Oncotarget

Research Papers:

An artificial lncRNA targeting multiple miRNAs overcomes sorafenib resistance in hepatocellular carcinoma cells

Shuyao Tang, Gang Tan, Xian Jiang, Peng Han, Bo Zhai, Xuesong Dong, Haiquan Qiao, Hongchi Jiang and Xueying Sun _

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Oncotarget. 2016; 7:73257-73269. https://doi.org/10.18632/oncotarget.12304

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Abstract

Shuyao Tang1, Gang Tan2, Xian Jiang1, Peng Han1, Bo Zhai2, Xuesong Dong1, Haiquan Qiao1, Hongchi Jiang1, Xueying Sun1

1The Hepatosplenic Surgery Center, Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China

2Department of General Surgery, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, China

Correspondence to:

Xueying Sun, email: [email protected], [email protected]

Keywords: sorafenib, hepatocellular carcinoma, drug resistance, LncRNA, miRNA

Received: June 13, 2016     Accepted: September 21, 2016     Published: September 28, 2016

ABSTRACT

Sorafenib resistance remains a major obstacle for the effective treatment of hepatocellular carcinoma (HCC), and a number of miRNAs contribute to this resistance. However, the regulatory networks of miRNAs are very complex, thus inhibiting a single miRNA may sequentially activate other compensatory pathways. In the present study, we generated an artificial long non-coding RNA (AlncRNA), which simultaneously targets multiple miRNAs including miR-21, miR-153, miR-216a, miR-217, miR-494 and miR-10a-5p. These miRNAs have been shown to be upregulated in sorafenib-resistant cells and participate in the mechanisms underlying sorafenib resistance. The AlncRNA contains tandem sequences of 6 copies of the complementary binding sequences to the target miRNAs and is expressed by an adenoviral vector (Ad5-AlncRNA). Infection of Ad5-AlncRNA into sorafenib-resistant HCC cells blocked the function of miRNAs, and sequentially inhibited the downregulation of PTEN and activation of AKT. Ad5-AlncRNA significantly inhibited proliferation and induced apoptosis of sorafenib-resistant cells and enhanced the effects of sorafenib in vitro and in animal models. Inhibition of autophagy decreased the sensitivity of sorafenib-resistant cells to Ad5-AlncRNA, while its induction had the opposite effect. These results indicate that targeting multiple miRNAs by the artificial lncRNA could be a potential promising strategy for overcoming sorafenib resistance in the treatment of HCC.


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