An artificial lncRNA targeting multiple miRNAs overcomes sorafenib resistance in hepatocellular carcinoma cells.
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.
The Hepatosplenic Surgery Center, Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China.
Shuyao
S
Tang
Department of General Surgery, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, China.
Gang
G
Tan
The Hepatosplenic Surgery Center, Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China.
Xian
X
Jiang
The Hepatosplenic Surgery Center, Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China.
Peng
P
Han
Department of General Surgery, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, China.
Bo
B
Zhai
The Hepatosplenic Surgery Center, Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China.
Xuesong
X
Dong
The Hepatosplenic Surgery Center, Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China.
Haiquan
H
Qiao
The Hepatosplenic Surgery Center, Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China.
Hongchi
H
Jiang
The Hepatosplenic Surgery Center, Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China.
Xueying
X
Sun
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D010671:Phenylurea Compounds / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D062085:RNA, Long Noncoding / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D000077157:Sorafenib; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D035683:MicroRNAs; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D062085:RNA, Long Noncoding; D009536:Niacinamide; D000077157:Sorafenib; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
drug resistance; hepatocellular carcinoma; miRNA; sorafenib; lncRNA
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