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Introduction
A total of 3 homologous genes of opiorphin, OPRPN (known as ProL1 previously), submaxillary gland androgen-regulated protein 3A (SMR3A) and SMR3B (1) are known in humans. OPRPN-derived opiorphin was reported to act as a potent inhibitor of two cell membrane-bound enkephalin-inactivating peptidases, neutral endopeptidase (NEP; CD10) and aminopeptidase N (APN; CD13) (2). CD10 and CD13 are widely distributed among a wide range of tissues and organs, which regulate signaling pathways mediating cell proliferation, survival and migration (3–5). Dysregulated expression of both proteins has been identified in various human tumor entities, such as pancreas, gastric, prostate, breast, lung and oral carcinomas (6–9).
Head and neck squamous cell carcinoma (HNSCC) is one of the most common human malignancies worldwide with a yearly incidence of 600,000 cases (10). The standard pillars of therapy are surgery, irradiation (IR), chemotherapy or a combination of these (11). Although treatment strategies have improved in the last decades, the global 5-year-survival rate for all HNSCC sites remains low at only 40–50% (10). Tumor recurrence after radiotherapy frequently develops and significantly hampers rehabilitation (12). The identification of valuable biomarkers and radioresistant molecules contributing to poor clinical outcomes may enable patient stratification to properly select a therapeutic regimen (13). Our previous data revealed variable protein expression patterns for both CD10 and CD13 in a cohort of patients with oropharyngeal squamous cell carcinoma (OPSCC). In addition, strong SMR3A protein expression was also found in 36% of all primary OPSCC in a tissue microarray which served as an unfavorable risk factor for clinical prognosis (14). Notably, an enrichment of SMR3A-positive cells was observed in the fraction of vital HNSCC cells after fractionated IR which was dependent on estrogen receptor 2 (ESR2) signaling (15). Moreover, dysregulated OPRPN was reported to be associated with invasion in breast cancer (16). To date, the understanding of the clinical relevance of opiorphin proteins in head and neck cancer is limited.
In the present study, OPRPN protein levels were investigated by immunohistochemical (IHC) staining on primary tumor samples of OPSCC patients. The association between expression patterns of OPRPN and SMR3A with clinical and histopathological features as well as progression-free (PFS) and disease-specific survival (DSS) were addressed. A potential function of OPRPN and SMR3A after fractionated IR, in part mimicking a clinically applied...