TGF-beta1 causes epithelial-mesenchymal transition in HaCaT derivatives, but induces expression of COX-2 and migration only in benign, not in malignant keratinocytes

Räsänen, Kati; Vaheri, Antti

doi:10.1016/j.jdermsci.2010.03.002

Cited by 52 publications

(55 citation statements)

References 45 publications

(50 reference statements)

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“…Immunofluorescence staining protocol has been described previously (18). Cells were fixed with Prefer fixative (Anatech, Battle Creek, MI), organotypic reconstructs were fixed with formalin.…”

Section: Methodsmentioning

confidence: 99%

Comparative Secretome Analysis of Epithelial and Mesenchymal Subpopulations of Head and Neck Squamous Cell Carcinoma Identifies S100A4 as a Potential Therapeutic Target

Räsänen

Sriswasdi

Valiga

et al. 2013

Molecular & Cellular Proteomics

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Epithelial-mesenchymal transition (EMT) is a key contributor in tumor progression and metastasis. EMT produces cellular heterogeneity within head and neck squamous cell carcinomas (HNSCC) by creating a phenotypically distinct mesenchymal subpopulation that is resistant to conventional therapies. In this study, we systematically characterized differences in the secretomes of E-cadherin high epithelial-like and E-cadherin low mesenchymal-like subpopulations using unbiased and targeted proteomics. A total 1765 proteins showed significant changes with 177 elevated in the epithelial subpopulation and 173 elevated in the mesenchymal cells. Key nodes in affected networks included NF B, Akt, and ERK, and most implicated cellular components involved various aspects of the extracellular matrix. In particular, large changes were observed in multiple collagens with most affected collagens at much higher abundance levels in the mesenchymal subpopulation. These cells also exhibited a secretome profile resembling that of cancer-associated fibroblastic cells (CAF). S100A4, a commonly used marker for cancer-associated fibroblastic cells, was elevated more than 20-fold in the mesenchymal cells and this increase was further verified at the transcriptome level. S100A4 is a known mediator of EMT, leading to metastasis and EMT has been proposed as a potential source of cancer-associated fibroblastic cells in solid tumors. S100A4 knockdown by small interfering RNA led to decreased expression, secretion and activity of matrix metalloproteinase 2, as verified by quantitative PCR, multiple reaction monitoring and zymography analyses, and reduced invasion in collagen-embedded spheroids. Further confirmation in three-dimensional organotypic reconstructs showed less invasion and advanced differentiation in the S100A4 RNA interference samples. Head and neck squamous cell carcinoma (HNSCC) 1 is the sixth most common cancer worldwide with high morbidity and mortality. Treatment options are limited; surgery, radiation and conventional chemotherapy are generally associated with considerable impairment to quality of life (1). Currently cetuximab, the anti-epidermal growth factor receptor (EGFR) monoclonal antibody, is the only FDA-approved molecularly targeted drug for HNSCC. Several clinical trials are underway that target EGFR or other tyrosine kinases, but many have failed to progress beyond Phase II (2). One reason behind the failure of new treatment options for HNSCC is resistance to therapy, which tumor heterogeneity is thought to provide.

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Section: Methodsmentioning

confidence: 99%

Comparative Secretome Analysis of Epithelial and Mesenchymal Subpopulations of Head and Neck Squamous Cell Carcinoma Identifies S100A4 as a Potential Therapeutic Target

Räsänen

Sriswasdi

Valiga

et al. 2013

Molecular & Cellular Proteomics

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“…Similarly, the upregulation of hepatocyte growth factor (HGF) in hepatocellular carcinoma cells promoted an EMT via COX-2 and protein kinase B (AKT) [92]. Finally, TGF-β induced EMT features COX-2 in benign but not malignant HaCaT keratinocytes [93].…”

Section: Cox-2 Is Associated With Breast Cancer Invasion Via Emtmentioning

confidence: 99%

New Insights on COX-2 in Chronic Inflammation Driving Breast Cancer Growth and Metastasis

