Figure 6.

Schematic illustration of the role of human papilloma virus (HPV) oncoproteins in the production of macrophage migration inhibitory factor (MIF). The oncoprotein E6 promotes the activation of the mTOR signaling pathway, thus leading to the upregulation of hypoxia inducible factor 1α (HIF-1α), which enhances the production of MIF and increases the production of lactate. The oncoprotein E7 drives the accumulation of the dimeric form of pyruvate kinase M2 (PKM2), thus leading to the conversion of pyruvate to lactate through lactate dehydrogenase (LDHA). Moreover, PKM2 interacts with HIF-1α to amplify the expression of HIF-1α target genes, including MIF and LDHA. Additionally, the HPV E2 protein localizes to the mitochondrial membrane, leading to the increased production of reactive oxygen species (ROS), which increases the stability of HIF-1α. The enrichment of MIF in the extracellular environment could promote the tumor immune escape by the accumulation of pro-tumoral immune cells such as tumor-associated macrophages (TAM), and by the decrease in antitumoral cells such as cytotoxic T cells, Langerhans/dendritic cells (DC), and natural killer (NK) cells. Complete arrows indicate data from the literature, and the red dotted arrow indicates a hypothesis.