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.
Highlights
As an important transcription inhibitor, the positive regulator of human malignancies/pro-oncogene FBI-1 is produced by Zbtb7A and plays important roles in cancerous cells’ proliferation or metastasis [1, 2]
The aerobic glycolysis/Warburg effect has been considered as an important feature of cancer cells featured with the elevated glucose uptake and lactate production, especially hepatocellular carcinoma (HCC), and often exhibits the aberrant metabolism feature characterized by the high level of glycolysis and glucose uptake even in the abundant oxygen condition [9,10,11]
It is well known that the Warburg effect feature as aerobic glycolysis is considered as the common feature of cancer cells, especially HCC, and alters the microenvironment of tumor lesions related to the proliferation, metastasis, and especially the resistance of cells to antitumor agents
Summary
As an important transcription inhibitor (the transcription suppressor), the positive regulator of human malignancies/pro-oncogene (positive regulator/pro-oncogene) FBI-1 (factor that binds to inducer of short transcripts-1) is produced by Zbtb7A (zinc finger and BTB domain protein family 7A) and plays important roles in cancerous cells’ proliferation or metastasis [1, 2]. The aerobic glycolysis/Warburg effect has been considered as an important feature of cancer cells featured with the elevated glucose uptake and lactate production, especially HCC, and often exhibits the aberrant metabolism feature characterized by the high level of glycolysis and glucose uptake even in the abundant oxygen condition [9,10,11]. Hypoxia-inducible factor alpha (HIF-1a), the most important regulator of hypoxia-related mechanisms, is often overexpressed in human cancers and associated with the poor prognosis [12,13,14,15,16]. HIF-1a is a promising target for HCC treatment
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