Differential activation of ERK signaling in HPV-related oropharyngeal squamous cell carcinoma
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 drive...
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| Main Authors: | , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
25 April 2019
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| In: |
Cancers
Year: 2019, Volume: 11, Issue: 4 |
| ISSN: | 2072-6694 |
| DOI: | 10.3390/cancers11040584 |
| Online Access: | Verlag, Volltext: https://doi.org/10.3390/cancers11040584 Verlag: https://www.mdpi.com/2072-6694/11/4/584 
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| Author Notes: | Chao Rong, Marie Muller, Christa Flechtenmacher, Dana Holzinger, Gerhard Dyckhoff, Olcay Cem Bulut, Dominik Horn, Peter Plinkert, Jochen Hess and Annette Affolter |
| Summary: | 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. |
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| Item Description: | Gesehen am 06.11.2019 |
| Physical Description: | Online Resource |
| ISSN: | 2072-6694 |
| DOI: | 10.3390/cancers11040584 |