scholarly journals Captopril, a Renin-Angiotensin System Inhibitor, Attenuates Features of Tumor Invasion and Down-Regulates C-Myc Expression in a Mouse Model of Colorectal Cancer Liver Metastasis

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2734
Author(s):  
Georgina E. Riddiough ◽  
Theodora Fifis ◽  
Katrina A. Walsh ◽  
Vijayaragavan Muralidharan ◽  
Christopher Christophi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Wnt Signaling ◽  
Partial Hepatectomy ◽  
Target Genes ◽  
Renin Angiotensin System ◽  
Specific Response ◽  
Liver Remnant ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Ras Genes

(1) Background: Recent clinical and experimental data suggests that the liver’s regenerative response following partial hepatectomy can stimulate tumor recurrence in the liver remnant. The Wnt/b-catenin pathway plays important roles in both colorectal cancer carcinogenesis and liver regeneration. Studies have shown that the Wnt/b-catenin pathway regulates multiple renin-angiotensin system (RAS) genes, whilst RAS inhibition (RASi) reduces tumor burden and progression. This study explores whether RASi attenuates features of tumor progression in the regenerating liver post-hepatectomy by modulating Wnt/b-catenin signaling. (2) Methods: Male CBA mice underwent CRLM induction, followed one week later by 70% partial hepatectomy. Mice were treated daily with captopril, a RASi, at 250mg/kg/day or vehicle control from experimental Day 4. Tumor and liver samples were analyzed for RAS and Wnt signaling markers using qRT-PCR and immunohistochemistry. (3) Results: Treatment with captopril reduced the expression of down-stream Wnt target genes, including a significant reduction in both c-myc and cyclin-D1, despite activating Wnt signaling. This was a tumor-specific response that was not elicited in corresponding liver samples. (4) Conclusions: We report for the first time decreased c-myc expression in colorectal tumors following RASi treatment in vivo. Decreased c-myc expression was accompanied by an attenuated invasive phenotype, despite increased Wnt signaling.

Gene variants of the renin–angiotensin system and hypertension: from a trough of disillusionment to a welcome phase of enlightenment?

2010 ◽  
Vol 118 (8) ◽  
pp. 487-506 ◽  
Author(s):  
Gavin R. Norton ◽  
Richard Brooksbank ◽  
Angela J. Woodiwiss
Keyword(s):  
Association Studies ◽  
Large Population ◽  
Renin Angiotensin System ◽  
Human Populations ◽  
Incomplete Penetrance ◽  
Gene Variants ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Ras Genes ◽  
The Impact

There is substantial evidence to suggest that BP (blood pressure) is an inherited trait. The introduction of gene technologies in the late 1980s generated a sharp phase of over-inflated prospects for polygenic traits such as hypertension. Not unexpectedly, the identification of the responsible loci in human populations has nevertheless proved to be a considerable challenge. Common variants of the RAS (renin–angiotensin system) genes, including of ACE (angiotensin-converting enzyme) and AGT (angiotensinogen) were some of the first shown to be associated with BP. Presently, ACE and AGT are the only gene variants with functional relevance, where linkage studies showing relationships with hypertension have been reproduced in some studies and where large population-based and prospective studies have demonstrated these genes to be predictors of hypertension or BP. Nevertheless, a lack of reproducibility in other linkage and association studies has generated scepticism that only a concerted effort to attempt to explain will rectify. Without these explanations, it is unlikely that this knowledge will translate into the clinical arena. In the present review, we show that many of the previous concerns in the field have been addressed, but we also argue that a considerable amount of careful thought is still required to achieve enlightenment with respect to the role of RAS genes in hypertension. We discuss whether the previously identified problems of poor study design have been completely addressed with regards to the impact of ACE and AGT genes on BP. In the context of RAS genes, we also question whether the significance of ‘incomplete penetrance’ through associated environmental, phenotypic or physiological effects has been duly accounted for; whether appropriate consideration has been given to epistatic interactions between genes; and whether future RAS gene studies should consider variation across the gene by evaluating ‘haplotypes’.

