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

Abstract

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.

Markers of Angiogenesis, Lymphangiogenesis, and Epithelial–Mesenchymal Transition (Plasticity) in CIN and Early Invasive Carcinoma of the Cervix: Exploring Putative Molecular Mechanisms Involved in Early Tumor Invasion

“…As expected, the MAP kinase cascade (ERK/MEK/MAPK), a well-recognized target for HPV oncogenes [ 61 , 62 ], was also identified upstream of invasion-associated transcriptome perturbations ( Figure 12 ). The genes involved in this pathway represent quite specific modulators of angiogenesis, invasion and immune response.…”

“…At the same time, IL1RN (inhibitor of IL1 signaling), DKK1 (inhibitor of WNT signaling), and proto-cadherin PCDH18 (inhibitor of EMT and invasion) showed decreased expression. As expected, the MAP kinase cascade (ERK/MEK/MAPK), a well-recognized target for HPV oncogenes [61,62], was also identified upstream of invasion-associated transcriptome perturbations ( Figure 12). The genes involved in this pathway represent quite specific modulators of angiogenesis, invasion and immune response.…”

“…Finally, to provide additional support for the significance of the identified signaling pathways for promotion of invasive behavior and angiogenesis of early-stage cervical cancer, a total of 201 upand downregulated DEGs were submitted to The Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database to construct a Protein-Protein Interaction (PPI) network, which As expected, the MAP kinase cascade (ERK/MEK/MAPK), a well-recognized target for HPV oncogenes [61,62], was also identified upstream of invasion-associated transcriptome perturbations ( Figure 12). The genes involved in this pathway represent quite specific modulators of angiogenesis, invasion and immune response.…”

An Infection-Based Murine Model for Papillomavirus-Associated Head and Neck Cancer

“…4D). Another biomarker that is upregulated in HPV-positive cancers is phospho-extracellular signal-regulated kinase (pERK), the active form of the effector ERK for mitogen-activated protein kinase (MAPK) signaling (48,49). Levels of pERK were elevated in our MmuPV1-induced tongue tumors, compared to those in mock-infected tongues (Fig.…”

Upregulation of long non‐coding RNA FOXD2‐AS1 promotes progression and predicts poor prognosis in tongue squamous cell carcinoma

“…However, the underlying molecular mechanism remains unknown. It has been reported that the NF‐kB and the ERK MAPK signaling pathways play an important role in the invasion and metastasis of cancers 16‐19 . Hence, western blotting was carried out to preliminarily test the molecular changes in NF‐kB and the ERK MAPK signaling pathways.…”