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

Shuyao Tang1, Gang Tan2, Xian Jiang1

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

Oncotarget
|October 1, 2016
PubMed

Insights

An artificial long non-coding RNA (AlncRNA) targets multiple cancer-promoting miRNAs to overcome sorafenib resistance in hepatocellular carcinoma (HCC). This strategy inhibits proliferation and induces apoptosis in resistant cells, offering a promising therapeutic approach.

Area of Science:

  • Oncology
  • Molecular Biology
  • Gene Regulation

Background:

  • Sorafenib resistance is a significant challenge in hepatocellular carcinoma (HCC) treatment.
  • MicroRNAs (miRNAs) play a complex role in regulating sorafenib resistance.
  • Targeting individual miRNAs can lead to compensatory pathway activation.

Purpose of the Study:

  • To develop an artificial long non-coding RNA (AlncRNA) capable of simultaneously targeting multiple resistance-associated miRNAs in HCC.
  • To evaluate the efficacy of this AlncRNA in overcoming sorafenib resistance in HCC cells and animal models.

Main Methods:

  • Generation of an AlncRNA with tandem binding sequences for six specific miRNAs (miR-21, miR-153, miR-216a, miR-217, miR-494, miR-10a-5p).
  • Expression of the AlncRNA using an adenoviral vector (Ad5-AlncRNA).
  • Assessment of AlncRNA effects on miRNA function, PTEN/AKT pathway, cell proliferation, apoptosis, and autophagy in vitro and in vivo.

Main Results:

  • Ad5-AlncRNA successfully blocked the function of targeted miRNAs in sorafenib-resistant HCC cells.
  • This inhibition led to decreased PTEN downregulation and AKT activation.
  • Ad5-AlncRNA significantly reduced proliferation, induced apoptosis, and enhanced sorafenib efficacy.
  • Autophagy modulation affected cellular sensitivity to Ad5-AlncRNA.

Conclusions:

  • Simultaneous targeting of multiple miRNAs using an engineered AlncRNA is a viable strategy to overcome sorafenib resistance in HCC.
  • This approach offers a potential therapeutic avenue for improving HCC treatment outcomes.
Keywords:
drug resistancehepatocellular carcinomamiRNAsorafeniblncRNA

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