression in different cells. Immunohistochemistry was performed to evaluate ANG protein expression across different WHO grades in a tissue microarray (TMA). Figure generation and statistical analysis were conducted using R software.
Results
ANG expression was associated with clinical features, malignant phenotypes, and genomic alterations. Based on significantly correlated genes of ANG, subsequent gene ontology (GO) and gene set enrichment analysis (GSEA) concordantly pointed to the significant association of ANG in immune-related biological processes. Moreover, ANG showed robust correlations with canonical immune checkpoint molecules, including PD1 signaling, CTLA4, TIM3, and B7H3. Gene sets variation analysis (GSVA) found that ANG was particularly associated with activities of macrophages and antigen presentation cells (APCs) in both LGG and GBM across different datasets. Furthermore, the higher-ANG milieu seemed to recruit monocyte–macrophage lineage and dendritic cells into the glioma microenvironment. According to scRNAseq analysis, ANG was mainly expressed by neoplastic cells and tumor-associated macrophages (TAMs) and was correlated with the initiation and progression of tumor cells and the polarization of TAMs. Finally, Kaplan–Meier plots demonstrated that higher expression of ANG was significantly correlated with shorter survival in gliomas. Cox regression analysis further confirmed ANG as an independent predictor of prognosis for gliomas of all three datasets.
Conclusion
ANG is significantly correlated with a range of malignant and aggressive characteristics in gliomas and reveals considerable prognostic value for glioma patients. ANG seems to be primarily associated with immune activities of macrophages and APCs in gliomas. Furthermore, ANG is mainly expressed in neoplastic cells and TAMs and is involved in the initiation and progression of neoplastic cells as well as macrophage polarization.
... Angiogenin (ANG) escalates the progression of bladder tumor. ANG upregulation promotes DNMT3b-induced MMP-2 overexpression and an enhancement in the metastasis (Peres et al., 2016). ANG is a potent modulator of PI3K/Akt in bladder cancer. ...
In addition to environmental conditions, lifestyle factors, and chemical exposure, aberrant gene expression and mutations involve in the beginning and development of urological tumors. Even in Western nations, urological malignancies are among the top causes of patient death, and their prevalence appears to be gender dependent. The prognosis for individuals with urological malignancies remains dismal and unfavorable due to the ineffectiveness of conventional treatment methods. PI3K/Akt is a popular biochemical mechanism that is activated in tumor cells as a result of PTEN loss. PI3K/Akt escalates growth and metastasis. Moreover, due to the increase in tumor cell viability caused by PI3K/Akt activation, cancer cells may acquire resistance to treatment. This review article examines the function of PI3K/Akt in major urological tumors including bladder, prostate, and renal tumors. In prostate, bladder, and kidney tumors, the level of PI3K and Akt are notably elevated. In addition, the activation of PI3K/Akt enhances the levels of Bcl-2 and XIAP, hence increasing the tumor cell survival rate. PI3K/Akt ] upregulates EMT pathways and matrix metalloproteinase expression to increase urological cancer metastasis. Furthermore, stimulation of PI3K/Akt results in drug- and radio-resistant cancers, but its suppression by anti-tumor drugs impedes the tumorigenesis.
... Natural flavonoid kaempferol, which is found in various vegetables and fruits, has powerful anti-cancer effects on bladder cancer. [28] A typical urological malignant tumor that has a significant negative impact on patients' quality of life is bladder cancer. Similar to the majority of other malignancies, little is known about the pathophysiology of bladder cancer. ...
Kaempferol, found in various plants and foods, has gained attention as
a useful )avonoid owing to its potential biological properties, including
anticancer characteristics. Recent research studies suggest that kaempferol
is e+ective in the inhibition and treatments of several forms of cancer, e.g.
lung, ovarian, breast and lung cancer. One probable mechanism of action of
kaempferol is its anti-in)ammatory and antioxidant potentials, which may
help to prevent DNA damage and inhibit the proliferation of cancerous cells.
Besides triggering apoptosis in cancerous cells, Kaempferol may also inhibit
the growth and relocation of cancerous cells. Moreover, kaempferol has
a very wide range of bioactivities, involving anti-in)ammatory and antioxidant e+ects. This includes understanding the optimal dosing and timing of
kaempferol treatment, as well as the potential interactions with other medications and the long-term safety of kaempferol use. Overall, the available
evidence and studies suggest that kaempferol may provide a potential natural agent for the prevention and treatments of cancers. Despite the promising 1ndings in preclinical and clinical research, further research is needed to
con1rm its e2cacy and understand the mechanisms of action, and to fully
explore the potential of kaempferol in di+erent cancers.
