The Role of EREG/EGFR Pathway in Tumor Progression

Abstract

Aberrant activation of the epidermal growth factor receptor (EGFR/ERBB1) by erythroblastic leukemia viral oncogene homolog (ERBB) ligands contributes to various tumor malignancies, including lung cancer and colorectal cancer (CRC). Epiregulin (EREG) is one of the EGFR ligands and is low expressed in most normal tissues. Elevated EREG in various cancers mainly activates EGFR signaling pathways and promotes cancer progression. Notably, a higher EREG expression level in CRC with wild-type Kirsten rat sarcoma viral oncogene homolog (KRAS) is related to better efficacy of therapeutic treatment. By contrast, the resistance of anti-EGFR therapy in CRC was driven by low EREG expression, aberrant genetic mutation and signal pathway alterations. Additionally, EREG overexpression in non-small cell lung cancer (NSCLC) is anticipated to be a therapeutic target for EGFR-tyrosine kinase inhibitor (EGFR-TKI). However, recent findings indicate that EREG derived from macrophages promotes NSCLC cell resistance to EGFR-TKI treatment. The emerging events of EREG-mediated tumor promotion signals are generated by autocrine and paracrine loops that arise from tumor epithelial cells, fibroblasts, and macrophages in the tumor microenvironment (TME). The TME is a crucial element for the development of various cancer types and drug resistance. The regulation of EREG/EGFR pathways depends on distinct oncogenic driver mutations and cell contexts that allows specific pharmacological targeting alone or combinational treatment for tailored therapy. Novel strategies targeting EREG/EGFR, tumor-associated macrophages, and alternative activation oncoproteins are under development or undergoing clinical trials. In this review, we summarize the clinical outcomes of EREG expression and the interaction of this ligand in the TME. The EREG/EGFR pathway may be a potential target and may be combined with other driver mutation targets to combat specific cancers.

Perinatal Exposure to Nicotine Alters Sperm RNA Profiles in Rats

“…Furthermore, earlier studies have revealed an IL-4/STAT-6/Tfec/IL-4Rα positive feedback regulatory loop, in which Tfec transcribes IL-4Rα expression to promote M2 programming in macrophages, which was implicated in asthma pathogenesis ( 57 ). In addition, several genes were involved in lung cancer and other lung diseases, such as Ceacam1 ( 58 , 59 ), Ereg ( 60 , 61 ) , Selp ( 62 , 63 ), and Pik3r5 ( 64 , 65 ). The most conspicuous genes among downregulated ones are members of the keratins (KRTs) and keratin-associated proteins (KRTAPs), including Krt34 , Krtap3-1 , and Krtap7-1 , which are important for epidermal development and hair follicle morphogenesis ( 66 , 67 ), respectively.…”

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“…This effect of CBS knockdown was associated with an increased expression of the micro-RNA miR-215-5p and a consequent decrease the expression of both epiregulin (EREG) and thymidylate synthetase (TYMS) [ 50 ]. Via these actions, CBS induces or enhances the EREG/EGFR pathway, which is considered an important effector of tumor progression and multidrug resistance in cancer [ 142 ].…”

The power of heteronemin in cancers

“…Epidermal growth factor receptors (EGFRs) are expressed on the surface of normal, nonmalignant cells, and overexpressed by cancer cells. The ligands of EGFR are epidermal growth factor (EGF), TGF-β, amphiregulin, and epiregulin [ 123 ]. Downstream of EGFR, the two principal signal transuding pathways are the PI3K/AKT/mTOR and RAS/RAF/MAPK cascades [ 123 , 124 ].…”

“…The ligands of EGFR are epidermal growth factor (EGF), TGF-β, amphiregulin, and epiregulin [ 123 ]. Downstream of EGFR, the two principal signal transuding pathways are the PI3K/AKT/mTOR and RAS/RAF/MAPK cascades [ 123 , 124 ]. However, the signal transducer and activator of the transcription 3 (STAT3) pathway also respond to EGFR signaling [ 123 , 124 ] and the insulin-like growth factor 1 (IGF-1) receptor can dimerize with EGFR and activate EGFR signaling.…”

“…Downstream of EGFR, the two principal signal transuding pathways are the PI3K/AKT/mTOR and RAS/RAF/MAPK cascades [ 123 , 124 ]. However, the signal transducer and activator of the transcription 3 (STAT3) pathway also respond to EGFR signaling [ 123 , 124 ] and the insulin-like growth factor 1 (IGF-1) receptor can dimerize with EGFR and activate EGFR signaling. In addition, downstream crosstalk between or among signaling cascades may occur.…”