miR-98 suppresses melanoma metastasis through a negative feedback loop with its target gene IL-6

Abstract

Dysregulated microRNA (miRNA) expression has a critical role in tumor development and metastasis. However, the mechanism by which miRNAs control melanoma metastasis is unknown. Here, we report reduced miR-98 expression in melanoma tissues with increasing tumor stage as well as metastasis; its expression is also negatively associated with melanoma patient survival. Furthermore, we demonstrate that miR-98 inhibits melanoma cell migration in vitro as well as metastatic tumor size in vivo. We also found that IL-6 is a target gene of miR-98, and IL-6 represses miR-98 levels via the Stat3-NF-κB-lin28B pathway. In an in vivo melanoma model, we demonstrate that miR-98 reduces melanoma metastasis and increases survival in part by reducing IL-6 levels; it also decreases Stat3 and p65 phosphorylation as well as lin28B mRNA levels. These results suggest that miR-98 inhibits melanoma metastasis in part through a novel miR-98-IL-6-negative feedback loop. A short, non-coding RNA molecule called microRNA-98 inhibits the metastatic potential of melanoma skin cancer. A team in China led by Xiao-gang Wang of Jinan University and Wei Liu of the Air Force General Hospital of PLA analyzed levels of microRNA-98 in tissue biopsies taken from people with different stages of melanoma. They observed reduced expression of microRNA-98 in melanoma samples at a more advanced stage. Presence of the microRNA was also associated with lower patient survival. Laboratory experiments showed that microRNA-98 inhibited the migration potential of melanoma cells in a dish. It also reduced the size of metastatic tumors in mice, in part by suppressing levels of an immune signaling molecule called interleukin-6. Interleukin-6 promoted metastasis by repressing the activity of microRNA-98.