TY - JOUR
T1 - TARBP2-mediated destabilization of Nanog overcomes sorafenib resistance in hepatocellular carcinoma
AU - Lai, Hui-Huang
AU - Li, Chih-Wei
AU - Hong, Chih-Chen
AU - Sun, Hung-Yu
AU - Chiu, Ching-Feng
AU - Ou, Da-Liang
AU - Chen, Pai-Sheng
N1 - Funding Information:
We thank Dr. Anne Gatignol for providing plasmids expressing Myc-TARBP2 and TARBP2 ∆C4. We thank Dr. Dong-Yan Jin for sharing the plasmids with Addgene. This study was supported by the Ministry of Science and Technology, Taiwan (MOST 105-2320-B-006-050, MOST 106-2320-B-006-038, MOST 106-2320-B-006-021, MOST 106-2314-B-002-229-MY3, and MOST 107-2320-B-006-068).
Publisher Copyright:
© 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.
PY - 2019/4
Y1 - 2019/4
N2 - 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.
AB - 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.
KW - Nanog
KW - TARBP2
KW - cancer stem cells
KW - hepatocellular carcinoma
KW - miRNA
KW - sorafenib resistance
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U2 - 10.1002/1878-0261.12449
DO - 10.1002/1878-0261.12449
M3 - Article
C2 - 30657254
SN - 1574-7891
VL - 13
SP - 928
EP - 945
JO - Molecular Oncology
JF - Molecular Oncology
IS - 4
ER -
