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MicroRNA-34a suppresses aggressiveness of hepatocellular carcinoma by modulating E2F1, E2F3, and Caspase-3

Authors Han R, Chen X, Li Y, Zhang S, Li R, Lu L

Received 23 January 2019

Accepted for publication 4 March 2019

Published 10 April 2019 Volume 2019:11 Pages 2963—2976

DOI https://doi.org/10.2147/CMAR.S202664

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Andrew Yee

Peer reviewer comments 3

Editor who approved publication: Dr Chien-Feng Li


Rui Han,1,2 Xinyi Chen,1 Ya Li,1,2 Shunjia Zhang,2 Ruibai Li,1 Lingeng Lu3,4

1Department of Oncology and Hematology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700 People’s Republic of China; 2Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, CT 06520, USA; 3Department of Chronic Disease Epidemiology, Yale School of Public Health, School of Medicine, Yale University, New Haven, CT, 06520-8034, USA; 4Center for Biomedical Data Science, Yale Cancer Center, Yale University, New Haven, CT, USA

Background: Accumulating evidence suggests an antineoplastic role of MicroRNA-34a (miR-34a) in human cancer. However, its precise biological functions stay largely elusive.
Purpose: Our study was aimed to investigate the impact of miR-34a on hepatocellular carcinoma (HCC) and its underlying apoptosis related mechanisms in vitro, as well as the association of miR-34aE2F1 and E2F3 expression with patient survival of HCC using publicly accessed datasets.
Methods: The HBV-expressing Hep3B and SNU-449 cell lines with or without enforced expression of miR-34a were in vitro cultured for cell proliferation, colony formation, wound healing, cell invasion, and 3D spheroid formation. Quantitative reverse transcription PCR (RT-qPCR) was performed for E2F1, E2F3 expression. Caspase-3 (CASP3) activity was determined using a CaspACETM, Assay System. Kaplan–Meier survival curves were used to analyze the associations of miR-34a, E2F1 and E2F3 expression and overall survival in HCC. Meta-analysis was performed to examine the differential expression of E2F1 and E2F3 between primary HCC vs normal tissues.
Results: The results in vitro showed that enforced miR-34a expression significantly inhibited cell proliferation, migration, and invasion of both Hep3B and SNU-449. RT-qPCR results demonstrated that miR-34a could significantly suppress E2F1 and E2F3 expression, particularly in SNU-449. CASP3 activity in both Hep3B and SNU-449 increased in miR-34a treatment group. Overexpressed E2F1 and E2F3 were observed in primary HCC vs normal tissues. Survival analyses showed that HCC patients with either high miR-34a, or low E2F1, or low E2F3 expression had better survival than their opposite counterparts, respectively.
Conclusion: Our study suggested thatmiR-34a can modulate the expression of E2F1, E2F3, and CASP3 activity, thereby repressing tumor aggressiveness and expediting apoptosis in liver cancer cells

Keywords: hepatocellular carcinoma, microRNA-34a, E2Fs, Caspase-3, prognosis

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