Early Growth Response-1 Induces and Enhances Vascular Endothelial Growth Factor-A Expression in Lung Cancer Cells

Shimoyamada, Hiroaki; Yazawa, Takuya; Sato, Hidemitsu; Okihara, Koji; Ishii, Jun; Sakaeda, Masashi; Kashiwagi, Kunihiro; Suzuki, Tsuyoshi; Mitsui, Hideaki; Woo, Tetsukan; Tajiri, Michihiko; Ohmori, Takahiro; Ogura, Takashi; Masuda, Munetaka; Oshiro, Hisashi; Kitamura, Hitoshi

doi:10.2353/ajpath.2010.091164

Cited by 57 publications

(58 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In an effort to better understand the mechanisms responsible for these cellular responses, we measured the expression of Egr-1 protein and found that TGZ stimulates the expression of Egr-1 in a concentrationdependent manner. Egr-1 is a member of the immediate early gene response family and encodes a nuclear phosphoprotein involved in the regulation of cell growth and differentiation in response to signals such as mitogens, growth factors and stress stimuli (19)(20)(21). However, evidence suggests that Egr-1 binding sites are located within region -73 to -51 of the NAG-1 promoter, and the overexpression of Egr-1 results in increased NGA-1 expression.…”

Section: Discussionmentioning

confidence: 97%

Troglitazone induces apoptosis in gastric cancer cells through the NAG-1 pathway

Wang

Bai

2010

Mol Med Rep

View full text Add to dashboard Cite

Abstract. The non-steroidal anti-inflammatory drug-activated gene (NAG-1) is a newly identified member of the transforming growth factor (TGF)-β superfamily and plays significant roles in regulating proliferation and pro-apoptotic activities. In the present study, we studied the regulation of NAG-1 by troglitazone in the cultured gastric cancer cell line BGC-823. MTT and TUNEL assays demonstrated that troglitazone potentially inhibits the proliferation of the gastric cancer cell line and induces apoptosis in vitro in a dose-and time-dependent manner. Troglitazone induced concentration-dependent NAG-1 expression in the BGC-823 cells, as assessed using immunocytochemistry. Furthermore, troglitazone increased Egr-1 protein levels in a concentration-dependent manner.In conclusion, the present study suggests that troglitazone markedly impedes proliferation and pro-apoptotic activities in BGC-823 cells, and the mechanism may partly be through the Egr-1 pathway.

show abstract

Section: Discussionmentioning

confidence: 97%

Troglitazone induces apoptosis in gastric cancer cells through the NAG-1 pathway

Wang

Bai

2010

Mol Med Rep

View full text Add to dashboard Cite

show abstract

“…[26][27][28][29][30][31] H1688, H441, and A549 were purchased from the American Type Culture Collection (ATCC, Manassas, VA, USA), and LC2/ad was obtained from the Riken Bioresource Center (Ibaraki, Japan). Non-small-cell lung cancer (NSCLC) cells were cultivated in Dulbecco's modified Eagle's medium, and SCLC cells were cultured in RPMI-1640 medium.…”

Section: Materials and Methods Cultured Lung Cancer Cellsmentioning

confidence: 99%

“…26 The equivalent volume of vehicle, 50% acetic acid for AZA (VCL1) or 100% ethanol for TSA (VCL2), was applied as a control.…”

Section: Bisulfite Sequencingmentioning

confidence: 99%

Neural lineage-specific homeoprotein BRN2 is directly involved in TTF1 expression in small-cell lung cancer

Sakaeda

Sato

Ishii

et al. 2013

Laboratory Investigation

Self Cite

View full text Add to dashboard Cite

Thyroid transcription factor 1 (TTF1) plays crucial roles in thyroid, lung, and developing brain morphogenesis. Because TTF1-expressing neoplasms are generated from organs and tissues that normally express TTF1, such as the thyroid follicular epithelium and peripheral lung airway epithelium, TTF1 is widely used as a cell lineage-specific and diagnostic marker for thyroid carcinomas and for lung adenocarcinomas with terminal respiratory unit (TRU) differentiation. However, among lung neuroendocrine tumors, small-cell carcinomas (small-cell lung cancers (SCLCs)), most of which are generated from the central airway, also frequently express TTF1 at high levels. To clarify how SCLCs express TTF1, we investigated the molecular mechanisms of its expression using cultivated lung cancer cells and focusing upon neural cellspecific transcription factors. Both SCLC cells and lung adenocarcinoma cells predominantly expressed isoform 2 of TTF1, and TTF1 promoter assays in SCLC cells revealed that the crucial region for activation of the promoter, which is adjacent to the transcription start site of TTF1 isoform 2, has potent FOX-, LHX-, and BRN2-binding sites. Transfection experiments using expression vectors for FOXA1, FOXA2, LHX2, LHX6, and BRN2 showed that BRN2 substantially upregulated TTF1 expression, whereas FOXA1/2 weakly upregulated TTF1 expression. BRN2 and FOXA1/2 binding to the TTF1 promoter was confirmed through chromatin immunoprecipitation experiments, and TTF1 expression in SCLC cells was considerably downregulated after BRN2 knockdown. Furthermore, the TTF1 promoter in SCLC cells was scarcely methylated, and immunohistochemical examinations using a series of primary lung tumors indicated that TTF1 and BRN2 were coexpressed only in SCLC cells. These findings suggest that TTF1 expression in SCLC is a cell lineage-specific phenomenon that involves the developing neural cell-specific homeoprotein BRN2.

