microRNA 223 Is Upregulated in the Multistep Progression of Barrett's Esophagus and Modulates Sensitivity to Chemotherapy by Targeting <i>PARP1</i>

Streppel, Mirte Mayke; Pai, Shweta G.; Campbell, Nathaniel R.; Hu, Chaoxin; Yabuuchi, Shinichi; Canto, Marcia Irene; Wang, Jean S.; Montgomery, Elizabeth A.; Maitra, Anirban

doi:10.1158/1078-0432.ccr-13-0601

Cited by 72 publications

(55 citation statements)

References 42 publications

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“…In addition, in esophageal cancer cells, PARP-1 was identified as a direct target gene of miR-223 (34). Indeed, in esophageal adenocarcinoma cells, decreased cancer growth was observed in cells with enforced miR-223 expression and subsequent reduced PARP-1.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, miR-223 was first described as a key player in regulating inflammation in many inflammation-related disorders including DNA damage (11,34,39). Thus, decreased expression in miR-223 in PAH might also play a role in the inflammatory processes by regulating hematopoietic cell differentiation and cytokine production (11), such as IL-6 (6), which also plays a critical role in PAH via STAT3 (29).…”

Section: Discussionmentioning

confidence: 99%

“…In cancer, PARP-1 expression is regulated by microRNA-223 (miR-223), a microRNA involved in DNA damage response (34). According to TargetScan 6.2, PARP-1 is in fact a predicted target of miR-223.…”

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confidence: 99%

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miR-223 reverses experimental pulmonary arterial hypertension

Meloche

Guen

Potus

et al. 2015

American Journal of Physiology-Cell Physiology

107

111

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nary arterial hypertension (PAH) is a devastating disease affecting lung vasculature. The pulmonary arteries become occluded due to increased proliferation and suppressed apoptosis of the pulmonary artery smooth muscle cells (PASMCs) within the vascular wall. It was recently shown that DNA damage could trigger this phenotype by upregulating poly(ADP-ribose)polymerase 1 (PARP-1) expression, although the exact mechanism remains unclear. In silico analyses and studies in cancer demonstrated that microRNA miR-223 targets PARP-1. We thus hypothesized that miR-223 downregulation triggers PARP-1 overexpression, as well as the proliferation/apoptosis imbalance observed in PAH. We provide evidence that miR-223 is downregulated in human PAH lungs, distal PAs, and isolated PASMCs. Furthermore, using a gain and loss of function approach, we showed that increased hypoxia-inducible factor 1␣, which is observed in PAH, triggers this decrease in miR-223 expression and subsequent overexpression of PARP-1 allowing PAH-PASMC proliferation and resistance to apoptosis. Finally, we demonstrated that restoring the expression of miR-223 in lungs of rats with monocrotaline-induced PAH reversed established PAH and provided beneficial effects on vascular remodeling, pulmonary resistance, right ventricle hypertrophy, and survival. We provide evidence that miR-223 downregulation in PAH plays an important role in numerous pathways implicated in the disease and restoring its expression is able to reverse PAH. miR-223; pulmonary hypertension; PARP-1; HIF-1␣; DNA damage PULMONARY ARTERIAL HYPERTENSION (PAH) is a serious condition characterized by obstruction of the precapillary pulmonary arterioles (PA) due to excessive vasoconstriction, inflammation, and imbalance between cells' proliferation and apoptosis within the arterial wall. This remodeling and obstruction of the PAs leads to increases in pulmonary vascular resistance, right ventricular (RV) failure, and death of patients. Despite recent therapeutic advances, most patients exhibit persistently poor exercise capacity and quality of life, with a 3-yr survival rate of 65% (12).Growing evidence underlines the importance of DNA damage in PAH etiology (9,19,23). Indeed, the sustained inflammation, RAGE expression (21), and metabolic stress (30) observed in PAH result in DNA damage-dependent activation of poly(ADP-ribose)polymerase 1 (PARP-1) in PA smooth muscle cells (PASMCs) of PAH patients (23). We recently showed that PARP-1 overexpression was responsible for enhanced PAH-PASMC proliferation and suppressed apoptosis (23). Nevertheless, the mechanisms that regulate this overexpression in PAH remain elusive.In cancer, PARP-1 expression is regulated by microRNA-223 (miR-223), a microRNA involved in DNA damage response (34). According to TargetScan 6.2, PARP-1 is in fact a predicted target of miR-223. Moreover, downregulation of miR-223 has been shown to mediate mechanical stretch-stimulated proliferation of vascular smooth muscle cells (33). Interestingly, Wang et al. (38) reported that miR-...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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miR-223 reverses experimental pulmonary arterial hypertension

