IRF-1 Inhibits Angiogenic Activity of HPV16 E6 Oncoprotein in Cervical Cancer

Abstract

HPV16 E6 oncoprotein is a member of the human papillomavirus (HPV) family that contributes to enhanced cellular proliferation and risk of cervical cancer progression via viral infection. In this study, interferon regulatory factor-1 (IRF-1) regulates cell growth inhibition and transcription factors in immune response, and acts as an HPV16 E6-binding cellular molecule. Over-expression of HPV16 E6 elevated cell growth by attenuating IRF-1-induced apoptosis and repressing p21 and p53 expression, but activating cyclin D1 and nuclear factor kappa B (NF-κB) expression. The promoter activities of p21 and p53 were suppressed, whereas NF-κB activities were increased by HPV16 E6. Additionally, the cell viability of HPV16 E6 was diminished by IRF-1 in a dose-dependent manner. We found that HPV16 E6 activated vascular endothelial growth factor (VEGF)-induced endothelial cell migration and proliferation as well as phosphorylation of VEGFR-2 via direct interaction in vitro. HPV16 E6 exhibited potent pro-angiogenic activity and clearly enhanced the levels of hypoxia-inducible factor-1α (HIF-1α). By contrast, the loss of function of HPV16 E6 by siRNA-mediated knockdown inhibited the cellular events. These data provide direct evidence that HPV16 E6 facilitates tumour growth and angiogenesis. HPV16 E6 also activates the PI3K/mTOR signalling cascades, and IRF-1 suppresses HPV16 E6-induced tumourigenesis and angiogenesis. Collectively, these findings suggest a biological mechanism underlying the HPV16 E6-related activity in cervical tumourigenesis.

Novel Anti-Angiogenic and Anti-Tumour Activities of the N-Terminal Domain of NOEY2 via Binding to VEGFR-2 in Ovarian Cancer

“…Co-IP was carried out as described previously ( Rho et al ., 2020 ). Briefly, cells were trypsinised and then centrifuged.…”

“…In vitro tube formation analysis was carried out as reported previously ( Rho et al ., 2020 ). HUVEC cells were seeded in Growth factor-reduced Matrigel (200 μL of 10 mg/mL; BD Biosciences) coated 24-well plate and then incubated for 48 h in M199 containing 1% FBS with/without 10 ng/mL VEGF.…”

Infection by High-Risk Human Papillomaviruses, Epithelial-to-Mesenchymal Transition and Squamous Pre-Malignant or Malignant Lesions of the Uterine Cervix: A Series of Chained Events?

“…Still in this regard, in vitro studies performed with SCC cell lines have shown that the E6 and E7 proteins of HR-HPVs can directly trigger EMT via the induction of Twist2, Zeb, Slug, or Snail expression and nuclear translocation [83,[98][99][100]. This is because both the E6 and E7 proteins of HR-HPVs can turn on the mitogen-activated protein kinases (MAPK)/extracellular-regulated kinases (ERK) and/or the phosphoinositide 3 kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathways (Figure 1) [101][102][103][104]. Triggering of these signaling pathways actuate the expression of Snail, Slug, Twist, and Zeb, as well as other EMT-promoting transcription factors (Figure 1), including STAT3 and nuclear factor-κB (NF-κB) [7][8][9][10][11].…”

Overexpression of IRF3 Predicts Poor Prognosis in Clear Cell Renal Cell Carcinoma

“… 4 In hepatocellular carcinoma (HCC) cells, interferon regulatory factor 1 (IRF1) and IRF2 were reported to upregulate the PD-L1 expression, affecting the effects of immune checkpoint blockade (ICB). 5 Rho et al 6 found that IRF1 inhibits tumorigenesis and angiogenesis induced by HPV16 E6 in cervical cancer. Chen et al 7 have identified IRF2 as a tumor suppressor, which could suppress the invasion and migration by decreasing the expression of MMP-1 in gastric cancer.…”