Hypoxia-induced exosomes promote hepatocellular carcinoma proliferation and metastasis via miR-1273f transfer.

ABSTRACT

Exosomes are present within the local hypoxic tumor microenvironment, where they are able to transfer microRNAs between cells, thereby, effectively mediating cell-cell communication. Hypoxia plays a pivotal role in the progression of many tumor types such as hepatocellular carcinoma (HCC), but how hypoxia-induced exosomes in HCC affect HCC cells remains uncertain. In the present study, we found that hypoxic conditions induced increased exosomal production by HCC cells, and these exosomes, in turn, enhanced the proliferation, migration, and invasiveness in addition to epithelial-to-mesenchymal transition (EMT) in HCC cells under normoxic conditions. When we analyzed these exosomes, we found that miR-1273f were present at higher levels under hypoxic conditions, and we determined that this miRNA was responsible for directly replicating the effects of hypoxic exosomes within HCC cells, in addition to activating the Wnt/ß-catenin signaling. We finally identified LHX6, which is a known inhibitor of the Wnt/ß-catenin pathway, to be a miR-1273f target. These results, thus, provide evidence that hypoxic conditions can lead HCC cells to express increased exosomes that facilitate miR-1273f expression in normoxic cells, thereby enhancing their malignant phenotype at least in part by targeting LHX6 for downregulation.