Abstract
Human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC) is biologically distinct from HPV-negative HNSCC. Outside of HPV-status, few tumor-intrinsic variables have been identified that correlate to improved survival. As part of exploratory analysis into the trace elemental composition of oropharyngeal squamous cell carcinoma (OPSCC), we performed elemental quanitification by X-ray fluorescence microscopy (XFM) on a small cohort (n = 32) of patients with HPV-positive and -negative OPSCC and identified in HPV-positive cases increased zinc (Zn) concentrations in tumor tissue relative to normal tissue. Subsequent immunohistochemistry of six Zn-binding proteins—zinc-α2-glycoprotein (AZGP1), Lipocalin-1, Albumin, S100A7, S100A8 and S100A9—revealed that only AZGP1 expression significantly correlated to HPV-status (p < 0.001) and was also increased in tumor relative to normal tissue from HPV-positive OPSCC tumor samples. AZGP1 protein expression in our cohort significantly correlated to a prolonged recurrence-free survival (p = 0.029), similar to HNSCC cases from the TCGA (n = 499), where highest AZGP1 mRNA levels correlated to improved overall survival (p = 0.023). By showing for the first time that HPV-positive OPSCC patients have increased intratumoral Zn levels and AZGP1 expression, we identify possible positive prognostic biomarkers in HNSCC as well as possible mechanisms of increased sensitivity to chemoradiation in HPV-positive OPSCC.
Highlights
As cofactors for multiple enzymes and proteins, essential trace elements—iron (Fe), copper (Cu), cobalt (Co), manganese (Mn) and zinc (Zn)—are required for normal biological functions[9]
By performing a targeted analysis of the expression of six Zn-binding proteins—Lipocalin-1, zinc-α2-glycoprotein (AZGP1), albumin, S100A7, S100A8 and S100A9—in tumors from oropharyngeal squamous cell carcinoma (OPSCC) patients (n = 68), we reveal AZGP1 is selectively overexpressed in a subpopulation of Human papillomavirus (HPV)-positive OPSCC patients and that its expression is an independent predictor of patient survival in this patient population
The elemental and protein-based analysis of OPSCC patients presented here is a coordinated strategy to develop new understandings of the pathogenesis of OPSCC. This is the first attempt to characterize the composition of OPSCC tumor tissue by trace elements using X-ray fluorescence microscopy (XFM) and to demonstrate that Zn-binding protein AZGP1 is a potential biomarker for positive prognosis in head and neck squamous cell carcinoma (HNSCC)
Summary
As cofactors for multiple enzymes and proteins, essential trace elements—iron (Fe), copper (Cu), cobalt (Co), manganese (Mn) and zinc (Zn)—are required for normal biological functions[9]. Elevated levels of some elements such as Fe, Cu and Zn have been detected in the serum and tumor tissue from patients with different types of cancers[10,11,12,13,14]. Ample evidence indicates that different types of aggressive hormonally-driven human cancers (i.e. breast, prostate and ovarian) have low intratumoral Zn levels relative to normal tissue[15,16,17]. By performing a targeted analysis of the expression of six Zn-binding proteins—Lipocalin-1, zinc-α2-glycoprotein (AZGP1), albumin, S100A7, S100A8 and S100A9—in tumors from OPSCC patients (n = 68), we reveal AZGP1 is selectively overexpressed in a subpopulation of HPV-positive OPSCC patients and that its expression is an independent predictor of patient survival in this patient population
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