show abstract

“…14,15 The association between Egr-1 and tumor angiogenesis has been observed in various tumor types. [16][17][18] A DNA-based enzyme and a siRNA that target Egr-1 suppress bFGF expression and tumor angiogenesis and growth in various cancer cell types. [18][19][20][21] In this study, we determined the mechanisms by which IGFBP-3 exerts its IGF-independent antiangiogenic antitumor activity.…”

Section: Introductionmentioning

confidence: 99%

Antiangiogenic antitumor activities of IGFBP-3 are mediated by IGF-independent suppression of Erk1/2 activation and Egr-1–mediated transcriptional events

Kim

Choi

Lee

et al. 2011

Blood

View full text Add to dashboard Cite

Most antiangiogenic therapies currently being evaluated in clinical trials target the vascular endothelial growth factor pathway; however, the tumor vasculature can acquire resistance to vascular endothelial growth factor-targeted therapy by shifting to other angiogenesis mechanisms. Insulin-like growth factor binding protein-3 (IGFBP-3) has been reported to suppress tumor growth and angiogenesis by both IGF-dependent and IGFindependent mechanisms; however, understanding of its IGF-independent mechanisms is limited. We observed that IGFBP-3 blocked tumor angiogenesis and growth in non-small cell lung cancer and head and neck squamous cell carcinoma. Conditioned media from an IGFBP-3-treated non-small cell lung cancer cell line displayed a significantly decreased capacity to induce HUVEC proliferation and aortic sprouting. In cancer cells, IGFBP-3 directly interacted with Erk1/2, leading to inactivation of Erk1/2 and Elk-1, and suppressed transcription of early growth response protein 1 and its target genes, basic fibroblast growth factor and platelet-derived growth factor. These data suggest that IGF-independent Erk1/2 inactivation and decreased IGFBP-3-induced Egr-1 expression block the autocrine and paracrine loops of angiogenic factors in vascular endothelial and cancer cells. Together, these findings provide a molecular framework of IGFBP-3's IGF-independent antiangiogenic antitumor activities. IntroductionAngiogenesis, the formation of new capillaries from existing blood vessels, is essential to carcinogenic processes, including solid tumor formation, growth, invasion, and metastasis. 1 Most tumors can stimulate angiogenesis by switching on the production of numerous cytokines and growth factors, including fibroblast growth factors (FGFs), vascular endothelial growth factors (VEGFs), and platelet-derived growth factors (PDGFs). 2 Several antiangiogenic agents are in various phases of clinical trials for human cancer; however, most of these agents target the VEGF signaling pathway. 3 Therefore, other potential therapeutic agents that block non-VEGF angiogenic pathways need to be evaluated.Insulin-like growth factor-binding protein-3 (IGFBP-3), a member of a family of 6 IGFBPs, has demonstrated antiproliferative, proapoptotic, antiangiogenic, and antimetastatic activity in a variety of cancer cells. [4][5][6][7][8] It may also have IGF-independent antitumor activities through cell-surface or intracellular protein interaction, its nuclear translocation, or its transcriptional regulation. 7,[9][10][11][12] However, the mechanisms that mediate IGFBP-3's IGF-independent antitumor activity have not been clearly defined.The 82-kDa phosphoprotein transcription factor early growth response protein 1 (Egr-1), an immediate early gene product, has been implicated in multiple cellular processes, including cell growth, apoptosis, wound healing, and angiogenesis. Mitogenic stimuli, including serum, PDGF, peptide growth factors, and B-Raf, and nonmitogenic stresses, including ␥-irradiation and hypoxia, activate Egr-1 expre...

show abstract

Early Growth Response-1 Induces and Enhances Vascular Endothelial Growth Factor-A Expression in Lung Cancer Cells

Abstract: Vascular endothelial growth factor-A (VEGF-A

Cited by 57 publications

References 53 publications

Troglitazone induces apoptosis in gastric cancer cells through the NAG-1 pathway

Troglitazone induces apoptosis in gastric cancer cells through the NAG-1 pathway

Neural lineage-specific homeoprotein BRN2 is directly involved in TTF1 expression in small-cell lung cancer

Antiangiogenic antitumor activities of IGFBP-3 are mediated by IGF-independent suppression of Erk1/2 activation and Egr-1–mediated transcriptional events

Contact Info

Product

Resources

About