Abstract 211: Myocardial Hypertrophy and Circulating RNAs

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Ravi V Shah ◽  
Olivia Ziegler ◽  
Kahraman Tanriverdi ◽  
Jian Rong ◽  
Martin Larson ◽  
...  
Keyword(s):  
Biological Process ◽  
Molecular Level ◽  
Myocardial Hypertrophy ◽  
Clinical Phenotype ◽  
Left Ventricular ◽  
Loss Of Function ◽  
Heart Study ◽  
Non Coding Rnas

While increased left ventricular mass (LVM) is strongly associated with incident heart failure (HF), events during transition from increased LVM to HF remain unclear. Extracellular non-coding RNAs (ex-RNAs) have been implicated in cardiac hypertrophy, though whether these ex-RNAs reflect important pathways in HF in humans is underexplored. In >2,000 individuals with concomitant M-mode echocardiography and ex-RNA measurements in the Framingham Heart Study, we found that lower circulating concentrations of three ex-RNAs—miR-20a-5p, miR-106b-5p, miR-17-5p—were associated with (1) greater LVM (+ one other pre-clinical phenotype, e.g., left atrial dimension or LVEDV) and (2) greater incident HF risk over a median follow-up 7.7 years ( Fig. A ). These 3 miRNAs were members of a tight cluster, regulating 883 mRNAs in common, associated with “hypertension” (OMIM) and biological process relevant to HF, including TGF-β signaling. We observed an increase in myocardial expression of these miRNAs during different phases of hypertrophy/HF development ( Fig. C, D ). Using gain and loss of function in vitro , our preliminary results suggest up-regulation of cardiomyocyte miR-106b expression abrogates expression of pathologic hypertrophy markers (ANP and BNP) during phenylephrine treatment, consistent with in silico results suggesting broad connections between miR-106b targets and natriuretic peptide signaling ( Fig. B, E-F ). These results provide translational evidence that circulating miRNAs associated with hypertrophy in patients may be protective in the transition from hypertrophy to HF at the molecular level.

Abstract 13944: Biracial Proteomic Profiling Reveals Novel Candidate Pathways in Left Ventricular Hypertrophy and Incident Heart Failure Specific to Black Individuals

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Daniel H Katz ◽  
Usman A Tahir ◽  
Debby Ngo ◽  
Mark Benson ◽  
Yan Gao ◽  
...  
Keyword(s):  
Heart Failure ◽  
Smoking Status ◽  
Left Ventricular ◽  
Proteomic Profiling ◽  
2D Echocardiography ◽  
Heart Study ◽  
Lv Mass ◽  
Leukotriene A4 ◽  
Incident Cases

Background: Increased left ventricular (LV) mass is associated with future adverse cardiovascular events including heart failure (HF). Both increased LV mass and HF disproportionately affect black individuals. To understand the mechanisms that drive disease, particularly in black individuals, we undertook a proteomic screen in a black cohort and compared it to a white cohort. Methods: We measured 1305 plasma proteins using an aptamer-based proteomic platform (SOMAscan™) in 1772 black participants in the Jackson Heart Study (JHS) with available baseline LV mass as assessed by 2D echocardiography, as well as 1600 free of HF with follow-up assessment of incident cases. Mean follow-up time was 11 years; 152 cases of incident HF hospitalization were identified. Models were adjusted for age, sex, body mass index, estimated glomerular filtration rate (as calculated by CKD-EPI equation), systolic blood pressure, hypertension treatment, presence of diabetes, total/HDL cholesterol, prevalent coronary disease, and current smoking status. Incident HF models were also adjusted for incident coronary heart disease. We then compared protein associations in JHS to those observed in whites from the Framingham Heart Study (FHS) to examine significant differences. Results: In JHS, there were 112 proteins associated with LV mass and 10 proteins associated with incident HF hospitalization with FDR <5%. Several proteins showed expected associations with both LV mass and HF, including N-terminal pro-BNP (β = 0.04 [0.02, 0.05], p = 1.0 x 10 -8 , HR = 1.46 [1.20, 1.79], p = 0.0002). The strongest association with LV mass was more novel: leukotriene A4 hydrolase (LKHA4) (β = 0.05 [0.04, 0.06], p = 2.6 x 10 -15 ). Conversely, Fractalkine/CX3CL1 showed a novel association with incident HF (HR = 1.32 [1.14, 1.54], p = 0.0003). While proteins like Cystatin C and N-terminal pro-BNP showed consistent effects in FHS, LKHA4 and Fractalkine were significantly different. Conclusions: We identify several novel biological pathways specific to black individuals hypothesized to contribute to the pathophysiologic cascade of LV hypertrophy and incident HF including LKHA4 and Fractalkine. Further studies are needed to validate these results and elucidate the detailed underlying mechanisms.