Hugo

Saunders

Ramsay

et al. 2015

J Mammary Gland Biol Neoplasia

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The medicinal use of aspirin stretches back to ancient times, before it was manufactured in its pure form in the late 19th century. Its accepted mechanistic target, cyclooxygenase (COX), was discovered in the 1970s and since this landmark discovery, the therapeutic application of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has increased dramatically. The most significant benefits of NSAIDs are in conditions involving chronic inflammation (CI). Given the recognized role of CI in cancer development, the use of long-term NSAID treatment in the prevention of cancer is an enticing possibility. COX-2 is a key driver of CI, and here we review COX-2 expression as a predictor of survival in various cancer types, including breast. Obesity and post-partum involution are natural inflammatory states that are associated with increased breast cancer risk. We outline the COX-2 mediated mechanisms contributing to the growth of cancers. We dissect the cellular mechanism of epithelial-mesenchymal transition (EMT) and how COX-2 may induce this to facilitate tumor progression. Finally we examine the potential regulation of COX-2 by c-Myb, and the possible interplay between c-Myb/COX-2 in proliferation, and hypoxia inducible factor-1 alpha (HIF1α)/COX-2 in invasive pathways in breast cancer.

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“…However, the mechanism behind the malicious activity of COX-2 remains unclear in lung adenocarcinoma. COX-2 is induced in inflammation and neoplasia by EGF, TGFβ, TNFα, hypoxia and UVB light (12)(13)(14)(15)(16) and is inhibited by the NSAIDs, cetuximab and celecoxib (17,18). Among the various regulators of COX-2 expression, p38, ERK1/2 (19), nuclear factor-κB and the activated protein-1 (20) pathways are well-known upstream mediators of COX-2 in inflammation and carcinogenesis (21)(22)(23).…”

Section: Introductionmentioning

confidence: 99%

EGF stimulates cyclooxygenase-2 expression through the STAT5 signaling pathway in human lung adenocarcinoma A549 cells

Cao

Yan²,

Zhang³

et al. 2011

Int J Oncol

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Abstract. The epidermal growth factor receptor (EGFR) can be activated by several growth factors within the tumor microenvironment, and it can activate several signaling pathways. For tumor development, these EGFR-related signaling pathways may converge on several common nuclear transcription factors, one such transcription factor being STAT5. STAT5 plays an important role in the oncogenic signal transduction pathway in non-small cell lung cancer. In this study, we examined whether the epidermal growth factor (EGF) can stimulate cyclooxygenase-2 (COX-2) expression in human lung adenocarcinoma A549 cells transfected with or without STAT5 siRNA or dominant-negative (DN)-STAT5, and identified the pathways involved in this response. We found that STAT5 siRNA significantly reduced EGF-induced COX-2 expression, and STAT5 phosphorylation. STAT5 phosphorylation predominantly mediates EGF-induced COX-2 promoter activity. STAT5 siRNA was found to inhibit COX-2 expression in resting A549 cells despite the absence of detectable activated phosphorylated STAT5. Using an adenoviral system, we expressed DN-STAT5 in human lung adenocarcinoma A549 cells in order to broaden the investigation and to determine the role of STAT5 in EGF-mediated COX-2 gene expression. The overexpression of DN-STAT5 significantly inhibited EGF-induced COX-2 expression, and we found that EGF induced the tyrosine phosphorylation of STAT5 and upregulated COX-2 expression. DN-STAT5 also blocked COX-2 promoter activity. Our results demonstrate that EGF stimulates COX-2 expression in human lung adenocarcinoma A549 cells via the activation of the STAT5 pathway and that COX-2 expression may be independent of phosphorylated STAT5 in A549 cells in vitro.

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TGF-beta1 causes epithelial-mesenchymal transition in HaCaT derivatives, but induces expression of COX-2 and migration only in benign, not in malignant keratinocytes

Cited by 52 publications

References 45 publications

Comparative Secretome Analysis of Epithelial and Mesenchymal Subpopulations of Head and Neck Squamous Cell Carcinoma Identifies S100A4 as a Potential Therapeutic Target

Comparative Secretome Analysis of Epithelial and Mesenchymal Subpopulations of Head and Neck Squamous Cell Carcinoma Identifies S100A4 as a Potential Therapeutic Target

New Insights on COX-2 in Chronic Inflammation Driving Breast Cancer Growth and Metastasis

EGF stimulates cyclooxygenase-2 expression through the STAT5 signaling pathway in human lung adenocarcinoma A549 cells

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