TARBP2-mediated destabilization of Nanog overcomes sorafenib resistance in hepatocellular carcinoma

Hui-Huang Lai, Chih-Wei Li, Chih-Chen Hong, Hung-Yu Sun, Ching-Feng Chiu, Da-Liang Ou, Pai-Sheng Chen

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)

Abstract

Hepatocellular carcinoma (HCC) is a lethal human malignancy and a leading cause of cancer-related death worldwide. Patients with HCC are often diagnosed at an advanced stage, and the prognosis is usually poor. The multikinase inhibitor sorafenib is the first-line treatment for patients with advanced HCC. However, cases of primary or acquired resistance to sorafenib have gradually increased, leading to a predicament in HCC therapy. Thus, it is critical to investigate the mechanism underlying sorafenib resistance. Transactivation response element RNA-binding protein 2 (TARBP2) is a multifaceted miRNA biogenesis factor that regulates cancer stem cell (CSC) properties. The tumorigenicity and drug resistance of cancer cells are often enhanced due to the acquisition of CSC features. However, the role of TARBP2 in sorafenib resistance in HCC remains unknown. Our results demonstrate that TARBP2 is significantly downregulated in sorafenib-resistant HCC cells. The TARBP2 protein was destabilized through autophagic–lysosomal proteolysis, thereby stabilizing the expression of the CSC marker protein Nanog, which facilitates sorafenib resistance in HCC cells. In summary, here we reveal a novel miRNA-independent role of TARBP2 in regulating sorafenib resistance in HCC cells.

Original languageEnglish
Pages (from-to)928-945
Number of pages18
JournalMolecular Oncology
Volume13
Issue number4
Early online dateJan 18 2019
DOIs
Publication statusPublished - Apr 2019

Keywords

  • Nanog
  • TARBP2
  • cancer stem cells
  • hepatocellular carcinoma
  • miRNA
  • sorafenib resistance

ASJC Scopus subject areas

  • Genetics
  • Molecular Medicine
  • Oncology
  • Cancer Research

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