Differential transmission of the molecular signature of RBSP3, LIMD1 and CDC25A in basal/ parabasal versus spinous of normal epithelium during head and neck tumorigenesis: A mechanistic study

• Published in: PloS one Vol. 13; no. 4; p. e0195937
• Main Authors: Sarkar, Shreya, Alam, Neyaz, Mandal, Syam Sundar, Chatterjee, Kabita, Ghosh, Supratim, Roychoudhury, Susanta, Panda, Chinmay Kumar
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 19.04.2018; Public Library of Science (PLoS)
• Subjects: Adult; Aged; Biochemistry; Biology and Life Sciences; Cancer; Carcinogenesis; Carcinoma, Squamous Cell - etiology; Carcinoma, Squamous Cell - mortality; Carcinoma, Squamous Cell - pathology; cdc25 Phosphatases - genetics; cdc25 Phosphatases - metabolism; Cell cycle; Cell Transformation, Neoplastic - genetics; Clonal deletion; Development and progression; Diagnosis; Diagnostic systems; Disease control; DNA Methylation; Epigenetics; Epithelium; Epithelium - metabolism; Epithelium - pathology; Etiology; Female; Gene deletion; Gene expression; Genes; Genetic aspects; Head & neck cancer; Head and neck cancer; Head and Neck Neoplasms - etiology; Head and Neck Neoplasms - mortality; Head and Neck Neoplasms - pathology; Health aspects; Human papillomavirus; Humans; Immunohistochemistry; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Invasiveness; Lasers; Lesions; LIM Domain Proteins - genetics; LIM Domain Proteins - metabolism; Male; Medical prognosis; Medicine and Health Sciences; Middle Aged; Mutation; Neck; Neoplasm Grading; Neoplasm Staging; Oncology; Pathology; Patients; Physical Sciences; Physiological aspects; Prognosis; Promoter Regions, Genetic; Risk factors; Squamous cell carcinoma; Squamous Cell Carcinoma of Head and Neck; Tobacco; Tumor suppressor genes; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Tumorigenesis; Tumors; Workflow; India
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0195937

Head and neck squamous cell carcinoma (HNSCC) is a global disease and mortality burden, necessitating the elucidation of its molecular progression for effective disease management. The study aims to understand the molecular profile of three candidate cell cycle regulatory genes, RBSP3, LIMD1 and CDC25A in the basal/ parabasal versus spinous layer of normal oral epithelium and during head and neck tumorigenesis. Immunohistochemical expression and promoter methylation was used to determine the molecular signature in normal oral epithelium. The mechanism of alteration transmission of this profile during tumorigenesis was then explored through additional deletion and mutation in HPV/ tobacco etiological groups, followed byclinico-pathological correlation. In basal/parabasal layer, the molecular signature of the genes was low protein expression/ high promoter methylation of RBSP3, high expression/ low methylation of LIMD1 and high expression of CDC25A. Dysplastic epithelium maintained the signature of RBSP3 through high methylation/ additional deletion with loss of the signatures of LIMD1 and CDC25A via deletion/ additional methylation. Similarly, maintenance and / or loss of signature in invasive tumors was by recurrent deletion/ methylation. Thus, differential patterns of alteration of the genes might be pre-requisite for the development of dysplastic and invasive lesions. Etiological factors played a key role in promoting genetic alterations and determining prognosis. Tobacco negative HNSCC patients had significantly lower alterations of LIMD1 and CDC25A, along with better survival among tobacco negative/ HPV positive patients. Our data suggests the necessity for perturbation of normal molecular profile of RBSP3, LIMD1 and CDC25A in conjunction with etiological factors for head and neck tumorigenesis, implying their diagnostic and prognostic significance.