Validation of HB-EGF and amphiregulin as targets for human cancer therapy

Yotsumoto, Fusanori; Yagi, Hiroshi; Suzuki, Satoshi; Oki, Eiji; Tsujioka, Hiroshi; Hachisuga, Touru; Sonoda, Kenzo; Kawarabayashi, Tatsuhiko; Mekada, Eisuke; Miyamoto, Shingo

doi:10.1016/j.bbrc.2007.11.015

Cited by 119 publications

(106 citation statements)

References 34 publications

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“…A significant role for AREG has been established in development and neoplasia (19,37,38). Similar to AGR2, AREG expression has also been detected in esophageal, gastric, breast, lung, stomach, colon, prostate, ovarian, and pancreatic cancers (4,5,(22)(23)(24)(25)(26)(27)(28).…”

Section: Discussionmentioning

confidence: 97%

The Human Adenocarcinoma-associated Gene, AGR2, Induces Expression of Amphiregulin through Hippo Pathway Co-activator YAP1 Activation

Dong¹,

Gupta²,

Pai³

et al. 2011

Journal of Biological Chemistry

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Anterior Gradient Homolog 2 (AGR2) is expressed by the normal intestine and by most human adenocarcinomas, including those derived from the esophagus, pancreas, lung, breast, ovary, and prostate. Xenografts of human adenocarcinoma cell lines in nude mice previously demonstrated that AGR2 supports tumor growth. In addition, AGR2 is able to induce in vitro a transformed phenotype in fibroblast and epithelial cell lines. The mechanism underlying the growth promoting effects of AGR2 is unknown. The present study shows that AGR2 induces expression of amphiregulin (AREG), a growth promoting EGFR ligand. Induced AREG expression in adenocarcinoma cells is able to rescue the transformed phenotype that is lost when AGR2 expression is reduced. Additional experiments demonstrate that AGR2 induction of AREG is mediated by activation of the Hippo signaling pathway co-activator, YAP1. Thus AGR2 promotes growth by regulating the Hippo and EGF receptor signaling pathways. Anterior Gradient Homolog 2 (AGR2)2 encodes a 17 kDa protein that is highly conserved in vertebrates. AGR2 was first described in Xenopus laevis, where its expression is responsible for the development of a glandular organ called the cement gland (1). A significant role in tissue regeneration was established for AGR2 in salamanders where it functions in nerve-dependent limb regeneration (2). AGR2 is also expressed by secretory cells in the normal murine intestine (3). In humans, enhanced AGR2 expression was first described in breast cancer, which was followed by similar observations in most human adenocarcinomas, including those derived from the esophagus, pancreas, lung, ovary, and prostate (4 -11). Both in vitro and in vivo studies demonstrated that AGR2 promotes tumor growth and metastasis (3,6,12). In adenocarcinoma cell lines and nontransformed fibroblasts, AGR2 induces cell proliferation and anchorage-independent growth in soft agar. Human adenocarcinoma cell lines grown in vivo as mouse xenografts result in smaller tumors when AGR2 expression is reduced (3, 6). In vitro studies examining cell migration suggested that AGR2 may function in a non-cell autonomous fashion (3).The mechanisms responsible for AGR2 effects on growth and transformation are unknown. AGR2 expression in humans is restricted to epithelial cells, for which the EGF signaling pathway serves a regulatory role in controlling cell growth. The present study tested the hypothesis that AGR2 affects cell signaling, and potentially that of the EGFR pathway, which has established significance in epithelial cancers. EXPERIMENTAL PROCEDURESCell Lines-H460 lung adenocarcinoma cells obtained from Dr. David Beer (University of Michigan, Ann Arbor, MI) were previously known as SEG-1 and was the focus of a previous publication (3). A recent report revealed that SEG-1 cells are actually H460 lung adenocarcinoma cells (13). The H460 cells used in this study were reassessed by Winand Dinjens, Erasmus Medical Center, Rotterdam, the Netherlands using the Powerplex 16 TM system (Promega Corp., Madison, WI) to...

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Section: Discussionmentioning

confidence: 97%

The Human Adenocarcinoma-associated Gene, AGR2, Induces Expression of Amphiregulin through Hippo Pathway Co-activator YAP1 Activation

Dong¹,

Gupta²,

Pai³

et al. 2011

Journal of Biological Chemistry

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“…Aberrant expression or ectodomain shedding of HB-EGF results in the development of various cancers: ovarian, pancreatic, liver, esophageal, melanoma, colon, gastric, and bladder, together with glioblastoma (9,11). HB-EGF has been demonstrated to promote cancer cell proliferation and migration by binding with EGF receptor (EGFR) or ERBB4 (12).…”

mentioning

confidence: 99%

Lung Cancer-derived Galectin-1 Enhances Tumorigenic Potentiation of Tumor-associated Dendritic Cells by Expressing Heparin-binding EGF-like Growth Factor

Kuo

Huang

Cheng

et al. 2012

Journal of Biological Chemistry

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Background: Communication between cancer cells and immune cells in their microenvironment leads to cancer progression. Results: Lung cancer-derived galectin-1 stimulates HB-EGF expression and triggers a release mechanism in tumor-associated dendritic cells that stimulates tumor cell growth and invasion. Conclusion: The galectin-1/HB-EGF cycle between cancer and dendritic cells enhances lung cancer progression. Significance: Galectin-1 is a potential therapeutic target for inhibiting tumor-promoting immune cells in the tumor microenvironment.

