Abstract
PurposeThe aim of this study was to define somatostatin (SST) and somatostatin receptor type 1 (SSTR1) methylation profiles for head and neck squamous cell carcinoma (HNSCC) tumors at diagnosis and follow up and to evaluate their prognostic significance and value as a biomarker.MethodsGene expression was measured by quantitative RT-PCR. Promoter methylation status was determined by quantitative methylation-specific PCR (Q-MSP) in HNSCC.ResultsMethylation was associated with transcription inhibition. SST methylation in 81% of HNSCC tumor specimens significantly correlated with tumor size (P = 0.043), stage (P = 0.008), galanin receptor type 2 (GALR2) methylation (P = 0.041), and tachykinin-1 (TAC1) (P = 0.040). SSTR1 hypermethylation in 64% of cases was correlated with tumor size (P = 0.037), stage (P = 0.037), SST methylation (P < 0.001), and expression of galanin (P = 0.03), GALR2 (P = 0.014), TAC1 (P = 0.023), and tachykinin receptor type 1 (TACR1) (P = 0.003). SST and SSTR1 promoter hypermethylation showed highly discriminating receiver operator characteristic curve profiles, which clearly distinguished HNSCC from adjacent normal mucosal tissues. Concurrent hypermethylation of galanin and SSTR1 promoters correlated with reduced disease-free survival (log-rank test, P = 0.0001). Among patients with oral cavity and oropharynx cancer, methylation of both SST and SSTR1 promoters correlated with reduced disease-free survival (log-rank test, P = 0.028). In multivariate logistic-regression analysis, concomitant methylation of galanin and SSTR1 was associated with an odds ratio for recurrence of 12.53 (95% CI, 2.62 to 59.8; P = 0.002).ConclusionsCpG hypermethylation is a likely mechanism of SST and SSTR1 gene inactivation, supporting the hypothesis that SST and SSTR1 play a role in the tumorigenesis of HNSCC and that this hypermethylation may serve as an important biomarker.
Highlights
Squamous cell carcinoma of the head and neck (HNSCC) is the sixth most frequent type of cancer. [1] The use of targeted drugs is an increasingly adopted anticancer strategy; the application of epidermal growth factor receptor (EGFR)-specific antibodies combined with radiotherapy is a prominent example
SST methylation in 81% of head and neck squamous cell carcinoma (HNSCC) tumor specimens significantly correlated with tumor size (P = 0.043), stage (P = 0.008), galanin receptor type 2 (GALR2) methylation (P = 0.041), and tachykinin-1 (TAC1) (P = 0.040)
CpG hypermethylation is a likely mechanism of SST and somatostatin receptor type 1 (SSTR1) gene inactivation, supporting the hypothesis that SST and SSTR1 play a role in the tumorigenesis of HNSCC and that this hypermethylation may serve as an important biomarker
Summary
Squamous cell carcinoma of the head and neck (HNSCC) is the sixth most frequent type of cancer. [1] The use of targeted drugs is an increasingly adopted anticancer strategy; the application of epidermal growth factor receptor (EGFR)-specific antibodies combined with radiotherapy is a prominent example. [6] Its main functions involve regulating endocrine and exocrine secretion, modulating motor activity, and inhibiting gastrin-stimulated gastric acid secretion in the gastrointestinal tract. [7] In recent years, several studies have suggested that SST functions as a tumor suppressor gene and possesses potent antitumor and antisecretory activities in several human cancers in vitro and in vivo. [7] SST suppresses tumor growth through distinct mechanisms that involve inhibition of growth factors and hormones, reduction in vascularization, and regulation of the immune system. [11] Promoter hypermethylation concomitant with transcriptional silencing of SSTR1 expression has been detected in EBV-positive gastric cancer cells.[12] Despite our understanding of gastrointestinal tract cancer, hypermethylation in head and neck cancer remains to be explored. The current findings provide novel direct epigenetic evidence in human patients for the involvement of SST in the process of human tumor suppression. [10] Kharmate et al reported that SSTR1 controls EGF-mediated cell survival via dissociation of an ErbB heteromeric complex. [13] Others recently reported that both SSTRs and ErbBs activate the MAPK pathway, as SST-induced MAPK activation results in delayed cell cycle progression, whereas EGF activation promotes proliferation. [14] detection of aberrant expression of SST/SSTR1 may be of potential use as a marker for selecting HNSCC patients who could benefit from additional targeted therapies
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