Meloche

Guen

Potus

et al. 2015

American Journal of Physiology-Cell Physiology

107

111

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“…Interestingly, miR-223 was found to have a tumor suppressor function by inhibiting migration and invasion through targeting Artemin, a tumor metastasis-related gene, in human esophageal carcinoma [178]. In line with this notion, it has been shown that miR-223 is overexpressed in the multiple step progression of Barrett's esophagus and modulates drug resistance via targeting PARR1 [179]. Interestingly, in a separate report, down-regulation of miR-223 was identified in hepatocellular carcinoma, while re-expression of miR-223 caused an inhibitory effect on cell viability in hepatocellular carcinoma cell lines [180].…”

Section: Regulation Of Fbw7 By Mir-223mentioning

confidence: 82%

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2014

Oncotarget

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ABSTRACT:FBW7 (F-box and WD repeat domain-containing 7) or Fbxw7 is a tumor suppressor, which promotes the ubiquitination and subsequent degradation of numerous oncoproteins including Mcl-1, Cyclin E, Notch, c-Jun, and c-Myc. In turn, FBW7 is regulated by multiple upstream factors including p53, C/EBP-δ, EBP2, Pin1, Hes-5 and Numb4 as well as by microRNAs such as miR-223, miR-27a, miR-25, and miR-129-5p. Given that the Fbw7 tumor suppressor is frequently inactivated or deleted in various human cancers, targeting FBW7 regulators is a promising anticancer therapeutic strategy.

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“…MiR-196a, which is described as a marker of progression from BE to EAC, can increase cell proliferation and anchorage-independent growth and inhibit apoptosis in EAC cell lines in vitro (281). The down-stream target for miR-196a are verified to be Annexin A1, S100 and JHesoAD1 showed more aggressive phenotype and also showed higher sensitivity for DNAdamaging agents (292).…”

Section: Micrornamentioning

confidence: 93%

Serum diagnostic glycoprotein biomarkers for Barrett's esophagus and esophageal adenocarcinoma

Shah¹

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Esophageal cancer is the eighth most commonly diagnosed cancer and the sixth most common cause of cancer related mortality globally. There are two different types of esophageal cancer, esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC), each accounting for half of the cases. EAC develops in the lower one third of the esophagus as a consequence of chronic gastroesophageal reflux disease (GERD) from precancerous metaplastic condition Barrett's esophagus (BE). Apart from GERD and BE which are major risk factors for EAC, other known risk factors include age, male gender, obesity, Caucasian race, low intake of fruits and vegetables in diet, and Helicobacter pylori negative status. Due to changing life style and prevalence of risk factors, the incidences of EAC have been rising for past few decades and now it has become one of the fastest growing malignancies. The survival rate is very poor with only 1 in 5 patients survive more than 5 years after EAC diagnosis, likely due to diagnosis at late stages. To diagnose early treatable dysplastic changes in progression from BE to EAC, BE patients undergo routine endoscopy-biopsies, with the biopsy evaluated by a histopathologist to confirm the dysplastic changes. This current method is invasive and prone to sampling error as well as interobserver variability. Endoscopy requires patient hospitalization and specialist appointment, leading to high expense. Moreover, BE is an asymptomatic condition which means a pool of BE patients are undiagnosed hence not enrolled into the surveillance program. Collectively, it has been shown that current endoscopy-biopsies based diagnostic is impractical and expensive for population wide BE screening or surveillance programs.In contrast to endoscopy-biopsy, biomarkers from the blood are amenable to populationscreening strategies, due to the ease of access and low cost of testing. Moreover, EAC pathogenesis has been associated with changes in the serum glycan profile. However, specific glycoproteins that undergo differential glycosylation are unknown. Therefore, the aims of this thesis were to (i) identify serum diagnostic glycoprotein biomarker candidates for BE and EAC using biomarker discovery pipeline, (ii) develop a targeted proteomics approach to measure biomarker candidates for timely verification, (iii) verify serum glycoprotein candidates in an independent patient cohort, and (iv) test feasibility of using electrochemical detection methodology for the glycoprotein detection.This translational research project utilizes lectins, naturally occurring proteins with specificity to bind with glycan structures, as affinity agents to isolate glycoproteins with different glycan structures. Our laboratory has previously established lectin magnetic bead array (LeMBA) methodology to identify serum glycoprotein biomarker candidates showing differential lectin ii binding (Loo et al., J Proteome Res 2010 and Choi et al., Electrophoresis 2011 Mass spectrometry methods employed for biomarker discovery and verification...

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microRNA 223 Is Upregulated in the Multistep Progression of Barrett's Esophagus and Modulates Sensitivity to Chemotherapy by Targeting PARP1

Cited by 72 publications

References 42 publications

miR-223 reverses experimental pulmonary arterial hypertension

miR-223 reverses experimental pulmonary arterial hypertension

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Serum diagnostic glycoprotein biomarkers for Barrett's esophagus and esophageal adenocarcinoma

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