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“…Quantitative real-time PCR RNA extraction, cDNA synthesis, and RT-PCR were conducted as previously described (17). Expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), EGF receptor (EGFR), VEGFA, ANGPTL4, PDGFB, HIF-1a, and NF-kB were detected with Assays-on-Demand primer and probe sets Hs99999905_m1, Hs00193306_m1, Hs00900054_m1, Hs01101127_m1, Hs00966522_m1, Hs00936371_m1, and Hs00765730_m1, respectively (Applied Biosystems).…”

Section: Xenograft Modelmentioning

confidence: 99%

“…The procedures used for TaqMan qRT-PCR analyses and the sequences of the oligonucleotide primer pairs, TaqMan probes for HB-EGF and amphiregulin (AREG; ref. 17). mRNA expression levels for individual genes are represented as relative expression units (REU).…”

Section: Xenograft Modelmentioning

confidence: 99%

“…This processing step is conducted by proteases via a mechanism known as ectodomain shedding. HB-EGF has been focused on as a promising target for many types of cancers, including TNBC (16)(17)(18). NF-kB, a member of the Rel-related proteins that includes p50, p52, v-Rel, c-Rel, RelA (p65), and RelB, is a transcription factor involved in a diversity of cellular processes, including the induction of hypoxia mediated by HB-EGF (19,20).…”

Section: Introductionmentioning

confidence: 99%

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Molecular Hierarchy of Heparin-Binding EGF-like Growth Factor–Regulated Angiogenesis in Triple-Negative Breast Cancer

Yotsumoto

Tokunaga

Oki

et al. 2013

Molecular Cancer Research

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Heparin-binding EGF-like growth factor (HB-EGF) is one of several proangiogenic factors and represents a possible therapeutic target for patients with triple-negative breast cancer (TNBC). However, the role of HB-EGF in promoting tumor aggressiveness in TNBC remains unclear. To investigate specific genes and pathways involved in TNBC tumorigenesis, we profiled gene expression changes in two TNBC cell lines under twodimensional culture (2DC) and three-dimensional culture (3DC) and in a tumor xenograft model. We identified simultaneous upregulation of HB-EGF, VEGFA, and angiopoietin-like 4 (ANGPTL4) in 3DC and tumor xenografts, compared with 2DC. We show that HB-EGF regulates the expression of VEGFA or ANGPTL4 via transcriptional regulation of hypoxia-inducible factor-1a and NF-kB. Furthermore, suppression of VEGFA or ANGPTL4 expression enhanced HB-EGF expression, highlighting a unique regulatory loop underlying this angiogenesis network. Targeted knockdown of HB-EGF significantly suppressed tumor formation in a TNBC xenograft model, compared with individual knockdown of either VEGFA or ANGPTL4, by reducing the expression of both VEGFA and ANGPTL4. In patients with TNBC, VEGFA or ANGPTL4 expression was also significantly correlated with HB-EGF expression. Low concentrations of exogenously added HB-EGF strongly activated the proliferation of endothelial cells, tube formation, and vascular permeability in blood vessels, in a similar fashion to high doses of VEGFA and ANGPTL4. Taken together, these results suggest that HB-EGF plays a pivotal role in the acquisition of tumor aggressiveness in TNBC by orchestrating a molecular hierarchy regulating tumor angiogenesis. Mol Cancer Res; 11(5); 506-17.

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Validation of HB-EGF and amphiregulin as targets for human cancer therapy

Cited by 119 publications

References 34 publications

The Human Adenocarcinoma-associated Gene, AGR2, Induces Expression of Amphiregulin through Hippo Pathway Co-activator YAP1 Activation

The Human Adenocarcinoma-associated Gene, AGR2, Induces Expression of Amphiregulin through Hippo Pathway Co-activator YAP1 Activation

Lung Cancer-derived Galectin-1 Enhances Tumorigenic Potentiation of Tumor-associated Dendritic Cells by Expressing Heparin-binding EGF-like Growth Factor

Molecular Hierarchy of Heparin-Binding EGF-like Growth Factor–Regulated Angiogenesis in Triple-Negative Breast Cancer

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