ErbB3 upregulation by the HNSCC 3D microenvironment modulates cell survival and growth

• Published in: Oncogene Vol. 35; no. 12; pp. 1554 - 1564
• Main Authors: Humtsoe, J O, Pham, E, Louie, R J, Chan, D A, Kramer, R H
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.03.2016; Nature Publishing Group
• Subjects: 13/1; 13/106; 13/51; 38/109; 42/109; 631/67/1536/1665; 82/1; 82/80; 96/1; AKT protein; Apoptosis; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Care and treatment; Cell Biology; Cell culture; Cell Division; Cell growth; Cell Line, Tumor; Cell receptors; Cell Survival; Conserved sequence; Development and progression; Enzyme inhibitors; Epidermal growth factor; ErbB protein; ErbB-3 protein; Genetic aspects; Genetic regulation; Head & neck cancer; Head and neck cancer; Head and neck carcinoma; Head and Neck Neoplasms - metabolism; Head and Neck Neoplasms - pathology; Health aspects; Human Genetics; Humans; Hypoxia; Hypoxia-inducible factor 1a; Internal Medicine; Medicine; Medicine & Public Health; Nests; Oncology; original-article; Protein expression; Protein-tyrosine kinase; Receptor, ErbB-3 - metabolism; Signal transduction; siRNA; Squamous cell carcinoma; Transcription; Tumor Microenvironment; Up-Regulation; United States
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2015.220

Head and neck squamous carcinomas (HNSCC) present as dense epithelioid three-dimensional (3D) tumor nests that can mediate signals via the human epidermal growth factor receptor (ErbB) tyrosine kinase family to promote intratumoral survival and growth. We examined the role of the tumor microenvironment on ErbB receptor family expression and found that the status of intercellular organization altered the receptor profile. We showed that HNSCC cells forced into tumor island-like 3D aggregates strongly upregulated ErbB3 at the level of transcription. Not only was the elevated ErbB3 responsive to HRG-β1-induced enhanced signaling mechanism, but also analysis by siRNA-knockdown and kinase inhibitor strategies revealed that the ErbB3/AKT signaling pathway was sufficient to enhance tumor cell survival and growth potential. Elevated ErbB3 expression in the high-density 3D culture system was strongly associated with hypoxia-induced HIF-1α. Hypoxia-regulated ErbB3 expression was mediated by the HIF-1α-binding consensus sequence in the ErbB3 proximal promoter. The findings show that the local 3D tumor microenvironment can trigger reprograming and switching of ErbB family members and thereby influence ErbB3-driven tumor growth.