miR-29a Modulates GSK3β/SIRT1-Linked Mitochondrial Proteostatic Stress to Ameliorate Mouse Non-Alcoholic Steatohepatitis

Yang, Ya‐Ling; Wang, Pei‐Wen; Wang, Feng‐Sheng; Lin, Hung‐Yu; Huang, Ying‐Hsien

doi:10.3390/ijms21186884

Cited by 28 publications

(18 citation statements)

References 51 publications

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“…Our previous study confirmed that miR-29a targets multiple biological function impacts, including attenuated shoulder stiffness fibrosis [34], liver fibrosis [8,12,35], and mitigated NAFLD [14,36], as well as influenced progression of HCC formation [26]. Similar findings have been confirmed by Song et al, who showed miR-29a downregulated Bcl-2 expression to ameliorate liver tumorigenesis [35].…”

Section: Discussionsupporting

confidence: 86%

MiR-29a Curbs Hepatocellular Carcinoma Incidence via Targeting of HIF-1α and ANGPT2

Huang

Lian

Wang

et al. 2022

IJMS

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A high-fat diet is responsible for hepatic fat accumulation that sustains chronic liver damage and increases the risks of steatosis and hepatocellular carcinoma (HCC). MicroRNA-29a (miR-29a), a key regulator of cellular behaviors, is present in anti-fibrosis and modulator tumorigenesis. However, the increased transparency of the correlation between miR-29a and the progression of human HCC is still further investigated. In this study, we predicted HIF-1α and ANGPT2 as regulators of HCC by the OncoMir cancer database and showed a strong positive correlation with HIF-1α and ANGPT2 gene expression in HCC patients. Mice fed the western diet (WD) while administered CCl4 for 25 weeks induced chronic liver damage and higher HCC incidence than without fed WD mice. HCC section staining revealed signaling upregulation in ki67, severe fibrosis, and steatosis in WD and CCl4 mice and detected Col3a1 gene expressions. HCC tissues significantly attenuated miR-29a but increased in HIF-1α, ANGPT2, Lox, Loxl2, and VEGFA expression. Luciferase activity analysis confirms that miR-29a specific binding 3′UTR of HIF-1α and ANGPT2 to repress expression. In summary, miR-29a control HIF-1α and ANGPT2 signaling in HCC formation. This study insight into a novel molecular pathway by which miR-29a targeting HIF-1α and ANGPT2 counteracts the incidence of HCC development.

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Section: Discussionsupporting

confidence: 86%

MiR-29a Curbs Hepatocellular Carcinoma Incidence via Targeting of HIF-1α and ANGPT2

Huang

Lian

Wang

et al. 2022

IJMS

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“…miR-29a has been demonstrated to have an important role in a multitude of pathophysiological processes, ranging from neurodegenerative diseases [16][17][18], cardiovascular diseases [19][20][21], pulmonary disorders [22,23], tendon disease [24], renal fibrosis [25], and scleroderma [26], and liver disease [27,28]. The hepatoprotective effect of miR-29a in the context of acute cholestasis and chronic diet stress has notably been demonstrated in our previous studies [29][30][31][32][33][34][35][36][37][38][39][40]. More importantly, a growing body of study has revealed the key role of miR-29a in the pathogenesis of HCC and its potential as a theragnostic target is notably emerging.…”

Section: Introductionmentioning

confidence: 71%

New Insights into the Role of miR-29a in Hepatocellular Carcinoma: Implications in Mechanisms and Theragnostics

Yang

Chang

et al. 2021

JPM

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Hepatocellular carcinoma (HCC) remains one of the most lethal human cancer globally. For advanced HCC, curable plan for advanced HCC is yet to be established, and the prognosis remains poor. The detail mechanisms underlying the progression of HCC tumorigenicity and the corruption of tumor microenvironment (TME) is complex and inconclusive. A growing body of studies demonstrate microRNAs (miRs) are important regulators in the tumorigenicity and TME development. Notably, mounting evidences indicate miR-29a play a crucial role in exerting hepatoprotective effect on various types of stress and involved in the progression of HCC, which elucidates their potential theragnostic implications. In this review, we reviewed the advanced insights into the detail mechanisms by which miR-29a dictates carcinogenesis, epigenetic program, and metabolic adaptation, and implicated in the sponging activity of competitive endogenous RNAs (ceRNA) and the TME components in the scenario of HCC. Furthermore, we highlighted its clinical significance in diagnosis and prognosis, as well as the emerging therapeutics centered on the activation of miR-29a.