scholarly journals Loss of Function in Dopamine Receptor‐3 (D3R) Attenuates Left Ventricular Cardiac Fibroblast Migration and Proliferation In Vitro

2019 ◽  
Vol 33 (S1) ◽  
Author(s):  
Andrew Kisling ◽  
Madaniah O Zakari ◽  
Musaad B Alsahly ◽  
Deepthy C Melit‐Thomas ◽  
Stefan Clemens ◽  
...  
Keyword(s):  
Dopamine Receptor ◽  
Left Ventricular ◽  
Cardiac Fibroblast ◽  
Loss Of Function ◽  
Fibroblast Migration ◽  
Proliferation In Vitro

scholarly journals Mir-30d Regulates Cardiac Remodeling by Intracellular and Paracrine Signaling

2021 ◽  
Vol 128 (1) ◽  
Author(s):  
Jin Li ◽  
Ane M. Salvador ◽  
Guoping Li ◽  
Nedyalka Valkov ◽  
Olivia Ziegler ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Chronic Phase ◽  
Left Ventricular ◽  
Model Systems ◽  
Locked Nucleic Acid ◽  
Loss Of Function ◽  
Paracrine Signaling

Rationale: Previous translational studies implicate plasma extracellular microRNA-30d (miR-30d) as a biomarker in left ventricular remodeling and clinical outcome in heart failure (HF) patients, although precise mechanisms remain obscure. Objective: To investigate the mechanism of miR-30d–mediated cardioprotection in HF. Methods and Results: In rat and mouse models of ischemic HF, we show that miR-30d gain of function (genetic, lentivirus, or agomiR-mediated) improves cardiac function, decreases myocardial fibrosis, and attenuates cardiomyocyte (CM) apoptosis. Genetic or locked nucleic acid–based knock-down of miR-30d expression potentiates pathological left ventricular remodeling, with increased dysfunction, fibrosis, and cardiomyocyte death. RNA sequencing of in vitro miR-30d gain and loss of function, together with bioinformatic prediction and experimental validation in cardiac myocytes and fibroblasts, were used to identify and validate direct targets of miR-30d. miR-30d expression is selectively enriched in cardiomyocytes, induced by hypoxic stress and is acutely protective, targeting MAP4K4 (mitogen-associate protein kinase 4) to ameliorate apoptosis. Moreover, miR-30d is secreted primarily in extracellular vesicles by cardiomyocytes and inhibits fibroblast proliferation and activation by directly targeting integrin α5 in the acute phase via paracrine signaling to cardiac fibroblasts. In the chronic phase of ischemic remodeling, lower expression of miR-30d in the heart and plasma extracellular vesicles is associated with adverse remodeling in rodent models and human subjects and is linked to whole-blood expression of genes implicated in fibrosis and inflammation, consistent with observations in model systems. Conclusions: These findings provide the mechanistic underpinning for the cardioprotective association of miR-30d in human HF. More broadly, our findings support an emerging paradigm involving intercellular communication of extracellular vesicle–contained miRNAs (microRNAs) to transregulate distinct signaling pathways across cell types. Functionally validated RNA biomarkers and their signaling networks may warrant further investigation as novel therapeutic targets in HF.

P1243Comparison of long-term clinical course and outcome of MYBPC3 - versus MYH7 - related hypertrophic cardiomyopathy

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
C Fumagalli ◽  
E Fedele ◽  
M Beltrami ◽  
N Maurizi ◽  
S Passantino ◽  
...  
Keyword(s):  
Heart Failure ◽  
Hypertrophic Cardiomyopathy ◽  
Diastolic Dysfunction ◽  
Systolic Dysfunction ◽  
Left Ventricular ◽  
Septal Myectomy ◽  
Lv Dysfunction ◽  
Instrumental Records