scholarly journals Renin–angiotensin system gene polymorphisms and colorectal cancer risk: a meta-analysis

2019 ◽  
Vol 20 (4) ◽  
pp. 147032031988193
Author(s):  
Zhen Cheng ◽  
Zhiwei Liu
Keyword(s):  
Colorectal Cancer ◽  
Cancer Risk ◽  
Angiotensin Converting Enzyme ◽  
Meta Analysis ◽  
Renin Angiotensin System ◽  
Recessive Model ◽  
Colorectal Cancer Risk ◽  
Converting Enzyme ◽  
Angiotensin System ◽  
Renin Angiotensin

Objective: The renin–angiotensin system gene has been implicated in the progression of colorectal cancer. Nevertheless, the details of that role remain controversial. We performed a meta-analysis to investigate the correlation between renin–angiotensin system gene polymorphisms and colorectal cancer. Methods: We retrieved relevant studies from PubMed and Embase. Subsequently, fixed or random-effects models were used to calculate pooled odds ratios (ORs) with 95% confidence intervals (CIs). Results: We identified six studies of the angiotensin-converting enzyme insertion/deletion (I/D) polymorphism, and two studies of the angiotensinogen M235T polymorphism. The angiotensin-converting enzyme I/D polymorphism did not significantly correlate with colorectal cancer risk in the total population (DD vs. II: OR 0.77, 95% CI 0.39–1.50; DI vs. II: OR 1.05, 95% CI 0.85–1.30; dominant model: OR 0.94, 95% CI 0.68–1.31; recessive model: OR 1.01, 95% CI 0.80–1.27). Similarly, the angiotensinogen M235T polymorphism was not associated with colorectal cancer risk (TT vs. MM: OR 1.38, 95% CI 0.52–3.67; TM vs. MM: OR 1.19, 95% CI 0.96–1.47; dominant model: OR 1.28, 95% CI 0.77–2.14; recessive model: OR 1.17, 95% CI 0.53–2.59). Conclusion: Our findings suggest that the angiotensin-converting enzyme I/D and angiotensinogen M235T polymorphisms are unlikely to correlate with colorectal cancer.

scholarly journals Relationship between drugs affecting the renin-angiotensin system and colorectal cancer: The MCC-Spain study

2017 ◽  
Vol 99 ◽  
pp. 178-184 ◽  
Author(s):  
Trinidad Dierssen-Sotos ◽  
Inés Gómez-Acebo ◽  
Camilo Palazuelos ◽  
Francisco Rodriguez-Moranta ◽  
Beatriz Pérez-Gómez ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Renin Angiotensin System ◽  
Angiotensin System ◽  
Renin Angiotensin

scholarly journals High Order Gene-Gene Interactions in Eight Single Nucleotide Polymorphisms of Renin-Angiotensin System Genes for Hypertension Association Study

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Cheng-Hong Yang ◽  
Yu-Da Lin ◽  
Shyh-Jong Wu ◽  
Li-Yeh Chuang ◽  
Hsueh-Wei Chang
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Renin Angiotensin System ◽  
High Order ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Ras Genes ◽  
Snp Interaction

Several single nucleotide polymorphisms (SNPs) of renin-angiotensin system (RAS) genes are associated with hypertension (HT) but most of them are focusing on single locus effects. Here, we introduce an unbalanced function based on multifactor dimensionality reduction (MDR) for multiloci genotypes to detect high order gene-gene (SNP-SNP) interaction in unbalanced cases and controls of HT data. Eight SNPs of three RAS genes (angiotensinogen,AGT; angiotensin-converting enzyme,ACE; angiotensin II type 1 receptor,AT1R) in HT and non-HT subjects were included that showed no significant genotype differences. In 2- to 6-locus models of the SNP-SNP interaction, the SNPs ofAGTandACEgenes were associated with hypertension (bootstrapping odds ratio [Boot-OR] = 1.972~3.785; 95%, confidence interval (CI) 1.26~6.21;P<0.005). In 7- and 8-locus model, SNP A1166C ofAT1Rgene is joined to improve the maximum Boot-OR values of 4.050 to 4.483; CI = 2.49 to 7.29;P<1.63E−08. In conclusion, the epistasis networks are identified by eight SNP-SNP interaction models.AGT,ACE, andAT1Rgenes have overall effects with susceptibility to hypertension, where the SNPs ofACEhave a mainly hypertension-associated effect and show an interacting effect to SNPs ofAGTandAT1Rgenes.

