Inhibition of hypoxia-induced miR-155 radiosensitizes hypoxic lung cancer cells.
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.
Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT, USA.
Imran A
IA
Babar
Jennifer
J
Czochor
Allison
A
Steinmetz
Joanne B
JB
Weidhaas
Peter M
PM
Glazer
Frank J
FJ
Slack
D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics / Q000528:radiation effects; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D011836:Radiation Tolerance / Q000235:genetics*
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; D034741:RNA, Small Interfering