Abstract
ObjectiveAlthough perineural invasion (PNI) is well-known to be correlated with and able to predict lymph node metastasis (LNM) in oral squamous cell carcinoma (OSCC), the clinical and molecular correlation between PNI and LNM has not been elucidated, and preoperative biomarkers for LNM prediction in OSCC are urgently needed.Materials and methodsThe correlation between PNI and LNM was retrospectively evaluated using a cohort of 218 patients diagnosed with OSCC. Candidate neuropeptides were screened based on TCGA database and verified via immunohistochemistry and Western blot analyses. ELISA was used to detect calcitonin gene-related peptide (CGRP) in patient plasma. In vitro assays were used to explore the effects of CGRP on OSCC cells.ResultsOSCC patients with PNI had a higher incidence of LNM (69.86% vs. 26.2%, P < 0.0001, n = 218). CGRP expression was upregulated in the PNI niche and in metastatic lymph nodes, and was correlated with poor overall survival of OSCC patients. Preoperative plasma CGRP levels were higher in OSCC patients (n = 70) compared to healthy donors (n = 60) (48.59 vs. 14.58 pg/ml, P < 0.0001), and were correlated with LNM (P < 0.0001) and PNI (P = 0.0002). Preoperative plasma CGRP levels alone yielded an AUC value of 0.8088 to predict LNM, and CGRP levels combined with preoperative T stage reached an AUC value of 0.8590. CGRP promoted proliferation and migration abilities of OSCC cells, which could be antagonized by either pharmacological or genetic blockade of the CGRP receptor.ConclusionsThe neuropeptide CGRP links PNI and LNM in OSCC, and preoperative plasma CGRP levels can be used to predict LNM in OSCC.
Highlights
Oral cancer is a common malignant tumor that occurs in the oral epithelial tissue, and more than 90% of cases of oral cancer are oral squamous cell carcinoma (OSCC) [1]
OSCC patients with perineural invasion (PNI) had a higher incidence of lymph node metastasis (LNM) (69.86% vs. 26.2%, P < 0.0001, n = 218)
calcitonin gene-related peptide (CGRP) expression was upregulated in the PNI niche and in metastatic lymph nodes, and was correlated with poor overall survival of OSCC patients
Summary
Oral cancer is a common malignant tumor that occurs in the oral epithelial tissue, and more than 90% of cases of oral cancer are oral squamous cell carcinoma (OSCC) [1]. One of the most prominent characteristics of OSCC is lymph node metastasis (LNM), even in early-stage disease, which is one of the most significant factors for patient prognosis [2,3,4]. Zhang et al BMC Cancer (2021) 21:1254 for early stage OSCC [2]. Nearly 70% of early stage OSCC patients undergo unnecessary neck dissection [5]. Many researchers have used molecular biomarkers for LNM prediction. Most of these biomarkers are based on mRNA or protein expression in tumor tissues [8,9,10], so are impractical for preoperative prediction. Preoperative biomarkers for LNM prediction that can be measured non-invasively are urgently needed
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