A cardiac-enriched microRNA, miR-378, blocks cardiac hypertrophy by targeting Ras signaling.

Nagalingam, Raghu S.; Sundaresan, Nagalingam R.; Gupta, Mahesh P.; Geenen, David L.; Solaro, R. John; Guptā, Madhu

doi:10.1074/jbc.a112.442384

Cited by 20 publications

(28 citation statements)

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“…In addition, reduced miR-378a-3p by flavonoid fisetin inhibited fat accumulation in the liver [30]. In organ fibrosis, miR-378a-3p has been reported to be abundant in cardiomyocytes and miR-378a-3p down-regulation contributes to the development of cardiac fibrosis involving a TGFβ1-dependent paracrine mechanism [16,31]. In this study, we found that miR-378a-3p was down-regulated in CCl 4 -treated rats and activated HSCs.…”

Section: Discussionmentioning

confidence: 58%

Activation of Hepatic Stellate Cells is Inhibited by microRNA-378a-3p via Wnt10a

Fan

Chen

et al. 2016

Cell Physiol Biochem

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Background/Aims: Wnt/β-catenin pathway is involved in liver fibrosis and microRNAs (miRNAs) are considered as key regulators of the activation of hepatic stellate cells (HSCs). A recent study showed the protective role of miR-378a-3p against cardiac fibrosis. However, whether miR-378a-3p suppresses Wnt/β-catenin pathway in liver fibrosis is largely unknown. Methods: miR-378a-3p expression was detected in carbon tetrachloride-induced liver fibrosis and activated HSCs. Effects of miR-378a-3p overexpression on HSC activation and Wnt/β-catenin pathway were analyzed. Bioinformatic analysis was employed to identify the potential targets of miR-378a-3p. Serum miR-378a-3p expression was analyzed in patients with cirrhosis. Results: Reduced miR-378a-3p expression was observed in the fibrotic liver tissues and activated HSCs. Up-regulation of miR-378a-3p inhibited HSC activation including cell proliferation, α-smooth muscle actin (α-SMA) and collagen expression. Moreover, miR-378a-3p overexpression resulted in Wnt/β-catenin pathway inactivation. Luciferase reporter assays demonstrated that Wnt10a, a member of Wnt/β-catenin pathway, was confirmed to be a target of miR-378a-3p. By contrast, miR-378a-3p inhibitor contributed to HSC activation, with an increase in cell proliferation, α-SMA and collagen expression. But all these effects were blocked down by silencing of Wnt10a. Notably, sera from patients with cirrhosis contained lower levels of miR-378a-3p than sera from healthy controls. Receiver operating characteristic curve analysis suggested that serum miR-378a-3p differentiated liver cirrhosis patients from healthy controls, with an area under the curve of ROC curve of 0.916. Conclusion: miR-378a-3p suppresses HSC activation, at least in part, via targeting of Wnt10a, supporting its potential utility as a novel therapeutic target for liver fibrosis.

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Section: Discussionmentioning

confidence: 58%

Activation of Hepatic Stellate Cells is Inhibited by microRNA-378a-3p via Wnt10a

Fan

Chen

et al. 2016

Cell Physiol Biochem

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“…Specifically, miR-378 expressions were found significantly higher in the serum of humans with alcohol use disorders (Ignacio et al 2015). MiR-378 includes both miR-378-5p and miR-378-3p, which are mature microRNAs derived from a common hairpin RNA precursor expressed from a single non-coding gene (Nagalingam et al 2013). Although neither miR-378-5p nor ALDH2 gene has been previously identified as a target of ethanol exposure, prior studies in ischemia conditions have shown a list of miRNAs that negatively regulate ALDH2 function could be associated with increased cardiomyocyte apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Increased expression of microRNA-378a-5p in acute ethanol exposure of rat cardiomyocytes

