ABSTRACT
Dysregulated expression of S100A7 is found in several cancers and plays an important role in tumor progression; however, its carcinogenic role in esophageal squamous carcinoma (ESCC) is still poorly understood. Here, we identified that the levels of S100A7 were remarkably upregulated in 341 tumor tissues (P < .001) and 274 serum samples (P < .001) of ESCC patients compared with normal control. It was an independent prognostic factor (P = .026). Furthermore, a new diagnostic model for ESCC based on serum S100A7, SCC, and crfra21-1 was established with area under curve (AUC) up to 0.863 (95% CI: 0.802-0.925). Mechanically, we found upregulated S100A7 could promote cell migration and proliferation through intracellular binding to JAB1 and paracrine interaction with RAGE receptors and then activates the downstream signaling pathways. In addition, exocrine S100A7 could promote M2 macrophage infiltration and polarization by up-regulating M2 macrophage associated proteins, and tumor angiogenesis by enhancing the activation of p-ErK and p-FAK pathways. Further animal experiments confirmed the role of S100A7 in promoting M2 macrophage infiltration and angiogenesis in ESCC. In conclusion, these findings highlighted the potential diagnostic and prognostic value of S100A7 in patients with ESCC. Meanwhile, our results reveal that S100A7 promotes tumor progression by activating oncogenic pathways and remodeling tumor microenvironment, which paving the way for the progress of S100A7 as a therapeutic target for cancer treatment.
Subject(s)
Esophageal Neoplasms/diagnosis , Esophageal Squamous Cell Carcinoma/diagnosis , Macrophages/immunology , S100 Calcium Binding Protein A7/metabolism , Animals , Biomarkers, Tumor/blood , Biomarkers, Tumor/metabolism , COP9 Signalosome Complex/metabolism , Cell Proliferation , Esophageal Neoplasms/blood supply , Esophageal Neoplasms/pathology , Esophageal Squamous Cell Carcinoma/blood supply , Esophageal Squamous Cell Carcinoma/pathology , Female , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Macrophages/cytology , Male , Mice , Mice, Inbred C57BL , Middle Aged , Neovascularization, Pathologic , Peptide Hydrolases/metabolism , Prognosis , RNA Interference , RNA, Small Interfering/metabolism , Receptor for Advanced Glycation End Products/metabolism , S100 Calcium Binding Protein A7/antagonists & inhibitors , S100 Calcium Binding Protein A7/blood , S100 Calcium Binding Protein A7/genetics , Signal TransductionSubject(s)
Benzoxazoles/pharmacology , Butyrates/pharmacology , Keratinocytes/drug effects , Psoriasis/drug therapy , S100 Calcium Binding Protein A7/antagonists & inhibitors , Cell Line , Drug Evaluation, Preclinical , Humans , PPAR alpha/agonists , PPAR alpha/metabolism , Psoriasis/immunology , Psoriasis/pathology , S100 Calcium Binding Protein A7/metabolism , Signal Transduction/drug effects , Signal Transduction/immunology , Tumor Necrosis Factor-alpha/metabolism , Up-Regulation/drug effectsABSTRACT
Psoriasis, a chronic immune-mediated inflammatory skin disease, is characterized by dysregulated keratinocyte proliferation. The EF-hand calcium binding protein S100A7 has been found to be overexpressed in psoriatic keratinocytes. It is know that S100A7 may interact with Jab1, a cofactor that stabilizes c-Jun. Jab1 is known to downregulate the expression of the cell cycle inhibitor p27Kip1 in some cancer models. In this study, we aimed to investigate the possible interaction between S100A7 and Jab1 and the downstream effects on p27 Kip1 expression in normal human keratinocyte cells transfected with S100A7 CRISPR activation plasmid and in archival psoriatic skin samples. Our results showed that the upregulated S100A7 colocalizes with Jab1 at the nuclear level in transfected cells and psoriatic skin samples. We also showed a differential protein expression of Jab1 between cytoplasmic and nuclear compartments, thus suggesting Jab1 translocation from nucleus to cytoplasm. p27 Kip1 protein expression patterns would imply a translocation from nucleus and a subsequent degradation of this protein. The upregulation of S1007 and its interaction with Jab1 would contribute to the p27 Kip1 -dependent impaired proliferation that characterizes psoriatic skin.
