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Abstract
Axl receptor tyrosine kinase is involved in the tumorigenesis and metastasis of many cancers. Axl expression was markedly higher in human papilloma virus type 16E6 (HPV16E6)-overexpressing HeLa (HE6F) cells and lower in HPV16E6-suppressing CaSki (CE6R) cells than in the controls. SiRNA-mediated knockdown of E6 expression led to increased phosphatase and tensin homolog (PTEN) phosphorylation at Ser380 and attenuated AKT phosphorylation. Expression of membrane-associated guanylate kinase inverted-2 (MAGI-2), an E6-induced degradation target, was induced in E6-siRNA-transfected cells. Moreover, myeloid zinc finger protein 1 (MZF1) binds directly to the Axl promoter in HE6F cells. Axl expression was regulated by HPV16E6-mediated PTEN/AKT signalling pathway, and Axl promoter activity was regulated through MZF1 activation in cervical cancer, which promoted malignancy. Axl silencing suppressed the metastasis of Caski cells and enhanced the susceptibility to NK cell-mediated killing of HE6F cells. In addition, the expression of Axl and MZF1 was highly correlated with clinical stage of cervical cancer and HPV16/18 infection. Taken together, Axl expression was induced by HPV16E6 in cervical cancer cells, suggesting that blockade of Axl signalling might be an effective way to reduce the progression of cervical cancer.
Highlights
Human papillomaviruses (HPVs) are small, non-enveloped viruses that induce squamous epithelial tumours[1]
We examined whether Axl expression in HE6F cells was decreased by transfection with an human papilloma virus type 16E6 (HPV16E6)-specific Small interfering RNA (siRNA)
The Axl receptor tyrosine kinase is known to be involved in the malignancy of various cancers[28], and high-risk HPV-positive cervical cells express Axl[19], the molecular mechanisms that upregulate Axl expression in response to the high-risk HPV16E6 oncogene are unclear
Summary
Human papillomaviruses (HPVs) are small, non-enveloped viruses that induce squamous epithelial tumours[1]. A unique feature of the HPV E6 oncoproteins is the presence of a PDZ (PSD-95⁄DLG⁄ZO-1) binding motif (PBM) at their C-termini Through this motif, E6 can interact with a large number of cellular proteins that contain PDZ domains, which play a critical role in anchoring proteins to the cell surface. A recent report suggested that MZF1 induces migration, invasion, and Axl gene expression in cervical cancer cells[19]. Axl is correlated with tumour progression and poor prognosis in various human carcinomas, the underlying molecular and cellular mechanisms associated with E6 oncoprotein are still unknown. We demonstrated a novel molecular mechanism by which HPV type 16 E6 oncoprotein induced Axl expression through the MAGI-2/PTEN/AKT signalling pathway in human cervical cancer cells. Our findings suggest that blockade of Axl signaling is required for the suppression of HPV16E6-mediated progression of cervical cancer
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