Transcript and proteome analysis reveals reduced expression of calgranulins in head and neck squamous cell carcinoma

Ely, Mariana Roesch; Nees, Matthias; Karsai, Syrus; Mägele, Ira; Bogumil, Ralf; Vorderwülbecke, Sonja; Ruess, Alexandra; Dietz, Andreas; Schnölzer, Martina; Bosch, Franz X.

doi:10.1016/j.ejcb.2005.01.003

Cited by 42 publications

(32 citation statements)

References 30 publications

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“…From our current findings, reduced levels of S100A8/A9 and resulting loss of function de-regulates growth in SCCs and would contribute to carcinogenesis. S100A8/A9 levels are generally low or not detectable in squamous carcinoma cells, whereas in inflammatory or hyperproliferative oral lesions and HNSCC tissues, S100A8/A9 complex is markedly down-regulated at both mRNA and protein levels compared to normal mucosa [31], [32]. Consistent with these findings, we found that HNSCC show approximately 10-fold lower S100A8 and S100A9 gene expression than NAT.…”

Section: Discussionsupporting

confidence: 86%

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S100A8/A9 (Calprotectin) Negatively Regulates G2/M Cell Cycle Progression and Growth of Squamous Cell Carcinoma

et al. 2013

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Malignant transformation results in abnormal cell cycle regulation and uncontrolled growth in head and neck squamous cell carcinoma (HNSCC) and other cancers. S100A8/A9 (calprotectin) is a calcium-binding heterodimeric protein complex implicated in cell cycle regulation, but the specific mechanism and role in cell cycle control and carcinoma growth are not well understood. In HNSCC, S100A8/A9 is downregulated at both mRNA and protein levels. We now report that downregulation of S100A8/A9 correlates strongly with a loss of cell cycle control and increased growth of carcinoma cells. To show its role in carcinogenesis in an in vitro model, S100A8/A9 was stably expressed in an S100A8/A9-negative human carcinoma cell line (KB cells, HeLa-like). S100A8/A9 expression increases PP2A phosphatase activity and p-Chk1 (Ser345) phosphorylation, which appears to signal inhibitory phosphorylation of mitotic p-Cdc25C (Ser216) and p-Cdc2 (Thr14/Tyr15) to inactivate the G2/M Cdc2/cyclin B1 complex. Cyclin B1 expression then downregulates and the cell cycle arrests at the G2/M checkpoint, reducing cell division. As expected, S100A8/A9-expressing cells show both decreased anchorage-dependent and -independent growth and mitotic progression. Using shRNA, silencing of S100A8/A9 expression in the TR146 human HNSCC cell line increases growth and survival and reduces Cdc2 inhibitory phosphorylation at Thr14/Tyr15. The level of S100A8/A9 endogenous expression correlates strongly with the reduced p-Cdc2 (Thr14/Tyr14) level in HNSCC cell lines, SCC-58, OSCC-3 and UMSCC-17B. S100A8/A9-mediated control of the G2/M cell cycle checkpoint is, therefore, a likely suppressive mechanism in human squamous cell carcinomas and may suggest new therapeutic approaches.

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Section: Discussionsupporting

confidence: 86%

“…S100A8/A9 protein expression is reduced in HNSCC as reported previously [31], [32]. In this study, we compared the expression of S100A8 and S100A9 subunit genes in matching HNSCC and normal adjacent (NAT) tissues using real-time quantitative reverse-transcription polymerase chain reaction (qRT-PCR).…”

Section: Resultsmentioning

confidence: 80%

S100A8/A9 (Calprotectin) Negatively Regulates G2/M Cell Cycle Progression and Growth of Squamous Cell Carcinoma

et al. 2013

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“…In this regard, it is of interest that human squamous cell tumors of head and neck, nasopharyngeal, esophageal and cervical tumors are derived from epithelial tissues where there is constitutive expression of S100A8/A9, but where downregulation of expression is characteristic of the cancers. Thus, in both human cancers and in mouse models, the effects of S100A8/A9 proteins appear to have varying “model‐dependent” outcomes.…”

