A microRNA checkpoint for Ca2+ signaling and overload in acute pancreatitis

Du, Wenya; Li, Geng; Shi, Na; Tang, Dongmei; Ferdek, Paweł; Jakubowska, Monika A.; Liu, Shiyu; Zhu, Xinyue; Zhang, Jiayu; Yao, Linbo; Sang, Xiongbo; Zou, Sailan; Liu, Tingting; Mukherjee, Rajarshi; Criddle, David N.; Zheng, Xiaofeng; Xia, Qing; Berggren, Per‐Olof; Huang, Wendong; Tian, Yan; Huang, Wei; Fu, Xianghui

doi:10.1016/j.ymthe.2022.01.033

Cited by 22 publications

(13 citation statements)

References 76 publications

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“…MiRNAs, the most well-studied class of regulatory ncRNAs, are endogenous short RNA molecules that play critical roles in human physiology and pathology through post-transcriptional gene silencing. [47][48][49][50] However, the link between miRNA-containing eccDNAs and tumorigenesis has not yet been investigated. Here, we found that about 50% of HCC eccDNAs encode ncRNAs, including miRNAs, lncRNAs, and pseudogenes.…”

Section: Discussionmentioning

confidence: 99%

Extrachromosomal circular MiR-17-92 amplicon promotes HCC

et al. 2023

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Background and Aims: Extrachromosomal circular DNAs (eccDNAs) are prevalent in cancer genomes and emerge as a class of crucial yet less characterized oncogenic drivers. However, the structure, composition, genomewide frequency, and contribution of eccDNAs in HCC, one of the most fatal and prevalent cancers, remain unexplored. In this study, we provide a comprehensive characterization of eccDNAs in human HCC and demonstrate an oncogenic role of microRNA (miRNA)-17-92-containing eccDNAs in tumor progression.Approach and Results: Using the circle-sequencing method, we identify and characterize more than 230,000 eccDNAs from 4 paired samples of HCC tumor and adjacent nontumor liver tissues. EccDNAs are highly enriched in HCC tumors, preferentially originate from certain chromosomal hotspots, and are correlated with differential gene expression. Particularly, a series of eccDNAs carrying the miRNA-17-92 cluster are validated by outward PCR and Sanger sequencing. Quantitative PCR analyses reveal that miRNA-17-92-containing eccDNAs, along with the expression of their corresponding miRNAs, are elevated in HCC tumors and associated with poor outcomes and the age of HCC patients. More intriguingly, exogenous expression of artificial DNA circles harboring the miR-17-92 cluster, which is synthesized by the ligase-assisted minicircle

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Section: Discussionmentioning

confidence: 99%

Extrachromosomal circular MiR-17-92 amplicon promotes HCC

et al. 2023

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“…Intracellular calcium release from the endoplasmic reticulum calcium store lowers the calcium concentration within the endoplasmic reticulum, which prompts the endoplasmic reticulum to form puncta with the plasmalemma, comprised of stromal interaction molecule 1 (STIM1), ORAI and TRP canonical cation (TRPC) channels, to allow extracellular calcium to replenish the endoplasmic reticulum [70]. Although calcium entry is normally dampened by store-operated calcium entry-associated regulatory factor (SARAF), expression of SARAF becomes downregulated [76], as is micro-RNA 26a, which normally dampens expression of TRPC channels [77], removing controls on calcium entry. Oxidative stress results, opening non-selective TRP melastatin 2 (TRPM2) channels [78].…”

Section: Pathophysiologymentioning

confidence: 99%

Acute Pancreatitis: Diagnosis and Treatment

Szatmary

Grammatikopoulos

Cai

et al. 2022

Drugs

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Acute pancreatitis is a common indication for hospital admission, increasing in incidence, including in children, pregnancy and the elderly. Moderately severe acute pancreatitis with fluid and/or necrotic collections causes substantial morbidity, and severe disease with persistent organ failure causes significant mortality. The diagnosis requires two of upper abdominal pain, amylase/lipase ≥ 3 ×upper limit of normal, and/or cross-sectional imaging findings. Gallstones and ethanol predominate while hypertriglyceridaemia and drugs are notable among many causes. Serum triglycerides, full blood count, renal and liver function tests, glucose, calcium, transabdominal ultrasound, and chest imaging are indicated, with abdominal crosssectional imaging if there is diagnostic uncertainty. Subsequent imaging is undertaken to detect complications, for example, if C-reactive protein exceeds 150 mg/L, or rarer aetiologies. Pancreatic intracellular calcium overload, mitochondrial impairment, and inflammatory responses are critical in pathogenesis, targeted in current treatment trials, which are crucially important as there is no internationally licenced drug to treat acute pancreatitis and prevent complications. Initial priorities are intravenous fluid resuscitation, analgesia, and enteral nutrition, and when necessary, critical care and organ support, parenteral nutrition, antibiotics, pancreatic exocrine and endocrine replacement therapy; all may have adverse effects. Patients with local complications should be referred to specialist tertiary centres to guide further management, which may include drainage and/or necrosectomy. The impact of acute pancreatitis can be devastating, so prevention or reduction of the risk of recurrence and progression to chronic pancreatitis with an increased risk of pancreas cancer requires proactive management that should be long term for some patients.

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“…Total RNAs were harvested using Tri-Reagent (MRC, TR118) and converted to cDNA using M-MLV Reverse Transcriptase (ThermoFisher, 28025021) as described previously [ 61 ]. QRT-PCR was performed using QuantiNova SYBR Green PCR Kit (QIAGEN, 208052) and fold-inductions of target mRNA ( S5 Table ) levels were calculated using 2 –ΔΔCt taking mock non-stimulated readings as the basal level sample and Gapdh as the control.…”

Section: Methodsmentioning

confidence: 99%

Targeting RNA G-quadruplex with repurposed drugs blocks SARS-CoV-2 entry

Tong

Sang

et al. 2023

PLoS Pathog

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The rapid emergence of SARS-CoV-2 variants of concern, the complexity of infection, and the functional redundancy of host factors, underscore an urgent need for broad-spectrum antivirals against the continuous COVID-19 pandemic, with drug repurposing as a viable therapeutic strategy. Here we report the potential of RNA G-quadruplex (RG4)-targeting therapeutic strategy for SARS-CoV-2 entry. Combining bioinformatics, biochemical and biophysical approaches, we characterize the existence of RG4s in several SARS-CoV-2 host factors. In silico screening followed by experimental validation identify Topotecan (TPT) and Berbamine (BBM), two clinical approved drugs, as RG4-stabilizing agents with repurposing potential for COVID-19. Both TPT and BBM can reduce the protein level of RG4-containing host factors, including ACE2, AXL, FURIN, and TMPRSS2. Intriguingly, TPT and BBM block SARS-CoV-2 pseudovirus entry into target cells in vitro and murine tissues in vivo. These findings emphasize the significance of RG4 in SARS-CoV-2 pathogenesis and provide a potential broad-spectrum antiviral strategy for COVID-19 prevention and treatment.

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A microRNA checkpoint for Ca2+ signaling and overload in acute pancreatitis

Cited by 22 publications

References 76 publications

Extrachromosomal circular MiR-17-92 amplicon promotes HCC

Extrachromosomal circular MiR-17-92 amplicon promotes HCC

Acute Pancreatitis: Diagnosis and Treatment

Targeting RNA G-quadruplex with repurposed drugs blocks SARS-CoV-2 entry

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