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Open AccessArticle

Differential Activation of ERK Signaling in HPV-Related Oropharyngeal Squamous Cell Carcinoma

1
Department of Otorhinolaryngology, Head and Neck Surgery, Heidelberg University Hospital, Heidelberg University, 69120 Heidelberg, Germany
2
Institute of Pathology, Heidelberg University Hospital, Heidelberg University, 69120 Heidelberg, Germany
3
Molecular Diagnostics of Oncogenic Infections, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
4
Department of Otorhinolaryngology, SLK Kliniken, Am Gesundbrunnen, 74078 Heilbronn, Germany
5
Department of Oral and Cranio-Maxillofacial Surgery, Heidelberg University Hospital, Heidelberg University, 69120 Heidelberg, Germany
6
Molecular Mechanisms of Head and Neck Tumors, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2019, 11(4), 584; https://doi.org/10.3390/cancers11040584
Received: 28 March 2019 / Revised: 12 April 2019 / Accepted: 23 April 2019 / Published: 25 April 2019
(This article belongs to the Special Issue Protein Kinases and Cancers)
Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) forms a distinct tumor entity with better survival clinical outcome. Numerous underlying molecular mechanisms have been postulated for differences in treatment response, but the impact of MEK/ERK signaling, a main driver of carcinogenesis in various cancers including OPSCC and key player mediating therapy resistance remains elusive. In a retrospective experimental cohort study, primary tumor samples from OPSCC patients (n = 124) were available on tissue microarrays (TMAs) and expression levels of phosphorylated ERK1/2 (pERK1/2) were detected by immunohistochemical staining. Correlations of pERK1/2 expression patterns with clinicopathological features and clinical outcome were evaluated by statistical analysis. A low pERK1/2 expression was strongly associated with HPV-related OPSCC, while primary tumors with high pERK1/2 staining showed a distinctly worse survival outcome and were associated with higher cellular differentiation. Co-activation of both ERK1/2 and AKT was a common event and was associated with unfavorable prognosis in our cohort. However, the combinatorial analysis of pAKT (Ser473) and pERK1/2 did not strengthen the predictive power of pERK1/2, suggesting that pERK1/2 plays a more significant function in OPSCC. In summary, our data provide a compelling experimental and statistical evidence that low levels of tumor cell intrinsic ERK1/2 activation contribute at least in part to the favorable outcome of HPV-related OPSCC. On the other hand, presented findings indicate that non-HPV-related OPSCC with elevated ERK phosphorylation are at high risk for treatment failure and might benefit from targeted therapy of MEK/ERK signaling. View Full-Text
Keywords: oropharyngeal squamous cell carcinoma; MAPK/ERK; AKT; prognostic biomarker; human papillomavirus; tissue microarray oropharyngeal squamous cell carcinoma; MAPK/ERK; AKT; prognostic biomarker; human papillomavirus; tissue microarray
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Rong, C.; Muller, M.; Flechtenmacher, C.; Holzinger, D.; Dyckhoff, G.; Bulut, O.C.; Horn, D.; Plinkert, P.; Hess, J.; Affolter, A. Differential Activation of ERK Signaling in HPV-Related Oropharyngeal Squamous Cell Carcinoma. Cancers 2019, 11, 584.

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