Abstract Introduction The presence of sarcomere mutations is a powerful predictor of heart failure-related outcomes in Hypertrophic Cardiomyopathy (HCM). However, whether the prevalence of left ventricular (LV) dysfunction differs in patients with mutations in the two most prevalent HCM-associated genes (i.e. MYBPC3 and MYH7) is unclear. Purpose To ascertain lifetime trends in prevalence of LV dysfunction in HCM associated with pathogenic or likely-pathogenic MYBPC3 versus MYH7 mutations. Methods Clinical and instrumental records of 402 HCM patients with MYBPC3 (N=251) or MYH7 (N=151) mutations were retrospectively reviewed. Presence of systolic dysfunction (ejection fraction [EF] <50%) and diastolic dysfunction (Grade II and III) were assessed for each patient. In vitro analysis of septal myectomy samples was performed to further compare electro-mechanic properties of MYBC3 and MYH7 patients. Results Patients were diagnosed at a mean age of 39±17 years and 63% were men. At first evaluation MYBPC3-HCM patients were less frequently obstructive (15% vs 26% in MYH7; p=0.005) and had lower LVEF (61±11% vs 64±9%; p=0.01). Prevalence of diastolic dysfunction increased with age and was lowest in MYBPC3 patients <40 years at diagnosis (19.5% vs 35.4% in MYH7, p=0.043). At a mean follow-up (FU) of 13±11 years, patients developed comparable left atrium enlargement (MYBPC3 52±29 ml/m2 vs 41±18 at baseline, p<0.001; MYH7 54±25ml/m2 vs 45±22, p=0.003). Prevalence of diastolic dysfunction was also similar. MYBPC3 patients had lower LVEF at final evaluation (61±11% vs 64±9% in MYH7, p=0.01) with greater prevalence of overt systolic dysfunction (EF<50%, MYBPC3 vs MYH7: 15% vs 5%, OR: 2.3 95% CI: 1.2–5.8, p=0.013). No significant differences were observed in terms of NYHA class change, atrial fibrillation, stroke, heart failure, appropriate ICD intervention or cardiovascular death. However, prevalence of NSVT was higher for MYBPC3 (39% vs 14% in MYH7, p<0.0001). At Cox multivariable analysis independent predictors of systolic dysfunction at follow-up were MYBPC3 positive status (HR 2.53 95% CI: 1.09–5.82, p=0.029) and age at initial evaluation (HR 1.03 95% CI 1.00–1.06, p=0.027). In vitro cross-sectional evaluation of myocardial samples taken during septal myectomy at different ages showed a decline in contraction-relaxation properties after age 40 in MYPBC3 carriers, but preserved function in MYH7 patients (Figure). Kinetic of myosin cross-bridges Conclusions In HCM patients, mutations in the MYBPC3 gene and early diagnosis are associated with slowly progressing systolic impairment leading to overt dysfunction in 15% compared to 5% in MYH7-HCM. However, outcome was similar in the two subsets. These differences in lifetime myocardial performance between the two most common HCM-associated genes suggest diverse pathways of disease progression, potentially amenable to requiring different molecular approaches.

scholarly journals The Biological Activity of Alkaloids from the Amaryllidaceae: From Cholinesterases Inhibition to Anticancer Activity

2016 ◽  
Vol 11 (10) ◽  
pp. 1934578X1601101 ◽  
Author(s):  
Klára Habartová ◽  
Lucie Cahlíková ◽  
Martina Řezáčová ◽  
Radim Havelek
Keyword(s):  
Molecular Level ◽  
Plant Family ◽  
Amaryllidaceae Alkaloids ◽  
Medicinal Properties ◽  
The Many ◽  
Small Chemical ◽  
Shed Light

Modern research has shown that Amaryllidaceae alkaloids represent a rich reservoir of potential small chemical molecules exhibiting several medicinal properties through various mechanisms. Among the many Amaryllidaceae compounds, galanthamine has been given a great amount of attention due to the fact that it possesses potent acetylcholinesterase inhibitory activity. In spite of the amount of evidence indicating the potential usefulness of Amaryllidaceae alkaloids in therapy, research groups have focused their attention on the other alkaloids present in this plant family. New investigations have shed light on many aspects of the structure of Amaryllidaceae alkaloids and on their semisynthetic modification, function, and mechanisms underlying in vitro and in vivo activity. In addition, Amaryllidaceae alkaloids have frequently been identified as having promising cytotoxic properties against cancer cell lines. While follow-up studies have repeatedly shown that Amaryllidaceae alkaloids and their derivatives demonstrate antiproliferative, cytotoxic and apoptosis-inducing activity, the mechanisms remain unclear. This review addresses the most important Amaryllidaceae alkaloids with anticancer potential, particularly those that have been studied for the purpose of gaining a better understanding of the basis of the activity at the cellular and molecular level.

