Differential Expression of Circulating Plasma miRNA-370 and miRNA-10a from Patients with Hereditary Hemorrhagic Telangiectasia

Abstract

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant, vascular disorder that presents with telangiectases and arteriovenous malformations. HHT is a genetically heterogeneous disorder, involving mutations in endoglin (ENG; HHT1) and activin receptor-like kinase 1 (ACVRL1/ALK1; HHT2) genes that account for over 85% of all HHT patients. The current diagnosis of HHT patients remains at the clinical level, but many suspected patients do not have a clear HHT diagnosis or do not show pathogenic mutations in HHT genes. This situation has prompted the search for biomarkers to help in the early diagnosis of the disease. We have analyzed the plasma levels in HHT patients of selected micro-RNAs (miRNAs), small single-stranded RNAs that regulate gene expression at the transcriptional level by interacting with specific RNA targets. A total of 16 HHT1 and 17 HHT2 plasma samples from clinically confirmed patients and 16 controls were analyzed in this study. Total RNA was purified from plasma, and three selected miRNAs (miRNA-10a, miRNA-214, and miRNA-370), related to the pathobiology of cardiovascular diseases and potentially targeting ENG or ALK1, were measured by quantitative polymerase chain reaction. Compared with controls, levels of miRNA-370, whose putative target is ENG, were significantly downregulated in HHT1, but not in HHT2, whereas the levels of miRNA-10a, whose putative target is ALK1, were significantly upregulated in HHT2, but not in HHT1. In addition, the levels of miRNA-214, potentially targeting ENG and ALK1, did not change in either HHT1 or HHT2 patients versus control samples. While further studies are warranted, these results suggest that dysregulated plasma levels of miRNA-370 or miRNA-10a could help to identify undiagnosed HHT1 or HHT2 patients, respectively.

Correlation Between Endoglin and Malignant Phenotype in Human Melanoma Cells: Analysis of hsa-mir-214 and hsa-mir-370 in Cells and Their Extracellular Vesicles

“…Emerging evidence support the involvement of cellular and EVs miRNAs in cancer progression, diagnosis, and prognosis [56][57][58][59], including melanoma [60][61][62]. Therefore, we investigated the effect of endoglin in the levels of miR-214 and miR-370 as they (i) have been found dysregulated in several cancer types, including skin cancers, (ii) are predicted to target endoglin [64], and (iii) differential expression of circulating miR-370 has been reported in plasma from patients with hereditary hemorrhagic telangiectasia type 1 (HHT1), an autosomal dominant disorder due to mutations in the endoglin gene [64]. We then measured by qRT-PCR hsa-miR-214 and hsa-miR-370 levels in cells and EVs from endoglinexpressing WM-164 cells (Fig.…”

“…Some miRNAs are specific for one or more skin cancer type, such as hsa-mir-21 and hsa-mir-221, which are observed in cutaneous melanoma and squamous carcinoma; while hsamir-155 has been detected in melanoma and cutaneous lymphoma. In this work, we have focused our studies on the pleiotropic hsamir-214 and hsa-mir-370, as they are predicted and have been shown to target endoglin [63,64]. Both, hsa-mir-214 and hsa-mir-370 are dysregulated in several other tumors, besides skin cancers, displaying contrasting behavior.…”

MicroRNA-132-3p, Downregulated in Myeloid Angiogenic Cells from Hereditary Hemorrhagic Telangiectasia Patients, Is Enriched in the TGFβ and PI3K/AKT Signalling Pathways

“…We have previously reported reduced levels of miRs-28-5p and -361-3p in HHT patient peripheral blood mononuclear cells (PBMCs), as well as elevated levels of circulating miR-210 in HHT patients with pulmonary AVMs [24,25]. Various other studies have identified miRNA dysregulation in HHT, but miRNA research in HHT is limited and an exact pathogenic role of any one miRNA has yet to be fully elucidated [26][27][28].…”

The role of nuclear medicine in a case of Rendu–Osler–Weber disease with pulmonary involvement

“…Over 90% of all HHT patients present chronic epistaxis due to nasal telangiectases by the age of 45 years. [ 4 ] Chronic bleeding from gastrointestinal telangiectases develops in at least 20% of patients. [ 4 ] Pulmonary AVM (PAVM) and hepatic AVM have been detected in 24%–40% and 41%–84% of HHT patients, respectively.…”

“…[ 4 ] Chronic bleeding from gastrointestinal telangiectases develops in at least 20% of patients. [ 4 ] Pulmonary AVM (PAVM) and hepatic AVM have been detected in 24%–40% and 41%–84% of HHT patients, respectively. [ 5 ]…”