HPV-16 impairs the subcellular distribution and levels of expression of protein phosphatase 1γ in cervical malignancy

HPV-16 impairs the subcellular distribution and levels of expression of protein phosphatase 1γ in cervical malignancy

BMC Cancer, April 2015

25886518

Takayuki Seiki, Kazunori Nagasaka, Christian Kranjec, Kei Kawana, Daichi Maeda, Hiroe Nakamura, Ayumi Taguchi, Yoko Matsumoto, Takahide Arimoto, Osamu Wada-Hiraike, Katsutoshi Oda, Shunsuke Nakagawa, Tetsu Yano, Masashi Fukayama, Lawrence Banks, Yutaka Osuga, Tomoyuki Fujii

The 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). Expression 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. We 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%). Together, 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.