Daily administration of interleukin-18 causes myocardial dysfunction in healthy mice

2005 ◽  
Vol 289 (2) ◽  
pp. H708-H714 ◽  
Author(s):  
Per Reidar Woldbæk ◽  
Jørn Bodvar Sande ◽  
Tævje Andreas Strømme ◽  
Per Kristian Lunde ◽  
Srdjan Djurovic ◽  
...  
Keyword(s):  
Myocardial Hypertrophy ◽  
Diastolic Pressure ◽  
Myocardial Dysfunction ◽  
Fold Increase ◽  
Left Ventricular ◽  
Daily Administration ◽  
Lv Function ◽  
Rat Cardiomyocytes ◽  
Adult Rat

Although increased levels of circulating interleukin (IL)-18 have been demonstrated in patients with cardiovascular diseases, the functional consequences of chronically increased circulating IL-18 with respect to myocardial function have not been defined. Thus we aimed to examine the effects of chronic IL-18 exposure on left ventricular (LV) function in healthy mice. Moreover, to clarify whether IL-18 has direct effects on the cardiomyocyte, we examined effects of IL-18 on cardiomyocytes in vitro. After 7 days of daily intraperitoneal injections of 0.5 μg IL-18 in healthy mice, a 40% ( P < 0.05) reduction in the LV maximal positive derivative, a 25% ( P < 0.05) reduction in the LV maximal rate of pressure decay, and a 2.8-fold ( P < 0.001) increase in the LV end-diastolic pressure were measured, consistent with myocardial dysfunction. Furthermore, we measured a 75% ( P < 0.05) reduction in β-adrenergic responsiveness to isoproterenol. IL-18 induced myocardial hypertrophy, and there was a 2.9-fold increase ( P < 0.05) in atrial natriuretic peptide mRNA expression in the LV myocardium. In vitro examinations of isolated adult rat cardiomyocytes being stimulated with IL-18 (0.1 μg/ml) exhibited an increase in peak Ca2+ transients ( P < 0.05) and in diastolic Ca2+ concentrations ( P < 0.05). In conclusion, this study shows that daily administration of IL-18 in healthy mice causes LV myocardial dysfunction and blunted β-adrenergic responsiveness to isoproterenol. A direct effect of IL-18 on the cardiomyocyte in vitro was demonstrated, suggesting that IL-18 reduces the responsiveness of the myofilaments to Ca2+. Finally, induction of myocardial hypertrophy by IL-18 indicates a role for this cytokine in myocardial remodeling.

scholarly journals Rare Loss-of-function Mutations of PTGIR Identified in Fibromuscular Dysplasia and Spontaneous Coronary Artery Dissection

2019 ◽  
Author(s):  
Adrien Georges ◽  
Juliette Albuisson ◽  
Takiy Berrandou ◽  
Délia Dupré ◽  
Aurélien Lorthioir ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Fibromuscular Dysplasia ◽  
Artery Dissection ◽  
Spontaneous Coronary Artery Dissection ◽  
Loss Of Function ◽  
Coronary Artery Dissection ◽  
Genetic Causes ◽  
Prostacyclin Receptor

