Role of HERG1 potassium channel in both malignant transformation and disease progression in head and neck carcinomas

Abstract

Evidence indicates that human ether à -go-go-related gene 1 (HERG1) voltage-gated potassium channels could represent new valuable membrane therapeutic targets and diagnostic/prognostic biomarkers in various cancers. This study is the first to investigate the expression pattern of HERG1 potassium channel subunit in both primary tumors and precancerous lesions to establish its clinical and biological role during the development and progression of head and neck squamous cell carcinomas. HERG1 protein expression was evaluated by immunohistochemistry in paraffin-embedded tissue specimens from 133 patients with laryngeal/ hypopharyngeal squamous cell carcinomas and 75 patients with laryngeal dysplasia, and correlated with clinical data. Our findings demonstrate that HERG1 is frequently aberrantly expressed in a high percentage of primary tumors (87%), whereas expression was negligible in both stromal cells and normal-adjacent epithelia. HERG1 expression increased during head and neck squamous cell carcinoma progression and was significantly associated with lymph node metastasis (P ¼ 0.04), advanced disease stages (Po0.001), regional tumor recurrence (P ¼ 0.004), distant metastasis (P ¼ 0.03) and reduced disease-specific survival (P ¼ 0.012, logrank test). HERG1-positive expression was also detected in 31 (41%) of 75 laryngeal dysplasias. Interestingly, HERG1 expression increased with the grade of dysplasia; however, HERG1 expression but not histology correlated significantly with increased laryngeal cancer risk (P ¼ 0.007). In addition, functional studies in head and neck squamous cell carcinoma-derived cell lines further revealed that HERG1 expression promotes anchorage-dependent and -independent cell growth and invasive capability, although independently of its ionconducting function. Our data demonstrate that HERG1 expression is a biologically and clinically relevant feature in head and neck squamous cell carcinoma progression and also during malignant transformation, and a promising candidate as cancer risk marker and therapeutic target for head and neck squamous cell carcinoma prevention and treatment. Keywords: cancer risk; dysplasia; head and neck squamous cell carcinoma; HERG1; immunohistochemistry; metastasis; potassium channelThe incidence of head and neck squamous cell carcinoma has been gradually increasing over the last three decades. It is the sixth leading cancer by incidence worldwide and only 40-50% of patients with head and neck squamous cell carcinoma will survive for 5 years.1 Two-thirds of the diagnosed tumors present with locally advanced or metastatic disease (stages III and IV) and patients survival is determined by the development of loco-regional recurrences, distant metastases and second primary tumors.2 In this context, the Received

Prognostic significance of E‐cadherin and β‐catenin expression in HPV‐negative oropharyngeal squamous cell carcinomas

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Prevalence of human papillomavirus in laryngeal and hypopharyngeal squamous cell carcinomas in northern Spain

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Bioelectrical regulation of cell cycle and the planarian model system

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