Wang

Song

Zhang

et al. 2017

Cell Stress and Chaperones

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Alcohol abuse is a risk factor for a distinct form of congestive heart failure, known as alcoholic cardiomyopathy (ACM). Here, we investigate how microRNAs may participate in the induction of cardiomyocyte apoptosis associated with ethanol exposure in vitro. Increasing the concentrations of ethanol to primary rat cardiomyocytes resulted in elevated apoptosis assessed by annexin V and propidium iodide staining, and reduced expression of an enzyme for alcohol detoxification aldehyde dehydrogenase 2 (ALDH2). These ethanol effects were accompanied by a substantial elevation of miR378a-5p. Driving miR-378a-5p overexpression in cardiomyocytes decreased ALDH2. The specific interaction of miR-378a-5p with the 3'UTR of ALDH2 was examined by luciferase reporter assays, and we found that miR-378a-5p activity depends on a complementary base pairing at the 3′-UTR region of ALDH2 mRNA. Finally, ethanol-induced apoptosis in cardiomyocytes was attenuated in the presence of anti-miR378a-5p. Collectively, these data implicate a likely involvement of miR-378a-5p in the stimulation of cardiomyocyte apoptosis through ALDH2 gene suppression, which might play a potential role in the pathogenesis of ACM.

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“…Most recently, high expression of miR-378 can even suppress the cell proliferation and induces apoptosis by targeting BRAF, as observed by Wang et al (13). Although the correlation between miR-378 and MAPK signaling pathway were revealed by substantial evidence, for example, Nagalingam et al emphasized Ras signaling could be one of the main targets of miR-378 in cardiac hypertrophy (14), however, the underlying mechanism of different subtypes of CRC, which correlated with sensitivity to the targeting therapy or regulation of miR-378 still remain unknown.…”

Section: Introductionmentioning

confidence: 96%

Lauric acid can improve the sensitization of Cetuximab in KRAS/BRAF mutated colorectal cancer cells by retrievable microRNA-378 expression

et al. 2015

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EGFR-inhibitor (Cetuximab) is one of the main targeted drugs used for metastatic colorectal carcinoma (CRC). The benefit from Cetuximab appears to be limited to a subtype of patients, not for the patients with tumors harboring mutated BRAF or KRAS genes; unfortunately, it accounts for ~40-50% of CRC cases. Previous studies have connected higher expression levels of miR-378 to be commonly presented in patients without BRAF or KRAS mutants than in mutated CRCs. The microRNA-378 (miR-378) is coexpressed with PGC-1β and can be easily induced by fatty acid, for example lauric acid. Therefore, we hypothesized that elevation of miR-378 expression in mutated CRCs may stimulate the cell response to Cetuximab. Herein, seven CRC cell lines with confirmed mutation status were involved in two parallel experiments; directly in vitro transfected miR-378 mimics, and using lauric acid to indirectly induce the level of miR-378 in cells. After the increase of miR-378 in cells by either direct or indirect approaches, sensitivity to Cetuximab was restored in all BRAF mutants (p-value <0.0001-0.0003), and half of KRAS mutants CRC (p-value 0.039-0.007). Further evidence was gained by decreasing expression of MEK and ERK2 proteins after transfection with miR-378; it was similar to the indirect induction by lauric acid approach. In conclusion, the present study demonstrated that lauric acid may efficiently induce miR-378 expression in CRC mutants, and both BRAF and a subtype of KRAS mutants presented significantly improved sensitivity to Cetuximab. Notably, BRAF mutants could even be inhibited in cell proliferation after elevated concentration of miR-378 in cells without combining with targeted therapy. This new approach may shed new light on BRAF or KRAS mutation in CRC patients for clinical trial, since lauric acid may easily be obtain from natural food, and it is supposed to be harmless to the cardiovascular system.

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A cardiac-enriched microRNA, miR-378, blocks cardiac hypertrophy by targeting Ras signaling.

Cited by 20 publications

References 0 publications

Activation of Hepatic Stellate Cells is Inhibited by microRNA-378a-3p via Wnt10a

Activation of Hepatic Stellate Cells is Inhibited by microRNA-378a-3p via Wnt10a

Increased expression of microRNA-378a-5p in acute ethanol exposure of rat cardiomyocytes

Lauric acid can improve the sensitization of Cetuximab in KRAS/BRAF mutated colorectal cancer cells by retrievable microRNA-378 expression

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