Hypoxic Cancer Cells-Derived Exosomes Strengthen the Development of Cancer Stem Cell-Like Properties Through Delivering LINC00665 in Thyroid Cancer Cells

Hypoxia is a common phenomenon for solid tumors due to a lack of effective vascular system, and has been deemed as an important factor that drives the progression of thyroid cancer (TC) via altering the characteristics of tumor cells. The present study suggested that hypoxic TC cells enhanced cancer stem cell properties and progression of TC by delivering long intergenic non-protein coding RNA 665 (LINC00665)-containing exosomes. Specifically, TPC1 cells were exposed to normoxic or hypoxic environment, and it was found that hypoxic TPC1 cells-secreted exosomes (H-exo) were enriched with LINC00665, compared to normoxic TPC1 cells-derived exosomes (N-exo). In addition, by establishing the in vitro exosomes-TC cells coculture system, we found that in contrast to N-exo, H-exo apparently promoted cell proliferation, epithelial mesenchymal transition (EMT) and cancer stem cell properties via delivering LINC00665. This was supported by the in vivo results that H-exo transferred LINC00665 to promote tumorigenesis and the expression of EMT and stemness-associated markers in xenograft tumor-bearing mice models. Further mechanical experiments validated that LINC00665 combined with EPHB4 mRNA to sustain its stability to enhance cancer aggressiveness of TC. Altogether, our findings verified that hypoxic TC cells-secreted exosomes regulated the LINC00665/EPHB4 axis to enhance cancer stem cell properties of TC, providing novel signatures for TC diagnosis and therapy.