AbstractBackgroundFibromuscular Dysplasia (FMD) and Spontaneous Coronary Artery Dissection (SCAD) are related, non-atherosclerotic arterial diseases mainly affecting middle-aged women. Little is known about their physiopathological mechanisms.ObjectivesWe aimed to identify rare genetic causes to elucidate molecular mechanisms implicated in FMD and SCAD.MethodsWe analyzed 29 exomes that included familial and sporadic FMD. Follow-up was conducted by targeted or Sanger sequencing (1,071 FMD and 365 SCAD patients) or lookups in exome (264 FMD) or genome sequences (488 SCAD), all independent and unrelated. We used TRAPD burden test to test for enrichment in patients compared to gnomAD controls. The biological effects of variants on receptor signaling and protein expression were characterized using transient overexpression in human cells.ResultsWe identified one rare loss-of-function variant (LoF) (MAFgnomAD=0.000075) shared by two FMD sisters in the prostaglandin I2 receptor (hIP) gene (PTGIR), a key player in vascular remodeling. Follow-up in >1,300 FMD patients revealed four additional LoF allele carriers and a putative enrichment in FMD (PTRAPD=8×10−4), in addition to several rare missense variants. We confirmed the LoFs (Q163X and P17RfsX6) and one missense (L67P) to severely impair hIP function in vitro. Genetic analyses of PTGIR in SCAD revealed one patient who carries Q163X, one with L67P and one carrying a rare splicing mutation (c.768+1C>G), but not a significant enrichment (PTRAPD=0.12) in SCAD.ConclusionsOur study shows that rare genetic mutations in PTGIR are enriched among FMD patients and found in SCAD patients, suggesting a role for prostacyclin signaling in non-atherosclerotic stenosis and dissection.Condensed abstractFibromuscular Dysplasia (FMD) and Spontaneous Coronary Artery Dissection (SCAD) are non-atherosclerotic arterial diseases predominantly affecting women. Their mechanisms and genetic causes are poorly understood. We identified rare loss-of-function mutations of the prostacyclin receptor gene (PTGIR) in several FMD and SCAD patients, including two affected sisters, and several unrelated patients. We also showed that a rare missense mutation of PTGIR severely impairs prostacyclin receptor function in vitro. Our data provide evidence for a role for prostacyclin signaling in the etiology of FMD and SCAD providing leads towards this mechanism.

scholarly journals Nucleotide, ribonucleotide and ribonucleoside binding belongs to differentially expressed genes in porcine epithelial oviductal cells during longterm primary cultivation

2019 ◽  
Vol 7 (4) ◽  
pp. 161-169
Author(s):  
Mariusz J. Nawrocki ◽  
Rafał Sibiak ◽  
Sandra Kałużna ◽  
Maciej Brązert ◽  
Piotr Celichowski ◽  
...  
Keyword(s):  
Biological Process ◽  
Molecular Level ◽  
Reproductive Function ◽  
Affymetrix Microarray ◽  
Reproductive Process ◽  
Primary Cultivation ◽  
Cyclic Dynamics ◽  
Gene Ontology Biological Process

AbstractThe oviduct play a crucial role in reproductive process, through facilitating successful embryo growth and conception. Oviduct activity is orchestrated by various factors, depending on cyclic dynamics, which crucially affect the success of reproductive function. The morphological modifications of oviducts in response to the female reproductive cycle are well established. However, detailed characterization at the molecular level is still needed. The present study, employed primary in vitro cell cultures and high-throughput transcriptome analysis via an Affymetrix microarray approach, described nucleotide, ribonucleotide and ribonucleoside binding patterns at a molecular level in oviduct epithelial cells (OECs). 222 genes were targeted belonging to four gene ontology biological process terms (GO BP): “adenyl nucleotide binding”, “adenyl ribonucleotide binding”, “ribonucleotide binding”, “ribonucleoside binding”, which showed the greatest variability in the level of mRNA expression during of long-term cultivation. In this group of genes, special attention was paid to those showing the greatest variability in relation to the reference measurement, including OASL, PIM1, ACTA2 and ABCA1.Running title: Oviductal nucleotide and nucleoside binding patterns

scholarly journals Amlexanox and Forskolin Prevents Isoproterenol-Induced Cardiomyopathy by Subduing Cardiomyocyte Hypertrophy and Maladaptive Inflammatory Responses

2021 ◽  
Vol 9 ◽  
Author(s):  
Gabriel Komla Adzika ◽  
Hongjian Hou ◽  
Adebayo Oluwafemi Adekunle ◽  
Ruqayya Rizvi ◽  
Seyram Yao Adzraku ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Troponin I ◽  
Inflammatory Responses ◽  
Myocardial Hypertrophy ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy ◽  
Myocardial Inflammation ◽  
Treatment Interventions ◽  
Pathological Cardiac Hypertrophy