The Potential Therapeutic Value of Renin-Angiotensin System Inhibitors in the Treatment of Colorectal Cancer

2021 ◽  
Vol 27 ◽  
Author(s):  
Ehsan Tabatabai ◽  
Majid Khazaei ◽  
Mohammad Reza Parizadeh ◽  
Mohammad Nouri ◽  
Seyed Mahdi Hassanian ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Therapeutic Potential ◽  
Critical Role ◽  
Renin Angiotensin System ◽  
Angiotensin Converting Enzyme Inhibitors ◽  
Angiotensin Ii Receptor ◽  
Converting Enzyme Inhibitors ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Promote Cell Proliferation

: Colorectal cancer is the third most common cancer globally. Despite extensive preclinical and clinical studies, it is still among the leading causes of cancer-related death, and a need for new therapeutic options is required. The renin-angiotensin system plays an important role in regulating blood pressure and cell growth. In addition to their hemodynamic effects, some of the renin-angiotensin system components, such as angiotensin, are also growth factors that promote cell proliferation and angiogenesis, and its dysregulation is reported to be associated with poor prognosis in colorectal cancer. Here we describe the critical role of the renin-angiotensin system pathway in colorectal cancer as well as the preclinical and clinical investigations renin-angiotensin system inhibitors: angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers as a potential therapeutic target in the treatment of colorectal cancer. Several studies have been shown that the inhibition of these pathways can reduce tumor growth and metastasis; however, some of the data remain inconsistent. There is accumulating evidence of the therapeutic potential of some inhibitors, such as Losartan which are now in clinical phases in the treatment of several malignancies using Nivolumab in combination with FOLFIRINOX in pancreatic cancer. Further investigations are warranted to improve the efficacy and selectivity of current and future anticancer strategies targeting renin-angiotensin systems.

scholarly journals Renin angiotensin system genes are biomarkers for personalized treatment of acute myeloid leukemia with Doxorubicin as well as etoposide

PLoS ONE ◽  
2020 ◽  
Vol 15 (11) ◽  
pp. e0242497
Author(s):  
Seyhan Turk ◽  
Can Turk ◽  
Muhammad Waqas Akbar ◽  
Baris Kucukkaraduman ◽  
Murat Isbilen ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Molecular Subtypes ◽  
Renin Angiotensin System ◽  
Response To Therapy ◽  
Gene Set Enrichment Analysis ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Ras Genes ◽  
Acute Myeloid

Despite the availability of various treatment protocols, response to therapy in patients with Acute Myeloid Leukemia (AML) remains largely unpredictable. Transcriptomic profiling studies have thus far revealed the presence of molecular subtypes of AML that are not accounted for by standard clinical parameters or by routinely used biomarkers. Such molecular subtypes of AML are predicted to vary in response to chemotherapy or targeted therapy. The Renin-Angiotensin System (RAS) is an important group of proteins that play a critical role in regulating blood pressure, vascular resistance and fluid/electrolyte balance. RAS pathway genes are also known to be present locally in tissues such as the bone marrow, where they play an important role in leukemic hematopoiesis. In this study, we asked if the RAS genes could be utilized to predict drug responses in patients with AML. We show that the combined in silico analysis of up to five RAS genes can reliably predict sensitivity to Doxorubicin as well as Etoposide in AML. The same genes could also predict sensitivity to Doxorubicin when tested in vitro. Additionally, gene set enrichment analysis revealed enrichment of TNF-alpha and type-I IFN response genes among sensitive, and TGF-beta and fibronectin related genes in resistant cancer cells. However, this does not seem to reflect an epithelial to mesenchymal transition per se. We also identified that RAS genes can stratify patients with AML into subtypes with distinct prognosis. Together, our results demonstrate that genes present in RAS are biomarkers for drug sensitivity and the prognostication of AML.

