The lncARSR/PTEN/Akt/nuclear factor‐kappa B feedback regulatory loop contributes to doxorubicin resistance in hepatocellular carcinoma. Issue 9 (9th June 2022)

• Record Type: Journal Article
• Authors: Li, Yaling; Li, Jun; Chen, Hongyan; Wang, Jiting; Jiang, Linhan; Tan, Xiaoxia
• Is Part Of: Journal of biochemical and molecular toxicology. Volume 36:Issue 9(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-06-09
• Subjects: doxorubicin -- feedback regulatory loop -- hepatocellular carcinoma -- lncARSR -- NF‐κB; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Toxicology -- Periodicals; 574
• DOI: 10.1002/jbt.23119
• Languages: English
• ISSNs: 1095-6670

Abstract

Abstract: Chemoresistance is a major obstacle to hepatocellular carcinoma (HCC) chemotherapy. Our previous study found that long noncoding RNA lncARSR (lncRNA Activated in RCC with Sunitinib Resistance) activated Akt signaling via repressing phosphatase and tensin homolog (PTEN) during doxorubicin resistance in HCC. The purpose of this study is to further explore lncARSR‐mediated mechanisms and roles during doxorubicin resistance in HCC. The expression of lncARSR was detected by real‐time quantitative polymerase chain reaction (qPCR). Nuclear factor‐kappa B (NF‐κB) activity was detected by NF‐κB luciferase reporter assays, western blot, and NF‐κB transcription factor assays. The effects of NF‐κB on lncARSR were detected by chromatin immunoprecipitation assay, promoter luciferase reporter assay, and real‐time qPCR. The effects of lncARSR/Akt/NF‐κB on doxorubicin resistance were detected by Cell Counting Kit‐8 assay, capsase‐3 activity assay, and terminal deoxynucleotidyl transferase‐mediated dUTP nick end labeling assay. lncARSR activated NF‐κB signaling through activation of Akt. NF‐κB transactivated lncARSR through directly binding lncARSR promoter and increasing lncARSR promoter activity. Akt transactivated lncARSR via activating NF‐κB signaling. Thus, lncARSR, Akt, and NF‐κB formed a positive feedback regulatory loop in HCC. Through this feedback loop, lncARSR auto‐regulated its transcription. Drug sensitivity assays showed that the lncARSR/Akt/NF‐κB feedback regulatory loop promoted doxorubicin resistance in HCC. These findings identified the lncARSR/Akt/NF‐κB feedback regulatory loop in HCC, which represent potential therapeutic targets for improving doxorubicin sensitivity in HCC.