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Epiregulin (EREG) is one of the members of the EGF family. In 1997, Toyoda et al. cloned and expressed the human EREG gene. Similar to other members of the EGF family, EREG is initially expressed as a transmembrane protein that is secreted to the extracellular form in a soluble form upon maturation. EREG, a member of the epidermal growth factor (EGF) family, is involved in a variety of tissue regeneration processes mediated by mesenchymal stem cells and plays a key role in the maintenance of MSCs.
EREG's Structural Function
Compared to other members of the EGF family, EREG has two unique characteristics: First, EREG is mainly expressed in placenta and peripheral blood leukocytes, while other EGF family members are widely expressed in normal tissues. Second, as one of the EGFR ligands, the binding of EREG to EGFR and the formation of heterodimers not only stimulate ErbB1, ErbB4 homodimers but also all possible ErbB heterodimers. Based on Northern blot, in situ hybridization analysis and functional studies, EREG was discovered as a local signaling medium and a network signal composed of the ErbB family, regulating a series of cellular functions under physiological and pathological conditions.
The study found that EREG showed stronger biological activity than other EGF members. It stimulates the proliferation of fibroblasts, hepatic progenitor cells, etc. by activating Erk/MAPK and Akt signaling systems, and plays an important role in anti-inflammatory, wound repair and liver regeneration. Studies have shown that EREG is a secreted dedifferentiating factor of vascular endothelial mesenchymal stem cells. In the differentiated rat aorta, the extracellular signal-regulated kinase (Erk) and p38/MAPK signals are involved in the revascularization process. Studies have shown that EREG has unique biological functions different from other members of the EGF family.
EREG Regulatory Signaling Pathway
Sunaga et al. showed that oncogenic mutations in the EGFR, KRAS or BRAF genes induce EREG overexpression by activating the MEK / ERK signaling pathway. Overproduction of EREG stimulates the EGFR/ErbB receptor to activate multiple downstream signaling pathways, including the MEK/ERK and PI3K/Akt pathways through the autocrine loop mechanism. Therefore, EREG may play a variety of carcinogenic effects, including regulation of cell proliferation, invasion, and metastasis. Therefore, it may contribute to the development of human cancer, including non-small-cell lung cancer (NSCLC). It is considered that half of the lung adenocarcinomas are mutated in EGFR, BRAF or KRAS in a mutually exclusive manner, and tumors having such driving mutations overexpress EREG. It is well believed that most NSCLCs can benefit from EREG targeted therapies. Although the exact mechanism of EREG regulation is unclear, EREG may be an excellent target for anticancer therapy, especially NSCLC. In addition, in vivo studies and clinical trials are necessary to elucidate the effectiveness of EREG-targeted therapy for NSCLC.
Figure 1. Oncogenic mutations for the upregulation of EREG expression.（Sunaga, et al. 2015)
Regulatory Effect of EREG on MSCs Function
EREG mainly affects the expression levels of a series of cytokines such as inflammatory factors and chemotactic factors in MSCs via the paracrine pathway. It enhances the viability of MSCs, improves the ischemic hypoxic microenvironment of local defects, and regulates the recruitment of inflammatory cells under it. This promotes MSCs-mediated anti-inflammatory, wound healing and injury repair treatments and has the effect of improving the local microenvironment. Harada et al. indicated that EREG induces paracrine expression of IL-6 and chemokines via the PI3K/Akt pathway, thereby regulating the response of keratinocytes to immune and inflammatory responses. And the local tissue closure of EREG inhibits the development of cytokine-induced inflammation. EREG plays an important role in in vitro expansion of MSCs, directed homing/migration to the target of injury, and multidirectional differentiation of MSCs. This suggests that EREG can be used to improve and promote homing/migration of MSCs, promote in vitro expansion of MSCs, and maintain their therapeutic potential.
The pluripotent MSCs-mediated injury tissue repair therapy has become the most prominent research direction in the field of regenerative medicine. However, the mechanism of directed differentiation of MSCs is not fully understood at present, and several research groups have found that there are differences in the expression of growth factors in MSCs in different cell environments. Therefore, the identification of expression patterns of growth factors involved in the proliferation and differentiation of MSCs in developmental and defect repair will provide a good way to understand the molecular mechanisms underlying MSCs-mediated regeneration. Studies have shown that in the presence of EGF, bFGF and other epidermal growth factors, hair follicle mesenchymal stem cells are more likely to maintain their osteogenic, adipogenic and chondrogenic differentiation potential. Gao et al. reported a significant up-regulation of EREG expression in dental pulp stem cells or root canal papilla stem cells by growth factor PCR and immunofluorescence analysis. Moreover, EREG is highly expressed in the dental papilla tissue of the late bell-shaped period of teeth development, thereby promoting the deposition of the interdental interstitium. Adult dental pulp cells can restore the differentiation ability of dental pulp tissue after they are induced by EREG.
Du et al. found that the BCOR/FBXL11 complex regulates the expression level of the EREG gene promoter region and affects the expression level of EREG, thereby regulating the ability of apical papillary stem cell-mediated osteogenic differentiation in nude mice. Studies have shown that EGF and bFGF pretreatment can enhance the neurogenic differentiation of BMSCs. It has also been reported that in liver injury, bone marrow-derived MSCs are infused and differentiated to promote regeneration, whereas hepatic progenitor cells differentiate into hepatocytes when co-cultured with BMSCs. Tomita et al. reported that EREG cooperates with FGF2 to regulate this process.