title: 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=0.04), advanced disease stages (P<0.001), regional tumor recurrence (P=0.004), distant metastasis (P=0.03) and reduced disease-specific survival (P=0.012, log-rank 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=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 ion-conducting 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.
authors.affiliation: Servicio de Otorrinolaringología, Instituto Universitario de Oncología del Principado de Asturias, Hospital Universitario Central de Asturias, Oviedo, Spain.
authors.forename: Sofía T
authors.initials: ST
authors.lastname: Menéndez
authors.forename: Juan P
authors.initials: JP
authors.lastname: Rodrigo
authors.forename: Saúl
authors.initials: S
authors.lastname: Alvarez-Teijeiro
authors.forename: M Ángeles
authors.initials: MÁ
authors.lastname: Villaronga
authors.forename: Eva
authors.initials: E
authors.lastname: Allonca
authors.forename: Aitana
authors.initials: A
authors.lastname: Vallina
authors.forename: Aurora
authors.initials: A
authors.lastname: Astudillo
authors.forename: Francisco
authors.initials: F
authors.lastname: Barros
authors.forename: Carlos
authors.initials: C
authors.lastname: Suárez
authors.forename: Juana M
authors.initials: JM
authors.lastname: García-Pedrero
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D018450:Disease Progression; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006801:Humans; D007012:Hypopharyngeal Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D053208:Kaplan-Meier Estimate; D007822:Laryngeal Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D007830:Larynx / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011230:Precancerous Conditions / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D011379:Prognosis; D012189:Retrospective Studies; D013030:Spain / Q000453:epidemiology; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; D051638:Ether-A-Go-Go Potassium Channels; C496884:KCNH1 protein, human