ArticlePloS one2013
Overexpression of p16(INK4a) in urothelial carcinoma in situ is a marker for MAPK-mediated epithelial-mesenchymal transition but is not related to human papillomavirus infection.
Article in PloS one, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers, 1 of them a synthesis that pooled it.
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Who cites it
17 citing papers in PubMed, 1 synthesis or guideline pooled it, 41 citations in OpenAlex.
- The association between human papillomavirus and bladder cancer: Evidence from meta-analysis and two-sample mendelian randomization.Journal of medical virology · 2023Pooled it
- HPV-positive cancers at uncommon sites: a narrative review.Oncology reviews · 2026Review
- Review
- Our experience diagnosing 225 patients with cervical glandular lesions: current technologies, lessons learned, and areas for improvement.Diagnostic pathology · 2024Article
- Prevalence of Human Papilloma Virus Infection in Bladder Cancer: A Systematic Review.Diagnostics (Basel, Switzerland) · 2022Review
- The small conductance calcium-activated potassium channel 3 (SK3) is a molecular target for Edelfosine to reduce the invasive potential of urothelial carcinoma cells.Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine · 2016Article
- Low prevalence of HPV detection and genotyping in non-muscle invasive bladder cancer using single-step PCR followed by reverse line blot.World journal of urology · 2015Article
- Article
- Targeting Hsp90 in urothelial carcinoma.Oncotarget · 2015Review
- The role of histologic subtype, p16(INK4a) expression, and presence of human papillomavirus DNA in penile squamous cell carcinoma.BMC cancer · 2015Article
- Hybrid Capture 2 is as effective as PCR testing for high-risk human papillomavirus in head and neck cancers.Applied immunohistochemistry & molecular morphology : AIMM · 2015Article
- Clinical significance of epithelial mesenchymal transition (EMT) in chronic obstructive pulmonary disease (COPD): potential target for prevention of airway fibrosis and lung cancer.Clinical and translational medicine · 2014Article
- Rho GTPases RhoA and Rac1 mediate effects of dietary folate on metastatic potential of A549 cancer cells through the control of cofilin phosphorylation.The Journal of biological chemistry · 2014Article
- The expression patterns of p53 and p16 and an analysis of a possible role of HPV in primary adenocarcinoma of the urinary bladder.PloS one · 2014Article
- Clinical significance of epithelial-mesenchymal transition.Clinical and translational medicine · 2014Review
- Specific activation of K-RasG12D allele in the bladder urothelium results in lung alveolar and vascular defects.PloS one · 2014Article
- Detection of human papillomavirus infection and p16 immunohistochemistry expression in bladder cancer with squamous differentiation.PloS one · 2014Article
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Authors and funding
10 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundThe 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
methodsIn 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.
resultsWe 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.
conclusionsOur 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.
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