Elucidation of the mechanism of malignant progression in the Lenvatinib-resistant hepatocellular carcinoma microenvironment

Background
We have studied TME crosstalk related to Lenvatinib resistance mechanisms, focusing on the transcription factor Nrf2 and exosome microRNAs.
Significance of the Nrf2/PINK1 pathway in the mechanism of Lenvatinib resistance:
3-4 fold Lenvatinib resistant strains were established using HCC line (Huh7/PLC), and Lenvatinib-resistant HCC (Lenv res HCC) showed enhanced tumor growth, invasiveness, cancer stem cell markers, as well as Nrf2 addiction/PINK 1 pathway, and enhanced mitophagy. Nrf2 knockdown cancelled all enhanced malignant properties as well as Lenvatinib resistance.
TME crosstalk by Exosome miRNA132: Obtained resistance in naive HCC
We identified miRNA132 associated with the PTEN-Nrf2 pathway by IPA dataset/miRDB/Targetscan and confirmed that exosome miRNA132, extracted from Lenv res HCC culture conditioned medium (Lenv res HCC CM) by ultracentrifugation, was highly expressed. Lenv res HCC CM induces Nrf2 addiction/enhanced proliferative invasion/enhanced resistance in non-resistant HCC, all of which were cancelled by miRNA132 knockdown.
TME crosstalk by Exosome miRNA301a-3p: TAM-mediated malignancy enhancing effect
We identified miRNA301a-2p associated with Nrf2/TAM by TCGA/miRDB/Targetscan and confirmed exosome miRNA301a-2 high expression in Lenv Res HCC CM. TAM conditioned by Lenv Res HCC CM (Res TAMs) induced Nrf2 addiction/enhanced proliferative invasiveness/enhanced resistance in non-res HCC than TAMs induced in non-res HCC (non res TAMs), all of which were cancelled by miRNA301a-2p knockdown.
Conclusion
Regulation of exosomal miRNAs with Nrf2 addiction may overcome tumor refractoriness against the mechanisms of tumor malignancy/resistance acquisition in TME of Lenvatinib-resistant HCC.