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Tumor‐associated macrophages (TAMs) are crucial components of the tumor microenvironment. They play vital roles in hepatocellular carcinoma (HCC) progression. However, the interactions between TAMs and HCC cells have not been fully characterized. In this study, TAMs were induced using human monocytic cell line THP‐1 cells in vitro to investigate their functions in HCC progression. S100 calcium‐binding protein A9 (S100A9), an inflammatory microenvironment‐related secreted protein, was identified to be significantly upregulated in TAMs. S100A9 expression in tumor tissues was associated with poor survival of HCC patients. It could enhance the stem cell‐like properties of HepG2 and MHCC‐97H cells by activating nuclear factor‐kappa B signaling pathway through advanced glycosylation end product‐specific receptor in a Ca2+‐dependent manner. Furthermore, we found that, after treatment with S100A9, HepG2 and MHCC‐97H cells recruited more macrophages via chemokine (CC motif) ligand 2, which suggests a positive feedback between TAMs and HCC cells. Taken together, our findings reveal that TAMs could upregulate secreted protein S100A9 and enhance the stem cell‐like properties of HCC cells and provide a potential therapeutic target for combating HCC. What's new? Prognosis of hepatocellular carcinoma (HCC) is influenced by tumor‐associated macrophages (TAMs) in the tumor microenvironment. Little is known, however, about how TAMs fuel HCC progression. This comparative analysis of RNA‐sequencing and whole‐genome expression profiling between TAMs and nonactivated M0 macrophages identified three common upregulated genes with potential impact on HCC prognosis. Among them, S100 calcium binding protein A9 (S100A9) was found to enhance stem cell‐like properties in HCC cells, via Ca2+‐dependent signaling along the AGER/NF‐κB axis. Moreover, S100A9 increased TAM infiltration by facilitating CCL2 secretion. The findings warrant further investigation of S100A9 secretion and enhanced HCC cell stemness by TAMs. [ABSTRACT FROM AUTHOR]

The aberrant expression of S100A8 and S100A9 is linked to nonresolving inflammation and ultimately to carcinogenesis, whereas the underlying mechanism that allows inflammation to progress to specific cancer types remains unknown. Here, we report that S100A8 was induced by inflammation and then promoted colorectal tumorigenesis downstream by activating Id3 (inhibitor of differentiation 3). Using gene expression profiling and immunohistochemistry, we found that both S100A8 and S100A9 were upregulated in the chemically-induced colitis-associated cancer mouse model and in human colorectal cancer specimens. Furthermore, we showed that S100A8 and S100A9 acted as chemoattractant proteins by recruiting macrophages, promoting the proliferation and invasion of colon cancer cell, as well as spurring the cycle that culminates in the acceleration of cancer metastasis in a nude mouse model. S100A8 regulated colon cancer cell cycle and proliferation by inducing Id3 expression while inhibiting p21. Id3 expression was regulated by Smad5, which was directly phosphorylated by Akt1. Our study revealed a novel mechanism in which inflammation-induced S100A8 promoted colorectal tumorigenesis by acting upstream to activate the Akt1-Smad5-Id3 axis. [ABSTRACT FROM AUTHOR]

S100/calgranulins (S100A8, S100A9 and S100A12) are key players of innate immune function and elevated levels are a characteristic feature of acute and chronic inflammation, and inflammation-associated carcinogenesis. However, reduced S100A8 and S100A9 expression has been detected for squamous cell carcinoma, including the head and neck region (HNSCC), which originate from mucosal epithelia with abundant expression of both proteins under physiological conditions. In contrast to S100A8 and S100A9, only sparse information is available for S100A12 and a comparative study of all three S100/calgranulins in HNSCC is still missing. We analyzed S100/calgranulin protein levels in a retrospective patient cohort ( n = 131) of oropharyngeal squamous cell carcinoma (OPSCC) by immunohistochemical staining of tissue microarrays. Common characteristics of all three S100/calgranulins were: ( i) abundant expression in supra-basal keratinocytes of normal mucosa with predominant nuclear staining, ( ii) low expression in 30.4-51.9% of primary OPSCCs and ( iii) variable accumulation of S100/calgranulin-positive immune cells in the tumor stroma. These features were associated with histopathological characteristics, such as tumor grade, lymph node metastasis and tumor stage. Furthermore, univariate and multivariate analysis revealed worse overall survival of OPSCC patients with simultaneous reduction of S100A8 and S100A12 expression, while expression of S100A9 or presence of the S100A8/S100A9 heterodimer had no impact, suggesting distinct regulation and function of individual S100/calgranulins in the pathogenesis of HNSCCs. [ABSTRACT FROM AUTHOR]

