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Programmed Death Ligand-1 (PD-L1) Regulated by NRF-2/MicroRNA-1 Regulatory Axis Enhances Drug Resistance and Promotes Tumorigenic Properties in Sorafenib-Resistant Hepatoma Cells
Dong Li*1, Fei-fan Sun*1, Dan Wang*1,Tao Wang*, Jing-jing Peng*, Jian-Qiong Feng*, Hua Li*, Chao Wang†, Dai-jun Zhou*, Hong Luo*, Zeng-qiang Fu*, Tao Zhang*
* Department of Oncology, The General Hospital of Western Theater Command, Chengdu, P.R. China
† Department of Pathology, The General Hospital of Western Theater Command, Chengdu, P.R. China
Oncology Research 2020, 28(7-8), 827-828. https://doi.org/10.3727/096504021X16280937554409
Abstract
Sorafenib, a multityrosine kinase inhibitor, is a standard treatment for advanced hepatocellular carcinoma
(HCC), but the clinical response to sorafenib is seriously limited by drug resistance. Programmed death ligand-1
(PD-L1) is one of the most important inhibitory molecules involved in tumor immune evasion. Recently, it
has been reported that PD-L1 could play crucial roles in drug resistance of many kinds of cancers. However,
the expression, function, and regulation of PD-L1 in sorafenib-resistant hepatoma cells remain unclear. In this
study, we reported that PD-L1 was overexpressed in sorafenib-resistant hepatoma cells, and shRNA-mediated
PD-L1 depletion attenuated drug resistance and suppressed the migration, invasion, colony formation, and
tumorigenesis in sorafenib-resistant hepatoma cells in vitro and in vivo. Mechanistic investigations indicated
that loss of microRNA-1 (miR-1), a tumor-suppressive microRNA, contributed to the PD-L1 upregulation in
sorafenib-resistant hepatoma cells, and PD-L1 was a direct regulatory target of miR-1. Further study revealed
that an oncogenic transcriptional factor, nuclear factor E2-related factor 2 (NRF-2), was induced in sorafenibresistant hepatoma cells and inhibited expression of miR-1 in vitro. From molecular mechanism insight back
to the functional verification, we eventually demonstrated that miR-1 executed its tumor-suppressive effects on
drug resistance and other malignant properties in sorafenib-resistant hepatoma cells partially by PD-L1 inhibition
in vitro and in vivo. In conclusion, our data suggested that a NRF-2/miR-1/PD-L1 regulatory axis contributed
to the development and maintenance of drug resistance and other tumorigenic properties in sorafenib-resistant
hepatoma cells and provided a potential therapeutic target for overcoming sorafenib resistance in HCC.
Keywords
Cite This Article
Li, D., Sun, F., Wang, D., Wang, T., Peng, J. et al. (2020). Programmed Death Ligand-1 (PD-L1) Regulated by NRF-2/MicroRNA-1 Regulatory Axis Enhances Drug Resistance and Promotes Tumorigenic Properties in Sorafenib-Resistant Hepatoma Cells.
Oncology Research, 28(7-8), 827–828.