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Suppression of miR-21-3p enhances TRAIL-mediated apoptosis in liver cancer stem cells by suppressing PI3K/Akt/Bad cascade via regulating PTEN

Authors Zhu Y, Tang H, Zhang L, Gong L, Wu G, Ni J, Tang X

Received 9 August 2018

Accepted for publication 19 October 2018

Published 22 January 2019 Volume 2019:11 Pages 955—968

DOI https://doi.org/10.2147/CMAR.S183328

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Colin Mak

Peer reviewer comments 3

Editor who approved publication: Dr Rituraj Purohit


Yingwei Zhu,1,* Hong Tang,2,* Lili Zhang,1 Lei Gong,1 Gaojue Wu,1 Jingbin Ni,1 Xuejun Tang1

1Department of Gastroenterology, The Affiliated Wuxi No.2 People’s Hospital of Nanjing Medical University, Wuxi, Jiangsu 214002, People’s Republic of China; 2Department of Pathology, The Affiliated Wuxi No.2 People’s Hospital of Nanjing Medical University, Wuxi, Jiangsu 214002, People’s Republic of China

*These authors contributed equally to this work

Background: TNF-related apoptosis-inducing ligand (TRAIL) functions as a selective apoptosis-inducing ligand in cancer cells with normal cells remaining unaffected; however, resistance limits its anticancer properties. Cancer stem cells (CSCs) are involved in the treatment of resistant cancer cases including liver cancer (LC). The aim of this study was to look into the approaches for increasing the sensitivity of liver cancer stem cells (LCSCs) toward TRAIL.
Methodology: PLC, HepG2 and Huh7 LC cell lines were used in this study. Quantitative reverse transcription PCR (qRT-PCR) analysis was done for evaluating the expression of miR-21-3b. Fluorescent-activated cell-sorting equipment was used for separation and identification of LCSCs and non-LCSCs. The cells were transfected with RNA along with miR-21-3p mimics, anti- miR-21-3p, miR-NC and the phosphatase and tensin homologue (PTEN) siRNA. MTT assay for cell viability, Luciferase assay for luciferase activity, Western blots for the expression of proteins and flow cytometry for the measurement of ROS and apoptosis, respectively, were carried out. Tumor xenografts nude mice were used for tumor growth in vivo.
Results: We found that miR-21-3p was overexpressed in LCSCs compared to non-LCSCs and that the suppression of miR-21-3p along with anti-miR-21-3p enhanced the sensitivity of LCSCs to TRAIL-mediated apoptosis. We further found that miR-21-3p regulated the expression of PTEN in Huh7-LCSCs directly and that the suppression of miR-21-3p enhanced the levels of PTEN. The study confirmed that inhibition of the PI3K/Akt/Bad signaling pathway was involved in enhancing TRAIL-mediated apoptosis of LC cells.
Conclusion: The study suggested that overexpression of miR-21-3p suppresses the sensitivity to TRAIL in LCSCs. This study concludes that the suppression of miR-21-3p is a potential approach for enhancing the sensitivity of LC cells toward TRAIL by PI3K/Akt/Bad cascade via the miR-21-3p/PTEN axis.

Keywords: TRAIL, liver cancer, miR-21-3p, PI3K, Akt, Bad, PTEN


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