Figure 5.

A simplified model of PKR-dependent nc886 activity in HPV(+) OPSCC

Nc886 hypermethylation acts as both a viral and a tumor sensor. HPV infection increases nc886 gene methylation, leading to reduced nc886 expression and lessening of its inhibition on PKR activity. Increased PKR activity results in increased phosphorylation of translation initiation factor eIF2 and blockage of cellular and viral protein translation, thus exhibiting anti-tumor and anti-viral effects. Additionally, in immune cells, increased PKR activity can increase IFN-β production and enhance immune response. The anti-tumor activity of nc886 hypermethylation in local epithelial cells and systemic immune cells both contribute to the better prognosis of HPV(+) compared with HPV(−) OPSCC patients. There are other PKR-independent activities downstream of nc886, which are not depicted in this diagram.