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“…The MIR29A expression features clinical significance in a variety of disease scenarios, including Alzheimer’s disease [ 15 ], Parkinson’s disease [ 16 ], ankylosing spondylitis [ 17 ], atherosclerosis [ 18 ], atrial fibrillation [ 19 ], active pulmonary tuberculosis [ 20 ], thoracic aneurysms [ 21 ], tendon disease [ 22 ], diabetes [ 23 ], scleroderma [ 24 ], cholestatic pediatric liver disease [ 25 ], and non-alcoholic fatty liver disease (NAFLD) [ 26 ]. Importantly, our previous studies have reported the hepatoprotective role of MIR29A in the scenario of cholestasis- or diet-induced steatohepatitis and liver fibrosis [ 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ], and growing evidence has revealed its regulatory role on HCC metastasis [ 13 , 39 ]. In terms of biological activity, MIR29A was reported to directly target VEGFA to perturb the wound healing process [ 40 ], and to directly target LOXL2 to impede tumor progression [ 41 ].…”

Section: Introductionmentioning

confidence: 99%

MIR29A Impedes Metastatic Behaviors in Hepatocellular Carcinoma via Targeting LOX, LOXL2, and VEGFA

Yang

Tsai

Chang

et al. 2021

IJMS

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Primary liver cancer accounts for the third most deadly type of malignant tumor globally, and approximately 80% of the cases are hepatocellular carcinoma (HCC), which highly relies on the activity of hypoxia responsive pathways to bolster its metastatic behaviors. MicroRNA-29a (MIR29A) has been shown to exert a hepatoprotective effect on hepatocellular damage and liver fibrosis induced by cholestasis and diet stress, while its clinical and biological role on the activity hypoxia responsive genes including LOX, LOXL2, and VEGFA remains unclear. TCGA datasets were retrieved to confirm the differential expression and prognostic significance of all genes in the HCC and normal tissue. The Gene Expression Omnibus (GEO) dataset was used to corroborate the differential expression and diagnostic value of MIR29A. The bioinformatic identification were conducted to examine the interaction of MIR29A with LOX, LOXL2, and VEGFA. The suppressive activity of MIR29A on LOX, LOXL2, and VEGF was verified by qPCR, immunoblotting, and luciferase. The effect of overexpression of MIR29A-3p mimics in vitro on apoptosis markers (caspase-9, -3, and poly (ADP-ribose) polymerase (PARP)); cell viability and wound healing performance were examined using immunoblot and a WST-1 assay and a wound healing assay, respectively. The HCC tissue presented low expression of MIR29A, yet high expression of LOX, LOXL2, and VEGFA as compared to normal control. Serum MIR29A of HCC patients showed decreased levels as compared to that of normal control, with an area under curve (AUC) of 0.751 of a receiver operating characteristic (ROC) curve. Low expression of MIR29A and high expression of LOX, LOXL2, and VEGFA indicated poor overall survival (OS). MIR29A-3p was shown to target the 3′UTR of LOX, LOXL2, and VEGFA. Overexpression of MIR29A-3p mimic in HepG2 cells led to downregulated gene and protein expression levels of LOX, LOXL2, and VEGFA, wherein luciferase reporter assay confirmed that MIR29A-3p exerts the inhibitory activity via directly binding to the 3′UTR of LOX and VEGFA. Furthermore, overexpression of MIR29A-3p mimic induced the activity of caspase-9 and -3 and PARP, while it inhibited the cell viability and wound healing performance. Collectively, this study provides novel insight into a clinical-applicable panel consisting of MIR29, LOX, LOXL2, and VEGFA and demonstrates an anti-HCC effect of MIR29A via comprehensively suppressing the expression of LOX, LOXL2, and VEGFA, paving the way to a prospective theragnostic approach for HCC.

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miR-29a Modulates GSK3β/SIRT1-Linked Mitochondrial Proteostatic Stress to Ameliorate Mouse Non-Alcoholic Steatohepatitis

Cited by 28 publications

References 51 publications

MiR-29a Curbs Hepatocellular Carcinoma Incidence via Targeting of HIF-1α and ANGPT2

MiR-29a Curbs Hepatocellular Carcinoma Incidence via Targeting of HIF-1α and ANGPT2

New Insights into the Role of miR-29a in Hepatocellular Carcinoma: Implications in Mechanisms and Theragnostics

MIR29A Impedes Metastatic Behaviors in Hepatocellular Carcinoma via Targeting LOX, LOXL2, and VEGFA

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