Role of metastasis-induced protein S100A4 in human non-tumor pathophysiologies

Abstract

S100A4, an important member of the S100 family of proteins, is best known for its significant role in promoting cancer progression and metastasis. In addition to its expression in tumors, upregulation of S100A4 expression has been associated with various non-tumor pathophysiology processes. However, the mechanisms underlying the role of S100A4 remain unclear. Activated “host” cells (fibroblasts, immunocytes, vascular cells, among others) secrete S100A4 into the extracellular space in various non-tumor human disorders, where it executes its biological functions by interacting with intracellular target proteins. However, the exact molecular mechanisms underlying these interactions in different non-tumor pathophysiologies vary, and S100A4 is likely one of the cross-linking factors that acts as common intrinsic constituents of biological mechanisms. Numerous studies have indicated that the S100A4-mediated epithelial–mesenchymal transition plays a vital role in the occurrence and development of various non-tumor pathophysiologies. Epithelial–mesenchymal transition can be categorized into three general subtypes based on the phenotype and function of the output cells. S100A4 regulates tissue fibrosis associated with the type II epithelial–mesenchymal transition via various signaling pathways. Additionally, S100A4 stimulates fibroblasts to secrete fibronectin and collagen, thus forming the structural components of the extracellular matrix (ECM) and stimulating their deposition in tissues, contributing to the formation of a pro-inflammatory niche. Simultaneously, S100A4 enhances the motility of macrophages, neutrophils, and leukocytes and promotes the recruitment and chemotaxis of these inflammatory cells to regulate inflammation and immune functions. S100A4 also exerts a neuroprotective pro-survival effect on neurons by rescuing them from brain injury and participates in angiogenesis by interacting with other target molecules. In this review, we summarize the role of S100A4 in fibrosis, inflammation, immune response, neuroprotection, angiogenesis, and some common non-tumor diseases as well as its possible involvement in molecular pathways and potential clinical value.

S100A4 Silencing Facilitates Corneal Wound Healing After Alkali Burns by Promoting Autophagy via Blocking the PI3K/Akt/mTOR Signaling Pathway

“…5 A, 5 B). The fibroblast growth factor (FGF) family plays an important role in cell development, proliferation, migration, and differentiation, 24 and the fibroblast specific protein 1 (FSP-1) is a marker of fibroblasts in tissue-remodeling organs. 25 Therefore, we detected FGF-3-positive and FSP-1-positive expression to assess corneal stromal cell fibrosis.…”

S100A4 May Be a Good Prognostic Marker and a Therapeutic Target for Colon Cancer

“…The effect of S100A4 protein has been identified in several malignant, benign, or inflammatory diseases [ 12 , 15 ]. The expression levels of S100A4 increase in rheumatoid arthritis, osteoarthritis, psoriasis, idiopathic inflammatory myopathies, inflammatory bowel diseases like Crohn's disease, cardiac hypertrophy, hepatic hemangiomas, and autoimmune diseases [ 6 , 12 , 18 , 19 ]. S100A4 protein expression activates the proinflammatory processes mediated by tumor necrosis factor (TNF)- α , IL-1p and IL-6, and toll-like receptor (TLR)-4, augmenting the inflammation [ 12 , 18 , 19 ].…”

Keratinocyte-specific deletion of SHARPIN induces atopic dermatitis-like inflammation in mice

“…Shoulder joints were more severely affected. S100A4 is involved in promoting cancer progression and metastasis, fibrosis, inflammation, immune response, neuroprotection, angiogenesis, and some common non-tumor diseases including being upregulated in cells infiltrating rheumatoid arthritis synovial tissue [71,72]. Images on the cre-recombinase website (http://www.informatics.jax.org/recombinase/specificity?id= MGI:3712292&system=skeletal+system; 6 Feb 2020) reveal that S100a4 is expressed in bone and bone marrow which helps to partially explain the joint specific lesions in these mice.…”