Figure 7

Schematic model of miR-375 as a master regulator in HPV-positive cancers. miR-375-mediated regulation simultaneously suppresses HPV E7, E6, E6AP, CIP2A, and 14-3-3ζ. As a result, the degradation of tumor suppressors p53 and RB is prevented, and p21 protein level increases. miR-375-mediated repression of CIP2A leads to degradation of oncogene MYC and also enhances p21 expression. Increase of transcriptional repressors (p53, p21, RB) and decrease of transcriptional activators (E6 and MYC) promotes TERT transcriptional reduction. miR-375-mediated repression of 14-3-3ζ inhibits nuclear translocation of TERT, thereby contributes to reduce telomerase activity. Overall, high miR-375 levels results in cell cycle arrest, telomerase inactivation and cell proliferation inhibition, which maintain homeostasis of normal epithelial cells. Solid lines represent “activated process” and dotted lines represent “inhibited process.” Molecules repressed or activated by miR-375 are distinguished by green and red colors, respectively.