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−/− 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−/− 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−/− 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−/− 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. [ABSTRACT FROM AUTHOR]

In our study, we for the first time assessed the association of galectin-7 and S100A9 with clinicopathological variables and survival outcomes in cervical squamous carcinoma patients and explored the underlying molecular mechanisms in cervical squamous carcinoma cell lines. Immunohistochemical analysis of 243 patient samples showed that the positive staining rate for galectin-7 and S100A9 gradually decreased from normal cervical tissue to intraepithelial neoplasia and to cervical squamous carcinoma. Both galectin-7 and S100A9 showed significant negative association with lymph node metastasis and staging of cervical squamous carcinoma. Cervical squamous carcinoma patients with negative staining of galectin-7 or S100A9 showed significantly lower 5-year overall survival rate than those with positive staining. Multivariate analysis with the Cox's proportional hazards model indicated that both galectin-7 and S100A9 had significant protective effect on cervical squamous carcinoma patients. Subsequent in vitro study in SiHa and C-33A human cervical squamous carcinoma cell lines revealed that knocking down galectin-7 or S100A9 enhanced tumor cell invasion and tumor cell viability against paclitaxel-induced apoptotic stress, likely through increasing the matrix metalloproteinase-9 expression and activating the phosphatidylinositol 3-kinase/Akt signaling pathway, respectively. Knocking down both galectin-7 and S100A9 produced a synergistic effect, with galectin-7 displaying more significant and consistent protective effects than S100A9 on cervical squamous carcinoma cells. In summary, our study for the first time provides clinicopathological and in vitro evidence showing that both galectin-7 and S100A9 play important protective roles in cervical squamous carcinoma, which provides fresh insights into the biology of cervical squamous carcinoma. [ABSTRACT FROM AUTHOR]

S100A8 and S100A9, two heterodimer-forming members of the cytosolic S100 Ca2+ signaling protein family, are overexpressed in various cancer types, including prostate cancer. They act as proinflammatory danger signals when secreted to the extracellular space and are thought to play an important role during tumorigenesis, affecting inflammatory processes, proliferation, invasion and metastasis of tumor cells. Despite this fact, little is known about tumor environmental factors influencing S100A8/A9 expression. The aim of this study was to test the effect of hypoxia and its master transcriptional regulator hypoxia-inducible factor 1 (HIF-1) on S100A8/A9 expression. Hypoxia treatment resulted in induction of S100A8/A9 protein and mRNA expression in prostate epithelial BPH-1 cells, the latter was also confirmed in the prostate cancer cell lines PC-3 and DU-145. Furthermore, overexpression of HIF-1α caused increase in S100A8/A9 protein and mRNA expression as well as secretion. Functional hypoxia response elements mediating promoter activation on HIF-1α overexpression were identified within the S100A8 and S100A9 promoters using promoter luciferase reporter constructs. Binding of HIF-1α to S100A8 and S100A9 promoters was confirmed by chromatin immunoprecipitation. Immunohistochemical analysis of a prostate cancer tissue array showed clear correlation of S100A8 and S100A9 with HIF-1α expression. Multivariate proportional hazard analysis revealed association of high S100A9 level with time to prostate cancer recurrence. In conclusion, we identified hypoxia and HIF-1 as novel regulators of S100A8/A9 expression in prostate cancer. S100A9 might be useful as prognostic marker for prostate cancer recurrence after radical prostatectomy. [ABSTRACT FROM AUTHOR]