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Article

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

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Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
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Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
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Department of Nuclear Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
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Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan
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Research Assistant Center, Show Chwan Memorial Hospital, Changhua 500, Taiwan
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Department of Pathology, Show Chwan Memorial Hospital, Changhua 500, Taiwan
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School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan
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Department of Health Food, Chung Chou University of Science and Technology, Changhua 510, Taiwan
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National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan
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Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
*
Authors to whom correspondence should be addressed.
Academic Editors: Andre Lechel and Reinhold Schirmbeck
Int. J. Mol. Sci. 2021, 22(11), 6001; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22116001
Received: 4 May 2021 / Revised: 29 May 2021 / Accepted: 31 May 2021 / Published: 1 June 2021
(This article belongs to the Special Issue Biological Interfaces in Gastrointestinal Cancer 2.0)
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. View Full-Text
Keywords: microRNA-29a; hepatocellular carcinoma; metastasis; lysyl oxidase; lysyl oxidase like 2; vascular endothelial growth factor A; diagnosis; prognosis microRNA-29a; hepatocellular carcinoma; metastasis; lysyl oxidase; lysyl oxidase like 2; vascular endothelial growth factor A; diagnosis; prognosis
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MDPI and ACS Style

Yang, Y.-L.; Tsai, M.-C.; Chang, Y.-H.; Wang, C.-C.; Chu, P.-Y.; Lin, H.-Y.; Huang, Y.-H. MIR29A Impedes Metastatic Behaviors in Hepatocellular Carcinoma via Targeting LOX, LOXL2, and VEGFA. Int. J. Mol. Sci. 2021, 22, 6001. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22116001

AMA Style

Yang Y-L, Tsai M-C, Chang Y-H, Wang C-C, Chu P-Y, Lin H-Y, Huang Y-H. MIR29A Impedes Metastatic Behaviors in Hepatocellular Carcinoma via Targeting LOX, LOXL2, and VEGFA. International Journal of Molecular Sciences. 2021; 22(11):6001. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22116001

Chicago/Turabian Style

Yang, Ya-Ling, Ming-Chao Tsai, Yen-Hsiang Chang, Chen-Chen Wang, Pei-Yi Chu, Hung-Yu Lin, and Ying-Hsien Huang. 2021. "MIR29A Impedes Metastatic Behaviors in Hepatocellular Carcinoma via Targeting LOX, LOXL2, and VEGFA" International Journal of Molecular Sciences 22, no. 11: 6001. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22116001

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