Abstract
BackgroundThe high risk Human Papillomavirus (HPV) E6 oncoproteins play an essential role in the development of cervical malignancy. Important cellular targets of E6 include p53 and the PDZ domain containing substrates such as hScrib and Dlg. We recently showed that hScrib activity was mediated in part through recruitment of protein phosphatase 1γ (PP1γ).MethodsExpression patterns of hScrib and PP1γ were assessed by immunohistochemistry of HPV-16 positive cervical intraepithelial neoplasm (CIN), classified as CIN1 (n = 4), CIN2 (n = 8), CIN3 (n = 8), cervical carcinoma tissues (n = 11), and HPV-negative cervical tissues (n = 8), as well as by subfractionation assay of the HPV-16 positive cervical cancer cell lines, CaSki and SiHa. To explore the effects of the HPV-16 oncoproteins, we have performed siRNA knockdown of E6/E7 expression, and monitored the effects on the expression patterns of hScrib and PP1γ.ResultsWe show that PP1γ levels in HPV-16 positive tumour cells are reduced in an E6/E7 dependent manner. Residual PP1γ in these cells is found mostly in the cytoplasm as opposed to the nucleus where it is predominantly found in normal cells. We have found a striking concordance with redistribution in the pattern of expression (9/11; 81.8%) and loss of PP1γ expression in HPV-16 positive cervical tumours (2/11; 18.2%). Furthermore, this loss of PP1γ expression and redistribution in the pattern of expression occurs progressively as the lesions develop (8/8; 100%).ConclusionTogether, these results suggest that PP1γ may be a novel target of the HPV-16 oncoproteins and indicate that it might be a potential novel biomarker for HPV-16 induced malignancy.
Highlights
The high risk Human Papillomavirus (HPV) E6 oncoproteins play an essential role in the development of cervical malignancy
We recently found that hScrib could interact with phosphatase 1γ (PP1γ) [29] a protein phosphatase that plays a critical role in controlling chromatin organization and has an important role in the DNA damage response pathway [30,31] This suggested that PP1γ expression patterns in cervical tumourigenesis might likewise be perturbed
We reasoned that if PP1γ was regulated directly by hScrib, this should be affected in HPV-16 induced malignancy
Summary
The high risk Human Papillomavirus (HPV) E6 oncoproteins play an essential role in the development of cervical malignancy. In the case of high risk HPV E6 oncoproteins, an intriguing class of targets that appear to be important for HPV E6 induced malignancy are the PDZ (PSD/Dlg/ZO) domain containing substrates [14,15]. These are bound by E6 via a short stretch of amino acids within the extreme carboxy terminal region of the E6 oncoprotein. We show that PP1γ is subject to a striking alteration in both its levels of expression and localisation, both as lesions develop, and in the tumour derived cell lines This altered pattern of expression is independent of hScrib, is due directly to E6/ E7 expression, and highlights PP1γ as potential novel biomarker of HPV induced neoplasia
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