Inhibition of hypoxia-induced miR-155 radiosensitizes hypoxic lung cancer cells

Abstract

miR-155 is a prominent microRNA (miRNA) that regulates genes involved in immunity and cancer-related pathways. miR-155 is overexpressed in lung cancer, which correlates with poor patient prognosis. It is unclear how miR-155 becomes increased in lung cancers and how this increase contributes to reduced patient survival. Here, we show that hypoxic conditions induce miR-155 expression in lung cancer cells and trigger a corresponding decrease in a validated target, FOXO3A. Furthermore, we find that increased levels of miR-155 radioprotects lung cancer cells, while inhibition of miR-155 radiosensitizes these cells. Moreover, we reveal a therapeutically important link between miR-155 expression, hypoxia, and irradiation by demonstrating that anti-miR-155 molecules also sensitize hypoxic lung cancer cells to irradiation. Our study helps explain how miR-155 becomes elevated in lung cancers, which contain extensive hypoxic microenvironments, and demonstrates that inhibition of miR-155 may have important therapeutic potential as a means to radiosensitize hypoxic lung cancer cells.

Keywords: :

• microRNAs
• miR-155
• hypoxia
• radiosensitizer
• lung cancer

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

The authors thank S. Rockwell, Y. Liu, and J. Mendes for lending us the mobile hypoxia chambers and helping with set-up; S. Nallur and D. Steinmetz for assistance with clonogenic assays; D. Hegan and Y. Lu for their advice and assistance. Z. Yun and Q. Lin for their valuable discussions and sharing of reagents. I.A.B. was the recipient of a Gilliam Fellowship (Howard Hughes Medical Institute) and a Harvey Fellowship (Mustard Seed Foundation). This work was supported by NIH grants (CA131301 to J.B.W. and F.J.S) (R01ES005775, R01CA148996 and P01CA129186 to P.M.G).