Intra-type genome variations of high risk Human papillomavirus (HPV) have been associated with a differential threat for cervical cancer development. In this work, the effect of HPV18 E6 isolates in Akt/PKB and Mitogen-associated protein kinase (MAPKs) signaling pathways and its implication in cell proliferation were analyzed. E6 from HPV types 16 and 18 are able to bind and promote degradation of Human disc large (hDlg). Our results show that E6 variants differentially modulate hDlg degradation, rebounding in levels of activated PTEN and PKB. HPV18 E6 variants are also able to upregulate phospho-PI3K protein, strongly correlating with activated MAPKs and cell proliferation. Data was supported by the effect of E6 silencing in HPV18-containing HeLa cells, as well as hDlg silencing in the tested cells. Results suggest that HPV18 intra-type variations may derive in differential abilities to activate cell-signaling pathways such as Akt/PKB and MAPKs, directly involved in cell survival and proliferation.

The alteration of glucose metabolism is one of the first biochemical characteristics associated with cancer cells since most of these cells increase glucose consumption and glycolytic rates even in the presence of oxygen, which has been called “aerobic glycolysis” or the Warburg effect. Human papillomavirus (HPV) is associated with approximately 5% of all human cancers worldwide, principally to cervical cancer. E6 and E7 are the main viral oncoproteins which are required to preserve the malignant phenotype. These viral proteins regulate the cell cycle through their interaction with tumor suppressor proteins p53 and pRB, respectively. Together with the viral proteins E5 and E2, E6 and E7 can favor the Warburg effect and contribute to radio- and chemoresistance through the increase in the activity of glycolytic enzymes, as well as the inhibition of the Krebs cycle and the respiratory chain. These processes lead to a fast production of ATP obtained by Warburg, which could help satisfy the high energy demands of cancer cells during proliferation. In this way HPV proteins could promote cancer hallmarks. However, it is also possible that during an early HPV infection, the Warburg effect could help in the achievement of an efficient viral replication.

Solid tumors carry out the formation of new vessels providing blood supply for growth, tumor maintenance, and metastasis. Several processes take place during tumor vascularization. In angiogenesis, new vessels are derived from endothelial cells of pre-existing vessels; while in vasculogenesis, new vessels are formed de novo from endothelial progenitor cells, creating an abnormal, immature, and disorganized vascular network. Moreover, highly aggressive tumor cells form structures similar to vessels, providing a pathway for perfusion; this process is named vasculogenic mimicry (VM), where vessel-like channels mimic the function of vessels and transport plasma and blood cells. VM is developed by numerous types of aggressive tumors, including ovarian carcinoma which is the second most common cause of death among gynecological cancers. VM has been associated with poor patient outcome and survival in ovarian cancer, although the involved mechanisms are still under investigation. Several signaling molecules have an important role in VM in ovarian cancer, by regulating the expression of genes related to vascular, embryogenic, and hypoxic signaling pathways. In this review, we provide an overview of the current knowledge of the signaling molecules involved in the promotion and regulation of VM in ovarian cancer. The clinical implications and the potential benefit of identification and targeting of VM related molecules for ovarian cancer treatment are also discussed.