... Natural flavonoid kaempferol, which is found in various vegetables and fruits, has powerful anti-cancer effects on bladder cancer. [28] A typical urological malignant tumor that has a significant negative impact on patients' quality of life is bladder cancer. Similar to the majority of other malignancies, little is known about the pathophysiology of bladder cancer. ...
Kaempferol, found in various plants and foods, has gained attention as a useful flavonoid owing to its potential biological properties, including anticancer characteristics. Recent research studies suggest that kaempferol is effective in the inhibition and treatments of several forms of cancer, e.g. lung, ovarian, breast and lung cancer. One probable mechanism of action of kaempferol is its anti-inflammatory and antioxidant potentials, which may help to prevent DNA damage and inhibit the proliferation of cancerous cells. Besides triggering apoptosis in cancerous cells, Kaempferol may also inhibit the growth and relocation of cancerous cells. Moreover, kaempferol has a very wide range of bioactivities, involving anti-inflammatory and antioxidant effects. This includes understanding the optimal dosing and timing of kaempferol treatment, as well as the potential interactions with other medications and the long-term safety of kaempferol use. Overall, the available evidence and studies suggest that kaempferol may provide a potential natural agent for the prevention and treatments of cancers. Despite the promising findings in preclinical and clinical research, further research is needed to confirm its efficacy and understand the mechanisms of action, and to fully explore the potential of kaempferol in different cancers.
... ANG and MMP-2 overexpression was correlated with a reduction in disease-free survival. [44] Thus, we surmised that ANG might promote trophoblast cell invasion and migration by regulating MMP-2. ...
Background:
Gestational trophoblastic diseases (GTDs) are characterized by vascular abnormalities of the trophoblast, but their pathogenesis is unknown. Angiogenin (ANG) and matrix metalloproteinase (MMP)-2, which are molecules implicated in the angiogenic process, may play some role in this process.
Material and methods:
We determined ANG and MMP-2 in the placental tissues of 26 patients who had a benign mole (BM), 12 patients with gestational trophoblast neoplasia (GTN) (1 invasive hydatidiform mole, 10 choriocarcinomas, and 1 placental-site trophoblastic tumor), and 28 normal chorionic villi (NCV) subjects using immunohistochemistry staining. We obtained the serum samples from 20 patients with GTDs and 20 early pregnant women and evaluated them by the enzyme linked immunosorbent assay.
Results:
ANG expression in GTN (66.7%) and BM (100%) samples were both significantly higher (strong/intermediate staining) than in NCV (60.7%) samples (P < .001). Similarly, the immunoreactivities of MMP-2 in the GTN (66.7%) and BM (80.8%) samples were significantly elevated compared to that of the NCV (57.1%) samples (P < .001). The levels of ANG and MMP-2 in the maternal serum of the GTN group were both significantly higher than those of the control group (P < .001). ANG and MMP-2 expressions were associated with gestation age, clinical stage, and FIGO stage. A positive correlation between ANG and MMP-2 expression was observed (rs = 0.725; P < .01).
Conclusion:
ANG and MMP-2 levels were significantly elevated in the placental tissues and maternal serum from patients with GTDs. Further studies with more patients may clarify the vascular abnormalities in GTDs and determine potential biomarkers in the differential diagnosis of GTDs.
... Among all DNMTs, DNMT3B plays a major pro-tumorigenic role in human melanoma [11]. In several studies, it has been shown that there is a significant relation between aberrant expression of tumor suppressors and increased expression of DNMT3B gene [21,22]. One of the important regulators of DNMT3B is small non-coding molecules called microRNAs [12]. ...
Aberrant expression of genes involved in methylation, including DNA methyltransferase 3 Beta ( DNMT3B ), can cause hypermethylation of various tumor suppressor genes. In this regard, various molecular factors such as microRNAs can play a critical role in regulating these methyltransferase enzymes and eventually downstream genes such as growth arrest specific 7 ( GAS7 ). Accordingly, in the present study we aimed to predict regulatory effect of miRNAs on DNMT3B and GAS7 genes expression in melanoma cell line. hsa-miR-203a-3p and hsa-miR-29a-3p were predicted and selected using bioinformatics software. The Real-time PCR technique was performed to investigate the regulatory effect of these molecules on the DNMT3B and GAS7 genes expression. Expression analysis of DNMT3B gene in A375 cell line showed that there was a significant increase compared to control ( p value = 0.0015). Analysis of hsa-miR-203a-3p and hsa-miR-29a-3p indicated the insignificant decreased expression in melanoma cell line compared to control ( p value < 0.05). Compared to control, the expression of GAS7 gene in melanoma cells showed a significant decrease ( p value = 0.0323). Finally, our findings showed that the decreased expression of hsa-miR-203a-3p and hsa-miR-29a-3p can hypothesize that their aberrant expression caused DNMT3B dysfunction, possible methylation of the GAS7 gene, and ultimately decreased its expression. However, complementary studies are necessary to definite comment.
