A targetable HB-EGF–CITED4 axis controls oncogenesis in lung cancer

Hsieh, Chun-Ming; Chou, Yu‐Ting; Kuo, Ming Han; Tsai, Hsiang‐Lin; Chang, Junn Liang; Wu, Cheng‐Wen

doi:10.1038/onc.2016.465

Cited by 15 publications

(17 citation statements)

References 39 publications

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“…Our data showed arsenic exposure caused HB-EGF to stimulate EGFR phosphorylation (p-EGFR) at Tyr 1068 and confirmed HB-EGF was highly expressed in As-T cells and most tumor tissues samples of 35 lung cancer cases. The latter observation consist with study by Yotsumoto and Hsieh that HB-EGF is the predominant EGFR ligand in lung cancer cells and EGFR mutation and that HB-EGF expression predicts poor survival in patients with primary lung tumors ( 35 , 36 ).…”

Section: Discussionmentioning

confidence: 89%

HB-EGF Activates the EGFR/HIF-1α Pathway to Induce Proliferation of Arsenic-Transformed Cells and Tumor Growth

Wang

et al. 2020

Front. Oncol.

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Arsenic was recently identified as a pollutant that is a major cause of lung cancer. Since heparin-binding EGF-like growth factor (HB-EGF) was reported to be a promising therapeutic target for lung cancer, we investigated the role and mechanism of HB-EGF during arsenic-induced carcinogenesis and development of lung cancer. HB-EGF expression were upregulated in As-T cells, lung cancer cell lines, and in most lung cancer tissue samples; and HB-EGF activated the EGFR/p-ERK/HIF-1α pathway and induced VEGF by regulating HIF-1α transcription. HIF-1α transcriptional stimulation by HB-EGF was facilitated by PKM2 and played an important role in HB-EGF's effect on cells. An HB-EGF inhibitor(CRM197, cross-reacting material 197) slowed cell proliferation and inhibited migration of As-T and A549 cells, and inhibited tumor growth. PKM2 also played an important role in the proliferation and migration in As-T cells. The positive staining ratios of EGFR phosphorylation (Y1068) and PKM2 were significantly higher in most cases of lung cancer than in paired normal tumor-adjacent lung tissues; and HB-EGF expression levels strongly correlated with p-EGFR expression levels. Thus, HB-EGF drives arsenic-induced carcinogenesis, tumor growth, and lung cancer development via the EGFR/PKM2/HIF-1α pathway.

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Section: Discussionmentioning

confidence: 89%

HB-EGF Activates the EGFR/HIF-1α Pathway to Induce Proliferation of Arsenic-Transformed Cells and Tumor Growth

Wang

et al. 2020

Front. Oncol.

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“…Heparin-binding epidermal growth factor (HB-EGF) is an epidermal growth factor receptor (EGFR) cognate ligand with mitogenic and chemotactic properties for fibroblasts and smooth muscle cells [262]. H. pylori infection results in the upregulation of HB-EGF gene expression, which is a potential serological biomarker for gastric cancer [263][264][265][266][267].…”

Section: Heparin-binding Epidermal Growth Factor and Matrix Metalloprmentioning

confidence: 99%

Mechanisms of the Epithelial–Mesenchymal Transition and Tumor Microenvironment in Helicobacter pylori-Induced Gastric Cancer

Baj

Korona-Głowniak

Forma

et al. 2020

Cells

118

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Helicobacter pylori (H. pylori) is one of the most common human pathogens, affecting half of the world's population. Approximately 20% of the infected patients develop gastric ulcers or neoplastic changes in the gastric stroma. An infection also leads to the progression of epithelial-mesenchymal transition within gastric tissue, increasing the probability of gastric cancer development. This paper aims to review the role of H. pylori and its virulence factors in epithelial-mesenchymal transition associated with malignant transformation within the gastric stroma. The reviewed factors included: CagA (cytotoxin-associated gene A) along with induction of cancer stem-cell properties and interaction with YAP (Yes-associated protein pathway), tumor necrosis factor α-inducing protein, Lpp20 lipoprotein, Afadin protein, penicillin-binding protein 1A, microRNA-29a-3p, programmed cell death protein 4, lysosomal-associated protein transmembrane 4β, cancer-associated fibroblasts, heparin-binding epidermal growth factor (HB-EGF), matrix metalloproteinase-7 (MMP-7), and cancer stem cells (CSCs). The review summarizes the most recent findings, providing insight into potential molecular targets and new treatment strategies for gastric cancer.

