S100 protein family in human cancer

Abstract

S100 protein family has been implicated in multiple stages of tumorigenesis and progression. Among the S100 genes, 22 are clustered at chromosome locus 1q21, a region frequently rearranged in cancers. S100 protein possesses a wide range of intracellular and extracellular functions such as regulation of calcium homeostasis, cell proliferation, apoptosis, cell invasion and motility, cytoskeleton interactions, protein phosphorylation, regulation of transcriptional factors, autoimmunity, chemotaxis, inflammation and pluripotency. Many lines of evidence suggest that altered expression of S100 proteins was associated with tumor progression and prognosis. Therefore, S100 proteins might also represent potential tumor biomarkers and therapeutic targets. In this review, we summarize the evidence connecting S100 protein family and cancer and discuss the mechanisms by which S100 exerts its diverse functions.

Keywords: S100 proteins; apoptosis; biomarker; invasion; migration; pluripotency; proliferation.

Figure 1

S100 proteins might have important roles during different steps of tumorigenic processes. S100 proteins are involved in many aspects of phenotypic features of cancer including regulation of cell differentiation, cell cycle progression, cell proliferation, cell apoptosis, cell motility, invasion and migration, tumor microenvironment and Cancer Stem Cells (CSCs) etc.

Figure 2

S100 proteins in RAGE signaling. S100 proteins can be secreted into the extracellular space, and crosslink with cell-surface receptor-RAGE and deliver signals inside the cell, thereby modulate cell survival, proliferation or apoptosis. Some S100 proteins (S100P, S100A8/A9, S100A12, S100A14, S100B) can interact with RAGE, subsequently activating the MAPK, PI-3K-AKT, and NF-κB signaling pathways, and thereby leading to the up-regulation of genes involved in cell survival and proliferation. In other cases, the apoptosis cascade is activated through the activation of JNK and caspases.

Figure 3

S100 proteins in EGF signaling. S100 proteins (S100A2, S100A4, S100A7) are induced by the activation of EGF/EGFR signaling. In turn, S100 proteins affect the activation of EGF/EGFR signaling and EGF/EGFR-mediated cell proliferation.

Figure 4

S100 proteins in p53 signaling. S100 proteins can be intracellularly located and regulate cell growth, cell-cycle progression and apoptosis by interacting with the relevant intracellular signal-regulation pathways. In particular, some S100 proteins can interact with p53 and affect p53 transcriptional activity, thereby resulting in the expression changes of p53 target genes involved in cell survival, proliferation and apoptosis.

Figure 5

S100 proteins are involved in cancer-stromal interplay. Many of S100 proteins are implicated in the communication between cancer cells and stromal cells such as fibroblasts, endothelial cells, and inflammatory cells including Tumor-associated Macrophages (TAMs), Myeloid Derived Suppressor Cells (MDCS), T lymphocytes, and neutrophils.