Section: Discussionmentioning

confidence: 99%

S100A9 has a protective role in inflammation‐induced skin carcinogenesis

McNeill

Hogg

2014

Intl Journal of Cancer

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The S100A8/A9 heterodimer is expressed by myeloid cells where its function has been extensively investigated. Immune cell S100A8/A9 promotes proinflammatory effects, and its absence is often associated with lack of leukocyte recruitment resulting in protection in terms of disease progression. S100A8/A9 is also expressed by certain epithelia, either constitutively as in mucosal epithelia or following stimulation as in skin keratinocytes. The role of the heterodimer in this context has not been as frequently explored. In this study, the incidence of skin papillomas induced by 7,12-dimethylbenz(a)anthracene (DMBA)/ 12-O-tetradecanoylphorbol-13-acetate (TPA) in S100a9 2/2 mice has been investigated. Unlike the immune disorders and certain models of cancer, absence of S100A8/A9 caused an increased incidence in skin of papillomas and, subsequently, squamous cell carcinomas. Although associated in S100a9 2/2 mice with increased recruitment of neutrophils and T cells, a bone marrow chimera experiment revealed the major defect to be primarily due to the absence of S100A8/A9 in the skin keratinocytes. S100a9 2/2 skin displayed enhanced Ki-67 expression over the time period of appearance of the papillomas suggesting an effect of S100A8/A9 in regulating proliferation in the epidermal layer. Thus, despite immune cell recruitment in S100a9 2/2 mouse skin that might have been predicted to promote tumor growth, it was the absence of S100A8/A9 in skin keratinocytes that dominated in terms of papilloma formation. The study highlights the importance of the S100A8/A9-expressing skin epidermal layer in controlling skin tumor formation and suggests that the influence of the heterodimer is dependent on the tissue context in which it is expressed.The S100A8/A9 heterodimer (MRP-8/MRP-14, calprotectin and calgranulin A/B) belongs to a family of 20 small Ca 21 -binding proteins that are coded for in the epithelial differentiation complex on human chromosome 1q21 and 3qF1-F2, the orthologous region in the mouse. 1-4 The heterodimer is constitutively expressed in myeloid cells such as neutrophils, monocytes, dendritic cells and platelets, with the level in neutrophil cytosolic protein constituting an abundance of 45%. 5 S100A8/ A9 is also constitutively expressed in certain mucosal epithelia and in other epithelial tissues such as skin under conditions of inflammation or injury. 6,7 Complex carbohydrates such as carboxylated glycans and heparan sulfate are bound by S100A8/ A9. 8,9 The glycans decorate receptor of advanced glycation end Products (RAGE) that acts as one well-studied type of target ligand. 10 S100A8/A9 also serves as a coreceptor of the toll-like receptor TLR4-MD2 complex enhancing the response to endotoxin lipopolysaccharide (LPS). 11 Mechanistic analysis has focused on myeloid cells with studies making use of the S100a9 2/2 mouse, which lacks not only S100A9 but also the protein of its partner S100A8 which is unstable in the absence of S100A9. 12,13 In these models, S100A8/ A9 is frequently associated with proinflammatory ef...

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“…In these squamous mucosal cancers, decreased S100A8/A9 and loss of cellular differentiation correlate and are inversely related to proliferation. Conversely, S100A8/A9 expressing SCCs appear less aggressive (Wang et al, 2004; Roesch et al, 2005; Sewell et al, 2007). …”

Section: Introductionmentioning

confidence: 99%

S100A8/A9 regulates MMP-2 expression and invasion and migration by carcinoma cells

Silva

Argyris

Zou

et al. 2014

The International Journal of Biochemistry & Cell Biology

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Intracellular calprotectin (S100A8/A9) functions in the control of the cell cycle checkpoint at G2/M. Dysregulation of S100A8/A9 appears to cause loss of the checkpoint, which frequently characterizes head and neck squamous cell carcinoma (HNSCC). In the present study, we analyzed carcinoma cells for other S100A8/A9-directed changes in malignant phenotype. Using a S100A8/A9-negative human carcinoma cell line (KB), transfection to express S100A8 and S100A9 caused selective down-regulation of MMP-2 and inhibited in vitro invasion and migration. Conversely, silencing of endogenous S100A8 and S100A9 expression in TR146 cells, a well-differentiated HNSCC cell line, increased MMP-2 activity and in vitro invasion and migration. When MMP-2 expression was silenced, cells appeared to assume a less malignant phenotype. To more closely model the architecture of cell growth in vivo, cells were grown in a 3D collagen substrate, which was compared to 2D. Growth on 3D substrates caused greater MMP-2 expression. Whereas hypermethylation of CpG islands occurs frequently in HNSCC, S100A8/A9-dependent regulation of MMP-2 could not be explained by modification of the upstream promoters of MMP2 or TIMP2. Collectively, these results suggest that intracellular S100A8/A9 contributes to the cancer cell phenotype by modulating MMP-2 expression and activity to regulate cell migration and mobility.

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Transcript and proteome analysis reveals reduced expression of calgranulins in head and neck squamous cell carcinoma

Cited by 42 publications

References 30 publications

S100A8/A9 (Calprotectin) Negatively Regulates G2/M Cell Cycle Progression and Growth of Squamous Cell Carcinoma

S100A8/A9 (Calprotectin) Negatively Regulates G2/M Cell Cycle Progression and Growth of Squamous Cell Carcinoma

S100A9 has a protective role in inflammation‐induced skin carcinogenesis

S100A8/A9 regulates MMP-2 expression and invasion and migration by carcinoma cells

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