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“…In wound healing assays, cellular damage by the scratch releases ATP, which stimulates the shedding of HB-EGF mediating the transactivation of EGFR ( Yin et al, 2007 ) could drive the differential migration of FBLN1 knockdown cells. Studies have shown FBLN1C binds HB-EGF ( Brooke et al, 2002 ), which is a prominently overexpressed ligand for EGFR in NSCLC ( Hsieh et al, 2017 ; Yotsumoto et al, 2017 ). This could in part contribute to the differential effect FBLN1C has relative to FBLN1D in EGFR dependent migration and wound closure.…”

Section: Discussionmentioning

confidence: 99%

Cell Derived Matrix Fibulin-1 Associates With Epidermal Growth Factor Receptor to Inhibit Its Activation, Localization and Function in Lung Cancer Calu-1 Cells

Harikrishnan

Joshi

Madangirikar

et al. 2020

Front. Cell Dev. Biol.

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Epidermal Growth Factor Receptor (EGFR) is a known promoter of tumor progression and is overexpressed in lung cancers. Growth factor receptors (including EGFR) are known to interact with extracellular matrix (ECM) proteins, which regulate their activation and function. Fibulin-1 (FBLN1) is a major component of the ECM in lung tissue, and its levels are known to be downregulated in non-small cell lung cancers (NSCLC). To test the possible role FBLN1 isoforms could have in regulating EGFR signaling and function in lung cancer, we performed siRNA mediated knockdown of FBLN1C and FBLN1D in NSCLC Calu-1 cells. Their loss significantly increased basal (with serum) and EGF (Epidermal Growth Factor) mediated EGFR activation without affecting net EGFR levels. Overexpression of FBLN1C and FBLN1D also inhibits EGFR activation confirming their regulatory crosstalk. Loss of FBLN1C and FBLN1D promotes EGFR-dependent cell migration, inhibited upon Erlotinib treatment. Mechanistically, both FBLN1 isoforms interact with EGFR, their association not dependent on its activation. Notably, cellderived matrix (CDM) enriched FBLN1 binds EGFR. Calu-1 cells plated on CDM derived from FBLN1C and FBLN1D knockdown cells show a significant increase in EGF mediated EGFR activation. This promotes cell adhesion and spreading with active EGFR enriched at membrane ruffles. Both adhesion and spreading on CDMs is significantly reduced by Erlotinib treatment. Together, these findings show FBLN1C/1D, as part of the ECM, can bind and regulate EGFR activation and function in NSCLC Calu-1 cells. They further highlight the role tumor ECM composition could have in influencing EGFR dependent lung cancers.

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A targetable HB-EGF–CITED4 axis controls oncogenesis in lung cancer

Cited by 15 publications

References 39 publications

HB-EGF Activates the EGFR/HIF-1α Pathway to Induce Proliferation of Arsenic-Transformed Cells and Tumor Growth

HB-EGF Activates the EGFR/HIF-1α Pathway to Induce Proliferation of Arsenic-Transformed Cells and Tumor Growth

Mechanisms of the Epithelial–Mesenchymal Transition and Tumor Microenvironment in Helicobacter pylori-Induced Gastric Cancer

Cell Derived Matrix Fibulin-1 Associates With Epidermal Growth Factor Receptor to Inhibit Its Activation, Localization and Function in Lung Cancer Calu-1 Cells

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