Regulation of Interleukin-6 in Head and Neck Squamous Cell Carcinoma Is Related to Papillomavirus Infection

Abstract

The prevalence of head and neck squamous cell carcinoma (HNSCC) related to human papillomavirus (HPV) is increasing, unlike tobacco- and alcohol-associated cancers. To gain a clearer understanding of the molecular mechanisms implicated in HNSCC, depending on the presence or not of a viral sequence, we investigated the expression of proteins detected in the tumor regions of HNSCC patients. Twenty-two untreated HNSCC patients were selected according to the presence of HPV-16. For six patients, tumor and controlateral healthy tissues were tested for viral detection before quantitative proteomic analysis. After confirmation by Western blot, proteins were connected into a network, leading to investigate interleukin-6 (IL-6) by immunocytochemistry and ELISA. 41 ± 5% of proteins quantified by proteomics were differentially expressed in tumor compared with healthy regions. Among them, 36 proteins were retained as modulated in HPV-16 positive or negative tumors, including cytokeratins, tubulins, annexin A1, and serpin B1. Network analysis suggested a central role of IL-6, confirmed by overexpression of IL-6 in tumor tissues as in sera of HPV-negative HNSCC compared with HPV-16-positive tumors. This modulation may contribute to the survival and proliferation of cancer cells, although it was not related to tumor stage or to the level of HPV-16 DNA.

Integrated Omic Analysis of Oropharyngeal Carcinomas Reveals Human Papillomavirus (HPV)–dependent Regulation of the Activator Protein 1 (AP-1) Pathway

“…SMC1A MCM7 NUP210 RCL GBP2 MCM2 DFFA PDS5B TXNL1 SUPT16H PUF60 MCM6 CTTN GBP3 SNX2 NUMA1 MCM4 HAT1 ACO1 HMGN1 MTAP ICAM1 PCNA KRT17 FEN1 HLA-DRA CSK SAMHD1 NAP1L4 MCM3 DNAJC9 CDKN2A 100 50 0 50 100 20 of these patients (42,43). Consistent with this hypothesis, we identified significant differences in expression profiles of immune response proteins in HPVϮ OPCs.…”

Novel Insights into Head and Neck Cancer using Next-Generation “Omic” Technologies

“…Nonetheless, consistent with gene expression studies, HPV-dependent upregulation of proteins involved in cell cycle, DNA replication processes, and downregulation of epidermal development/cell differentiation pathways was corroborated, and downregulation of keratinization and extracellular matrix proteins was newly observed (50)(51)(52) …”

IL6 is associated with response to dasatinib and cetuximab: Phase II clinical trial with mechanistic correlatives in cetuximab-resistant head and neck cancer

“…Furthermore, IL6/JAK/STAT3 plays a key role in the tumor microenvironment through both autocrine and paracrine IL6 signaling [32], involving contributions from both stromal and immune cells. While IL6 may be a general prognostic biomarker, an indicator of HPV status or a surrogate for an inflammatory signature in recurrent/metastatic HNSCC, as in patients with newly diagnosed HNSCC treated with curative-intent therapy [33–39], our data suggest it is a predictive biomarker in the specific context of dasatinib-cetuximab treatment for patients with cetuximab-resistant, recurrent/metastatic disease. Baseline activation of IL6/JAK/STAT3 signaling may thus confer de novo resistance to dasatinib-cetuximab, precluding clinical benefit.…”