Chronic catecholamine stress (CCS) induces the occurrence of cardiomyopathy—pathological cardiac hypertrophy (PCH), which is characterized by left ventricular systolic dysfunction (LVSD). Recently, mounting evidence has implicated myocardial inflammation in the exacerbation of pathological cardiac remodeling. However, there are currently no well-defined treatment interventions or regimes targeted at both the attenuation of maladaptive myocardial hypertrophy and inflammation during CCS to prevent PCH. G protein-coupled receptor kinase 5 (GRK5) and adenylyl cyclases (ACs)-cAMP mediates both cardiac and inflammatory responses. Also, GRK5 and ACs are implicated in stress-induced LVSD. Herein, we aimed at preventing PCH during CCS via modulating adaptive cardiac and inflammatory responses by inhibiting GRK5 and/or stimulating ACs. Isoproterenol-induced cardiomyopathy (ICM) was modeled using 0.5 mg/100 g/day isoproterenol injections for 40 days. Alterations in cardiac and inflammatory responses were assessed from the myocardia. Similarities in the immunogenicity of cardiac troponin I (cTnI) and lipopolysaccharide under CCS were assessed, and Amlexanox (35 μM/ml) and/or Forskolin (10 μM/ml) were then employed in vitro to modulate adaptive inflammatory responses by inhibiting GRK5 or activating ACs-cAMP, respectively. Subsequently, Amlexanox (2.5 mg/100 g/day) and/or Forskolin (0.5 mg/100 g/day) were then translated into in vivo during CCS to modulate adaptive cardiac and inflammatory responses. The effects of Amlexanox and Forskolin on regulating myocardial systolic functions and inflammatory responses during CCS were ascertained afterward. PCH mice had excessive myocardial hypertrophy, fibrosis, and aggravated LVSD, which were accompanied by massive CD68+ inflammatory cell infiltrations. In vitro, Forskolin-AC/cAMP was effective than Amlexanox-GRK5 at downregulating proinflammatory responses during stress; nonetheless, Amlexanox and Forskolin combination demonstrated the most efficacy in modulating adaptive inflammatory responses. Individually, the translated Amlexanox and Forskolin treatment interventions were ineffective at subduing the pathological remodeling and sustaining cardiac function during CCS. However, their combination was potent at preventing LVSD during CCS by attenuating maladaptive myocardial hypertrophy, fibrosis, and inflammatory responses. The treatment intervention attained its potency mainly via Forskolin-ACs/cAMP-mediated modulation of cardiac and inflammatory responses, coupled with Amlexanox inhibition of GRK5 mediated maladaptive cascades. Taken together, our findings highlight the Amlexanox and Forskolin combination as a potential therapeutic intervention for preventing the occurrence of pathological cardiac hypertrophy during chronic stress.

scholarly journals LncRNA SNHG17 interacts with LRPPRC to stabilize c-Myc protein and promote G1/S transition and cell proliferation

2021 ◽  
Vol 12 (11) ◽  
Author(s):  
Jin-Yu Liu ◽  
Ya-Jing Chen ◽  
Huan-Hui Feng ◽  
Zhan-Li Chen ◽  
Yun-Long Wang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Cell Growth ◽  
Loss Of Function ◽  
Pentatricopeptide Repeat ◽  
Non Coding Rnas ◽  
The Stability ◽  
High Level

AbstractOncogenic c-Myc is a master regulator of G1/S transition. Long non-coding RNAs (lncRNAs) emerge as new regulators of various cell activities. Here, we found that lncRNA SnoRNA Host Gene 17 (SNHG17) was elevated at the early G1-phase of cell cycle. Both gain- and loss-of function studies disclosed that SNHG17 increased c-Myc protein level, accelerated G1/S transition and cell proliferation, and consequently promoted tumor cell growth in vitro and in vivo. Mechanistically, the 1-150-nt of SNHG17 physically interacted with the 1035-1369-aa of leucine rich pentatricopeptide repeat containing (LRPPRC) protein, and disrupting this interaction abrogated the promoting role of SNHG17 in c-Myc expression, G1/S transition, and cell proliferation. The effect of SNHG17 in stimulating cell proliferation was attenuated by silencing c-Myc or LRPPRC. Furthermore, silencing SNHG17 or LRPPRC increased the level of ubiquitylated c-Myc and reduced the stability of c-Myc protein. Analysis of human hepatocellular carcinoma (HCC) tissues revealed that SNHG17, LRPPRC, and c-Myc were significantly upregulated in HCC, and they showed a positive correlation with each other. High level of SNHG17 or LRPPRC was associated with worse survival of HCC patients. These data suggest that SNHG17 may inhibit c-Myc ubiquitination and thus enhance c-Myc level and facilitate proliferation by interacting with LRPPRC. Our findings identify a novel SNHG17-LRPPRC-c-Myc regulatory axis and elucidate its roles in G1/S transition and tumor growth, which may provide potential targets for cancer therapy.

Sign in / Sign up

Export Citation Format

Share Document