Oxidative stress signatures are related with a mesenchymal-like phenotype and an unfavorable prognosis in a subgroup of oropharyngeal squamous cell carcinoma

Introduction:

OPSCC patients frequently develop unfavorable metastases and inoperable local and regional recurrences. HPV-positive OPSCC await a favorable prognosis in general, however, patients present with higher tendency for metastasis. Recent publications including our own work showed that a subgroup of HPV-positive OPSCC present with oxidative stress signatures and mesenchymal like phenotype.

Materials and Methods:

We collected 51 OPSCC samples including 28 HPV-positive cases with both FFPE and fresh frozen tissue available. Expression of key components of the EMT, retinoic acid and oxidative stress pathways including NRF2, AKR1C1/3, ALDH1A2, Frizzled 10, β-Catenin, E-Cadherin, Vimentin, miR-9 and miR-16 – 2 were determined by RT-qPCR, in situ hybridization and/or immunohistochemistry. The impact of viral oncogenes on EMT-relevant components was addressed in primary human keratinocytes overexpressing HPV16-E6 and/or -E7.

Results:

Expression analysis revealed that subgroups of OPSCC mostly related to HPV-infection present with increased oxidative stress response (NRF2, AKR1C1/3) going along with activating EMT pathway signatures (Frizzled 10, β-Catenin, E-Cadherin, Vimentin, miR-9 and miR-16 – 2), frequent metastasis, and inversely correlated to retinoic acid synthesis (ALDH1A2). Moreover, in vitro experiments showed that HPV16-E6 is capable to induce miR-9, miR-16 – 2 and β-Catenin expression.

Conclusion:

OPSCC presenting with upregulation of oxidative stress response signatures have a higher tendency to undergo EMT. Frizzled 10 expression known to be regulated by retinoic acid was highly correlated to ALDH1A2 expression and inversely correlated to EMT and oxidative stress. Our data implicate that subgroups of tumors might benefit from adjuvant treatment with retinoids.

Publikationsverlauf

Publikationsdatum:
23. April 2019 (online)