Abstract
Head and neck squamous cell carcinoma (HNSCC) development is a multistage process includes the normal, dysplasia and squamous cell carcinoma (SCC) stages. Recently, increasing evidence has suggested that the tumor microenvironment (TME) is an integral part of malignant transformation. Exploring certain key node genes in TME for future intervention in dysplasia to interrupt oral carcinogenesis was the primary goal of this research. To achieve this goal, systems biology approaches were first applied to the epithelia and fibroblasts collected at sequential stages in a 4-nitroquinoline-1-oxide (4NQO) - induced rat oral carcinogenesis model. Through bioinformatics network construction, IL-1β was identified as one of the key node genes in TME during carcinogenesis. Immunohistochemical staining of human and rat samples demonstrated that IL-1β expression patterns were parallel to the stages of malignant transformation. Silencing IL-1β with lentivirus-delivered shRNA significantly inhibited oral squamous cell carcinoma cell growth both in vivo and in vitro. Based on these findings, we hypothesized that IL-1β may be a chemoprevention target in TME during oral carcinogenesis. Therefore, we targeted IL-1 in the TME by oral mucosal injection of an IL-1 receptor antagonist in 4NQO rats. The results demonstrated that targeting IL-1 could interrupt oral carcinogenesis by reprogramming the TME.
Highlights
Head and neck squamous cell carcinoma (HNSCC) development is a multistage process includes the normal, dysplasia and squamous cell carcinoma (SCC) stages
Clustering analysis showed that epithelial samples from the same group clustered together, while one fibroblasts sample from the dysplasia group clustered with the normal group (Fig. 1A)
The tumor microenvironment (TME) refers to the dynamic cellular and extra-cellular components that surround tumor cells at each stage of carcinogenesis; it consist of a complex network of fibroblasts, endothelial cells, blood vessels and immune cells, along with secreted factors such as cytokines, growth factors and numerous extracellular matrix (ECM) components[9,10]
Summary
Head and neck squamous cell carcinoma (HNSCC) development is a multistage process includes the normal, dysplasia and squamous cell carcinoma (SCC) stages. Exploring certain key node genes in TME for future intervention in dysplasia to interrupt oral carcinogenesis was the primary goal of this research To achieve this goal, systems biology approaches were first applied to the epithelia and fibroblasts collected at sequential stages in a 4-nitroquinoline-1oxide (4NQO) - induced rat oral carcinogenesis model. Because all the components of the TME work as a complex network, the identification of key node genes in the TME is necessary for future intervention at the dysplasia stage to interrupt oral carcinogenesis for clinical purposes. To achieve this goal, a reliable animal model is a prerequisite. Through bioinformatics network construction and subsequent verification, interleukin 1 beta (IL-1β ) was identified as one of the key node genes during www.nature.com/scientificreports/
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