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Background  The role of human papillomavirus (HPV) in bladder carcinogenesis remains controversial. Overexpression of p16 INK4a , a surrogate marker for infection with oncogenic HPV in other tumours, has been described for urothelial carcinoma  in situ  (UCIS). Our goal was therefore to evaluate whether overexpression of p16 INK4a  is associated with HPV infection and to identify mechanisms of p16 INK4a  upregulation in UCIS.    Materials and Methods  In 60 tissue specimens from a total of 45 patients (UCIS and controls), we performed p16 INK4a  immunohistochemistry followed by detection and subclassification of HPV DNA. In a subset of samples, we tested for gene amplification of p16 INK4a  applying fluorescence  in situ  hybridization (FISH). RAS/MAPK signalling and epithelial-mesenchymal transition (EMT) was assessed using immunohistochemistry. Finally, we transfected urothelial carcinoma cells with  KRAS  and examined the expression of p16 INK4a  as well as markers of EMT.    Results  We found overexpression of p16 INK4a  in 92.6% of UCIS and in all cervical intraepithelial neoplasia (CIN) controls. In contrast, we detected high-risk HPV DNA in 80% of CIN, but none in UCIS. There was no gene amplification of p16 INK4a . High levels of phosphorylated kinases and urokinase plasminogen activator (uPA) and loss of membraneous E-cadherin were detected in UCIS.  KRAS  transfection of urothelial carcinoma cells led to upregulation of p16 INK4a  and uPA accompanied by loss of E-cadherin that could be inhibited by application of the kinase-inhibitor Sorafenib.    Conclusions  Our results show that overexpression of p16 INK4a  in UCIS is neither associated with HPV infection nor p16 INK4a  gene amplification but is a consequence of enhanced RAS/MAPK signalling that promotes EMT, possibly due to Sorafenib-sensitive paracrine secretion of the EMT activator uPA. These findings might open a novel therapeutic option for localized but aggressive urothelial cancer.

plos one

Overexpression of p16INK4a in Urothelial Carcinoma In Situ Is a Marker for MAPK-Mediated Epithelial-Mesenchymal Transition but Is Not Related to Human Papillomavirus Infection