... Angiogenin (ANG) is a secreted ribonuclease best known for its ability to promote blood vessel formation (Lyons et al., 2017). It has been reported to promote the metastasis of colorectal cancer cells (Li et al., 2019), proliferation and invasion of lung squamous carcinoma cells , and tumorigenesis in bladder cancer (Peres et al., 2016). Additionally, ANG can mediate tumour angiogenesis in prostate cancer and the proliferation in prostate cancer cells (Vanli and Guo-Fu, 2015). ...
... ANG may be a stress-induced factor that protects adjacent or distant cells from the deleterious effects of environmental stress. Studies have demonstrated ANG to induce cell survival, proliferation, endothelial tube formation, xenograft angiogenesis, cell migration, angiogenesis, and tumour suppressor gene expression (Miyake et al., 2015;Peres et al., 2016). Hence, ANG may protect NPC cells from the radiationinduced hypoxia-modulated environmental stress and induce cell survival, proliferation, and radio-resistance. ...
Background: Despite the development of such multiple therapeutic approaches, approximately 20% patients experience recurrence. Identification of molecular markers for stratifying the different risks of tumour recurrence and progression is considered imperative.
Methods: We used a RayBio Human Cytokine Antibody Array that simultaneously detected the levels of 297 proteins and profiled the conditioned medium of HONE1 cells and the radioresistant NPC cells HONE1-IR. We found Angiogenin(ANG) expression to be significantly increased in HONE1-IR and HONE1-IR cells exposed to 4-Gy X-ray radiation.
Results: We investigated the expression of ANG in NPC tissues and explored its prognostic significance in patients with NPC. We found that ANG expression was increased in recurrent NPC tissues. Elevated expression of ANG induced radio-resistance in NPC cells, in addition to being significantly associated with shorter PFS, OS, and LRFS in patients with NPC. Multivariate analysis results revealed that ANG was an independent prognostic factor that predicted PFS, OS, and LRFS. Furthermore, a nomogram model was generated to predict OS in terms of ANG expression.
Conclusion: Our results found the radioresistant function of ANG and proved the clinical prognostic significance of ANG, and the results could help predict radio-sensitivity and stratify high-risk patients or tumour recurrence.
... Besides these, we implemented the immunofluorescence assay, and the result showed that DNMT3b is colocalized with MMP-2. Integrating our investigation and published articles [7,36,37], we assume that MMP-2 upregulation may be due to DNMT3b SUMOylation. ...
Paclitaxel is a common chemotherapeutic agent in cancer treatment, while it often causes chemotherapy-induced peripheral neuropathy (CIPN), which manifested as hyperalgesia and allodynia, and its mechanism remains largely unknown. The previous study has shown that matrix metalloproteinase-2 (MMP-2) plays a pivotal role in spinal nerve ligation (SNL) induced neuropathic pain, but its function in CIPN and exact molecular mechanisms underlying upregulation is not explored. Our present study revealed that MMP-2 is also upregulated in paclitaxel induced neuropathic pain (NP), and knockdown it by siRNA can ameliorate mechanical allodynia. Since DNA methylation is closely related to gene transcription, we explored the methylation status of the MMP-2 gene and demonstrated that MMP-2 upregulation is related to the reduced methylation level of its promoter. DNA methylation is mediated by DNA methyltransferases (DNMTs), and previous studies suggested that three main types of DNMTs can undergo SUMOylation. Our next study revealed that SUMO1 modification of DNMT3b is significantly enhanced. Intrathecal administration of SUMOylation inhibitor, ginkgolic acid (GA), could reverse enhanced SUMO1 modification of DNMT3b and upregulation of MMP-2 in the model rats. Further investigation suggested that DNMT3b binding activity to the promoter region of the MMP-2 gene is significantly decreased in paclitaxel treated rats, and the administration of GA can reverse these effects, which is also accompanied by changes in the promoter methylation status of the MMP-2 gene. Our study demonstrates that MMP-2 up-regulation mediated by DNMT3b SUMOylation is essential for paclitaxel induced NP development, which brings us new therapeutic options for CIPN.
