Significance of the Overexpression of Substance P and Its Receptor NK-1R in Head and Neck Carcinogenesis: A Systematic Review and Meta-Analysis

SIMPLE SUMMARY: Head and neck cancer is the sixth most frequent type of cancer, with more than 600,000 new cases/year, and it is responsible for around 300,000 deaths/year. Substance P (SP) is a peptide of the tachykinin family whose functions are related to a large number of physiological mechanisms in humans. The implications of SP in human carcinogenesis have recently been reported through the stimulation of its receptor NK-1R, or directly through the effects derived from the constitutive activation of NK-1R. With this background, we have shown, through a systematic review and meta-analysis, evidence that the upregulation of SP and NK-1R are oncogenic events involved in head and neck carcinogenesis, probably acting in the early stages of malignization. Our findings also highlight translational opportunities for SP/NK-1R as potential therapeutic targets in head and neck cancer. ABSTRACT: The objective of our study has been, through a systematic review and meta-analysis, to increase the scientific evidence on the implications of SP and its receptor NK-1R in head and neck carcinogenesis. We searched studies published before May-2020 without date and publication language restrictions (PubMed, Embase, Web of Science, Scopus). We evaluated the quality of the studies included (QUIPS tool). We performed heterogeneity, sensitivity, small-study effects, and subgroup analyses. A total 16 studies and 1308 cases met inclusion criteria. Qualitative evaluation demonstrated that not all studies were performed with the same scientific rigor, finding the greatest risk of bias in the study confounding and prognostic factors measurement domains. Quantitative evaluation showed a greater SP/NK-1R overexpression in malignant head and neck lesions compared to benign lesions (p = 0.02), and that expression was observed in malignant salivary gland pathology. Likewise, we found a higher overexpression of NK-1R compared to SP (p = 0.02). In conclusion, the results of this systematic review and meta-analysis show evidence that the upregulation of SP and NK-1R are oncogenic events involved in head and neck carcinogenesis, probably acting in the early stages of malignization. In addition, there is evidence of a greater relevance of the upregulation of the NK-1R receptor compared to SP, which highlights the interest in deepening the development of targeted therapies on the receptor. Future studies assessing the relationships between SP/NK-1R among subjects with head and neck tumors could consider the recommendations given in this systematic review and meta-analysis to improve and standardize future research.