Abstract
BackgroundS100A8 and S100A9, two heterodimer-forming members of the S100 family, aberrantly express in a variety of cancer types. However, little is known about the mechanism that regulates S100A8/S100A9 co-expression in cancer cells.MethodsThe expression level of S100A8/S100A9 measured in three squamous cell carcinomas (SCC) cell lines and their corresponding xenografts, as well as in 257 SCC tissues. The correlation between S100A8/S100A9, Hippo pathway and F-actin cytoskeleton were evaluated using western blot, qPCR, ChIP and Immunofluorescence staining tests. IncuCyte ZOOM long time live cell image monitoring system, qPCR and Flow Cytometry measured the effects of S100A8/S100A9 and YAP on cell proliferation, cell differentiation and apoptosis.ResultsHere, we report that through activation of the Hippo pathway, suspension and dense culture significantly induce S100A8/S100A9 co-expression and co-localization in SCC cells. Furthermore, these expressional characteristics of S100A8/S100A9 also observed in the xenografts derived from the corresponding SCC cells. Importantly, Co-expression of S100A8/S100A9 detected in 257 SCC specimens derived from five types of SCC tissues. Activation of the Hippo pathway by overexpression of Lats1, knockdown of YAP, as well as disruption of F-actin indeed obviously results in S100A8/S100A9 co-expression in attached SCC cells. Conversely, inhibition of the Hippo pathway leads to S100A8/S100A9 co-expression in a manner opposite of cell suspension and dense. In addition, we found that TEAD1 is required for YAP-induced S100A8/S100A9-expressions. The functional studies provide evidence that knockdown of S100A8/S100A9 together significantly inhibit cell proliferation but promote squamous differentiation and apoptosis.ConclusionsOur findings demonstrate for the first time that the expression of S100A8/S100A9 is inducible by changes of cell shape and density through activation of the Hippo pathway in SCC cells. Induced S100A8/S100A9 promoted cell proliferation, inhibit cell differentiation and apoptosis.
Highlights
S100A8 and S100A9, two heterodimer-forming members of the S100 family, aberrantly express in a variety of cancer types
The percentage of S100A8/S100A9-positive cells increased from less than 1% under normal culture conditions to above 40% after dense 2 days (Fig. 1g) and significantly decreased after the dense cells were reseeded at the pre-dense density and returned to the original ratio after three cell passages (Additional file 2: Figure S1)
S100A8/S100A9 inhibits cell apoptosis induced by suspension and dense culture Because suspension and dense culture leads to cell apoptosis, even for cancer cells, we explore the function of S100A8/S100A9 in suspended and dense squamous cell carcinomas (SCC) cells
Summary
S100A8 and S100A9, two heterodimer-forming members of the S100 family, aberrantly express in a variety of cancer types. It is important to identify the molecules that inhibit the aberrant proliferation of SCC, as it may help in improve the clinical treatments of SCCs. S100A8 (calgranulin A) and S100A9 (calgranulin B), two heterodimer-forming members of the S100 family, were originally discovered as immunogenic proteins expressed and secreted by neutrophils [2]. Aberrant expression of S100A8/S100A9 complex was detected in a variety of cancer tissues, including in squamous cell carcinomas of the esophagus, oral cavity, and cervix [2, 12,13,14,15]. Few studies have investigated whether S100A8/ S100A9 displayed co-expressions in SCC tissues and how these two proteins regulated in SCC cells
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