3-Nitrobenzanthrone promotes malignant transformation in human lung epithelial cells through the epiregulin-signaling pathway

Chen, Kuan Yuan; Tseng, Chien-Hua; Feng, Po Hao; Sun, Wei; Ho, Shu-Chuan; Lin, Cheng; Hiệp, Nguyễn Văn; Luo, Ching Shan; Tseng, Yu Ting; Chen, Tzu Tao; Liu, Wen‐Te; Lee, Kang Yun; Wu, Sheng

doi:10.1007/s10565-021-09612-1

Cited by 5 publications

(7 citation statements)

References 70 publications

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“…We have previously reported that EREG was predominantly expressed in LUAD compared with lung squamous cell carcinoma and that elevated EREG expression was an independent prognostic marker in patients with LUAD [48,49]. Consistent with these findings, several studies have demonstrated that high EREG expression is associated with unfavorable overall survival for patients with LUAD [42,47,50]. Previous survival analyses using TCGA datasets have indicated that patients with LUAD with high EREG expression had significantly shorter survival rates than those with low EREG expression [42,50].…”

Section: Oncogenic Roles Of Ereg In Lung Cancersupporting

confidence: 67%

“…EREG expression was increased in lung tumors induced by the environmental carcinogen of urethane in a murine experimental model [46]. Recently, Chen et al [47] demonstrated that long-term exposure to 3-nitrobenzanthrone, which is a carcinogen in diesel exhaust, promotes malignant transformation in human bronchial epithelial cells through the EREG-mediated activation of the MEK/ERK and PI3K/AKT pathways. This is accompanied by the synergistic activation of IL-6 signaling, leading to lung tumorigenicity.…”

Section: Physiological Role Of Ereg In Human Airway Epithelial Cellsmentioning

confidence: 99%

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Role of Epiregulin in Lung Tumorigenesis and Therapeutic Resistance

Sunaga,

Miura,

Masuda

et al. 2024

Cancers

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Epidermal growth factor (EGF) signaling regulates multiple cellular processes and plays an essential role in tumorigenesis. Epiregulin (EREG), a member of the EGF family, binds to the epidermal growth factor receptor (EGFR) and ErbB4, and it stimulates EGFR-related downstream pathways. Increasing evidence indicates that both the aberrant expression and oncogenic function of EREG play pivotal roles in tumor development in many human cancers, including non-small cell lung cancer (NSCLC). EREG overexpression is induced by activating mutations in the EGFR, KRAS, and BRAF and contributes to the aggressive phenotypes of NSCLC with oncogenic drivers. Recent studies have elucidated the roles of EREG in a tumor microenvironment, including the epithelial–mesenchymal transition, angiogenesis, immune evasion, and resistance to anticancer therapy. In this review, we summarized the current understanding of EREG as an oncogene and discussed its oncogenic role in lung tumorigenesis and therapeutic resistance.

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Section: Oncogenic Roles Of Ereg In Lung Cancersupporting

confidence: 67%

Section: Physiological Role Of Ereg In Human Airway Epithelial Cellsmentioning

confidence: 99%

Role of Epiregulin in Lung Tumorigenesis and Therapeutic Resistance

Sunaga,

Miura,

Masuda

et al. 2024

Cancers

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“…Our recent findings revealed that a potential carcinogen, 3-nitrobenzanthrone (3-NBA), induced the downregulation of p53 protein and the transformation of lung epithelial cells. EREG overexpression markedly led to tumorigenesis in 3-NBA-transformed cells through the activation of PI3K/AKT and MEK/ERK pathways [ 44 ]. Increased levels of EREG activate EGFR downstream pathways and synergistically enhance IL-6/STAT3 signaling in malignant tumor progression [ 45 ].…”

Section: Critical Role Of Ereg In Early Tumor Developmentmentioning

confidence: 99%

The Role of EREG/EGFR Pathway in Tumor Progression

Cheng

Feng

Lee

et al. 2021

IJMS

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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.

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“…However, we cannot exclude the importance of other EGFR ligands in the development of LUAD. Our previous findings revealed that higher EREG expression in LUAD but not LUSC was correlated with shorter OS ( 48 ). In addition, EREG produced by TAMs causes NSCLC cell EGFR-tyrosine kinase inhibitor resistance in the TME ( 49 ).…”

Section: Discussionmentioning

confidence: 94%

Heparin binding epidermal growth factor–like growth factor is a prognostic marker correlated with levels of macrophages infiltrated in lung adenocarcinoma

et al. 2022

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BackgroundThe interactions between tumor cells and the host immune system play a crucial role in lung cancer progression and resistance to treatment. The alterations of EGFR signaling have the potential to produce an ineffective tumor-associated immune microenvironment by upregulating a series of immune suppressors, including inhibitory immune checkpoints, immunosuppressive cells, and cytokines. Elevated Heparin-binding EGF-like growth factor (HB-EGF) expression, one EGFR ligand correlated with higher histology grading, worse patient prognosis, and lower overall survival rate, acts as a chemotactic factor. However, the role of heparin-binding epidermal growth factor-like growth factor (HB-EGF) in the accumulation of immune cells in the tumor microenvironment remains unclear.MethodsThe clinical association of HB-EGF expression in lung cancer was examined using the Gene Expression Omnibus (GEO) repository. HB-EGF expression in different cell types was determined using single-cell RNA sequencing (scRNA-seq) dataset. The correlation between HB-EGF expression and cancer-immune infiltrated cells was investigated by performing TIMER and ClueGo pathways analysis from TCGA database. The chemotaxis of HB-EGF and macrophage infiltration was investigated using migration and immunohistochemical staining.ResultsThe high HB-EGF expression was significantly correlated with poor overall survival in patients with lung adenocarcinoma (LUAD) but not lung squamous cell carcinoma (LUSC). Moreover, HB-EGF expression was correlated with the infiltration of monocytes, macrophages, neutrophils, and dendritic cells in LUAD but not in LUSC. Analysis of scRNA-seq data revealed high HB-EGF expression in lung cancer cells and myeloid cells. Results from the pathway analysis and cell-based experiment indicated that elevated HB-EGF expression was associated with the presence of macrophage and lung cancer cell migration. HB-EGF was highly expressed in tumors and correlated with M2 macrophage infiltration in LUAD.ConclusionsHB-EGF is a potential prognostic marker and therapeutic target for lung cancer progression, particularly in LUAD.

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3-Nitrobenzanthrone promotes malignant transformation in human lung epithelial cells through the epiregulin-signaling pathway

Cited by 5 publications

References 70 publications

Role of Epiregulin in Lung Tumorigenesis and Therapeutic Resistance

Role of Epiregulin in Lung Tumorigenesis and Therapeutic Resistance

The Role of EREG/EGFR Pathway in Tumor Progression

Heparin binding epidermal growth factor–like growth factor is a prognostic marker correlated with levels of macrophages infiltrated in lung adenocarcinoma

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