MiR-375 Impairs the Invasive Capabilities of Hepatoma Cells by Targeting HIF1α Under Hypoxia

Background and Aims Hypoxia represents one of the most pervasive microenvironmental stresses in HCC due to the overwhelming growth and inadequate blood supply. HIF1 alpha as an important transcription factor participates in the regulation of various biological behaviors of HCC cells under hypoxia. Our previous study indicated that miR-375 is a hypoxia-associated miRNA. However, the interaction between miR-375 and HIF1 alpha remains unclear. Methods Bioinformatic analysis was performed for miRNA screening. qRT-PCR, western blotting, and immunohistochemical staining were used to detect the expression of related molecules. Bioinformatic analysis and dual luciferase assay were used to predict and further confirm the target association. Transwell chamber assay and flow cytometry were, respectively, used to detect migration, invasion and apoptosis of hepatoma cells. Results MiR-375 presented an obviously differential expression in human HCCs versus background livers (BLs) and HCCs versus normal liver tissues (NLTs). In rat models, miR-375 was gradually declined during hepatocarcinogenesis. HIF1 alpha was remarkably upregulated at protein level rather than at mRNA level in human HCCs versus BLs, HCCs versus NLTs, BLs versus NLTs, and in rat fibrotic livers versus NLTs. HIF1 alpha was determined to be a target of miR-375. MiR-375 inhibitor induced the migration and invasive capabilities and attenuated apoptosis of hepatoma cells under hypoxia. Depriving HIF1 alpha by siRNA could partially reverse the function of miR-375 inhibitor under hypoxia. Conclusions MiR-375 impairs the invasive capabilities of HCC cells by targeting HIF1 alpha under hypoxia.

Automated summary

MiR-375 shows differential expression in HCC, targeting HIF1α to impair invasive capabilities of HCC cells, suggesting potential therapeutic value.