141. METHYLATION OF GENES OF THE RENIN ANGIOTENSIN SYSTEM (RAS) IN EARLY HUMAN AMNION

2010 ◽  
Vol 22 (9) ◽  
pp. 59 ◽  
Author(s):  
C. M. Mitchell ◽  
T. Zakar ◽  
S. D. Sykes ◽  
K. G. Pringle ◽  
E. R. Lumbers
Keyword(s):  
Cpg Island ◽  
Cpg Islands ◽  
Renin Angiotensin System ◽  
Angiotensin System ◽  
Human Amnion ◽  
Early Gestation ◽  
Renin Angiotensin ◽  
Ras Genes ◽  
Prorenin Receptor ◽  
Cpg Island Methylation

The renin angiotensin system (RAS) genes angiotensin converting enzyme (ACE), angiotensin II type 1 receptor (AGTR1) and prorenin receptor (ATP6AP2) have CpG islands at their promoters, so these genes may be regulated by CpG island methylation as may the expression of two proteases implicated in prorenin activation (cathepsin D {CTSD} and kallikrein 1 {KLK1}). We measured CpG island methylation of 3 RAS genes and of CTSD and KLK1 in amnion using the Methyl-Profiler assay (SA Biosciences), which discriminates methyl-CpG density between hypermethylated, intermediately methylated and unmethylated CpG islands. DNA from human amnion collected between 10–17.8 weeks gestation, at elective caesarean section and after labour at term was analysed. The bulk (>80%) of CpG islands in all genes examined except for KLK1 was unmethylated and without intermediate methylation throughout gestation, while the rest was hypermethylated. There was no change in methylation density with labour (Table 1). In early gestation KLK1 methylation was greater than ACE, AGTR1 and ATP6AP2 (P < 0.05). KLKI methylation shifted towards the unmethylated state after labour (P < 0.05). There were correlations between methylation of ACE, AGTR1 and ATP6AP2 (P < 0.02) but not between RAS genes and KLKI. This suggests that the 3 RAS genes in amnion are not controlled by CpG island methylation. It is likely, however, that KLK1 is silenced in early gestation amnion partially by CpG island methylation, which is reduced by term. Since Kallikrein 1 can activate prorenin, the methylation status of this gene may regulate RAS activity in amnion during gestation.

scholarly journals Cardiovascular Disease, Single Nucleotide Polymorphisms; and the Renin Angiotensin System: Is There a MicroRNA Connection?

2010 ◽  
Vol 2010 ◽  
pp. 1-13 ◽  
Author(s):  
Terry S. Elton ◽  
Sarah E. Sansom ◽  
Mickey M. Martin
Keyword(s):  
Cardiovascular Disease ◽  
Single Nucleotide Polymorphisms ◽  
Mirna Gene ◽  
Renin Angiotensin System ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Ras Genes ◽  
Inhibit Gene Expression

Essential hypertension is a complex disorder, caused by the interplay between many genetic variants, gene-gene interactions, and environmental factors. Given that the renin-angiotensin system (RAS) plays an important role in blood pressure (BP) control, cardiovascular regulation, and cardiovascular remodeling, special attention has been devoted to the investigation of single-nucleotide polymorphisms (SNP) harbored in RAS genes that may be associated with hypertension and cardiovascular disease. MicroRNAs (miRNAs) are a family of small,∼21-nucleotide long, and nonprotein-coding RNAs that recognize target mRNAs through partial complementary elements in the3′-untranslated region (3′-UTR) of mRNAs and inhibit gene expression by targeting mRNAs for translational repression or destabilization. Since miRNA SNPs (miRSNPs) can create, destroy, or modify miRNA binding sites, this review focuses on the hypothesis that transcribed target SNPs harbored in RAS mRNAs, that alter miRNA gene regulation and consequently protein expression, may contribute to cardiovascular disease susceptibility.

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