Knockdown of FBI-1 Inhibits the Warburg Effect and Enhances the Sensitivity of Hepatocellular Carcinoma Cells to Molecular Targeted Agents via miR-3692/HIF-1α

Juan Liu; Chao Yang; Xiao-Mei Huang; Pan-Pan Lv; Ya-Kun Yang; Jin-Na Zhao; Si-Yuan Zhao; Wan-Jun Sun

doi:10.3389/fonc.2021.796839

Knockdown of FBI-1 Inhibits the Warburg Effect and Enhances the Sensitivity of Hepatocellular Carcinoma Cells to Molecular Targeted Agents via miR-3692/HIF-1α

Front Oncol. 2021 Nov 12:11:796839. doi: 10.3389/fonc.2021.796839. eCollection 2021.

Authors

Juan Liu¹, Chao Yang¹, Xiao-Mei Huang¹, Pan-Pan Lv¹, Ya-Kun Yang¹, Jin-Na Zhao¹, Si-Yuan Zhao², Wan-Jun Sun¹

Affiliations

¹ Department of Hematology, PLA Rocket Force Characteristic Medical Center, Beijing, China.
² Department of Neurosurgery, Beijing Huicheng Medical Research Institute, Beijing, China.

Abstract

The transcription suppressor factor FBI-1 (the factor that binds to inducer of short transcripts-1) is an important regulator of hepatocellular carcinoma (HCC). In this work, the results showed that FBI-1 promoted the Warburg effect and enhances the resistance of hepatocellular carcinoma cells to molecular targeted agents. Knockdown of FBI-1 via its small-interfering RNA (siRNA) inhibited the ATP level, lactate productions, glucose uptake or lactate dehydrogenase (LDH) activation of HCC cells. Transfection of siFBI-1 also decreased the expression of the Warburg-effect-related factors: hypoxia-inducible factor-1 alpha (HIF-1α), lactate dehydrogenase A (LDHA), or GLUT1, and the epithelial-mesenchymal transition-related factors, Vimentin or N-cadherin. The positive correlation between the expression of FBI-1 with HIF-1α, LDHA, or GLUT1 was confirmed in HCC tissues. Mechanistically, the miR-30c repressed the expression of HIF-1α by binding to the 3'-untranslated region (3'-UTR) of HIF-1α in a sequence-specific manner, and FBI-1 enhanced the expression of HIF-1α and HIF-1α pathway's activation by repressing the expression of miR. By modulating the miR-30c/HIF-1α, FBI-1 promoted the Warburg effect or the epithelial-mesenchymal transition of HCC cells and promoted the resistance of HCC cells to molecular targeted agents.

Keywords: HIF-1α; advanced hepatocellular carcinoma; aerobic glycolysis/Warburg effect; microRNA; molecular targeted agents resistance; the factor that binds to inducer of short transcripts-1.