Human papilloma virus and tobacco-associated modulation of NOTCH1 pathway during development of head and neck squamous cell carcinoma: Clinical importance

Abstract

Background: Modulation of NOTCH1 pathway during development of head and neck squamous cell carcinoma (HNSCC) was evaluated with human papillomavirus (HPV) infection and/or tobacco habit to define the molecular mechanism of transformation of normal oral epithelium into neoplastic tissue. Materials and Methods: Comprehensive messenger RNA (mRNA) expression profile of NOTCH1 pathway genes (NOTCH1, JAG1/2, HES1, HEY1, and FBXW7) in HNSCC samples was mined from five different datasets followed by validation at genetic/expression level (RNA/protein). Results: Differential expression pattern of the NOTCH1 pathway genes was seen in different datasets. In our HNSCC samples, high mRNA expression of NOTCH1, JAG1/2, HES1, HEY1 was seen with a significant increase particularly in NOTCH1 and HES1 expression in HPV+ ve (H+) samples. However, no such change in mRNA expression of FBXW7 was noted. In immunohistochemical analysis, high/medium expressions of activated NOTCH1 (NICD)/FBXW7/HES1 proteins were seen in basal/parabasal layers of adjacent normal oral epithelium than in the spinous layers with prevalent expression in H+ samples, followed by increased expression with the progression of the disease. A similar trend was seen in the H+ and/or tobacco+ve (T+) samples, except H-T- group. Infrequent copy number variation was seen in NOTCH1/JAG1/JAG2 loci in HNSCC samples. High/medium expression of NICD/HES1 protein showed overall poor patient outcome, though patients under H+ T– group showed better survival. Conclusion: Our data showed that activated NOTCH1 pathway in basal/parabasal layers of the oral epithelium was gradually aggravated during the development of HNSCC with a distinct association with HPV infection and tobacco habit.