We recently reported that the accumulation of myeloid-derived suppressor cells (MDSC), defined as CD33+HLA-DR−Lin−, plays a direct role in the pathogenesis of myelodysplastic syndrome (MDS). In particular, CD33 is strongly expressed in MDSC isolated from patients with MDS where it plays an important role in MDSC-mediated hematopoietic suppressive function through its activation by S100A9. Therefore, we tested whether blocking this interaction with a fully human, Fc-engineered monoclonal antibody against CD33 (BI 836858) suppresses CD33-mediated signal transduction and improves the bone marrow microenvironment in MDS. We observed that BI 836858 can reduce MDSC by antibody-dependent cellular cytotoxicity (ADCC), which correlated with increases in granule mobilization and cell death. BI 836858 can also block CD33 downstream signaling preventing immune-suppressive cytokine secretion, which correlates with a significant increase in the formation of CFU-GM and BFU-E colonies. Activation of the CD33 pathway can cause reactive oxygen species (ROS)-induced genomic instability but BI 836858 reduced both ROS and the levels of double strand breaks and adducts (measured by comet assay and γH2AX). This work provides the ground for the development of a novel group of therapies for MDS aimed at MDSC and their disease-promoting properties with the goal of improving hematopoiesis in patients.

Background: Acute kidney injury (AKI) is a severe complication of sepsis; however, no effective drugs have been found. Activation of the nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome is a major pathogenic mechanism of AKI induced by lipopolysaccharide (LPS). Autophagy, a process of intracellular degradation related to renal homeostasis, effectively restricts inflammatory responses. Herein, we explored the potential protective mechanisms of dexmedetomidine (DEX), which has confirmed antiinflammatory effects, on LPS-induced AKI. Methods: AKI was induced in rats by injecting 10 mg/kg of LPS intraperitoneally (i.p.). Wistar rats received intraperitoneal injections of DEX (30 µg/kg) 30 min before an intraperitoneal injection of LPS. Atipamezole (ATI) (250 µg/kg) and 3-methyladenine (3-MA) (15 mg/kg) were intraperitoneally injected 30 min before the DEX injection. Results: DEX significantly attenuated renal injury. Furthermore, DEX decreased activation of the NLRP3 inflammasome and expression of interleukins 1b and 18. In addition, autophagy-related protein and gene analysis indicated that DEX could significantly enhance autophagy. Finally, we verified the pharmacological effects of DEX on the 5′adenosine monophosphate-activated protein kinase (AMPK)/mechanistic target of rapamycin (mTOR) pathway. Atip and 3-MA significantly reversed the protective effects of DEX. Conclusions: Our results suggest that the protective effects of DEX were mediated by enhanced autophagy via the a 2-adrenoreceptor/AMPK/mTOR pathway, which decreased

Inflammatory microenvironment is an important factor for promoting cancer invasion and metastasis, but the underlying molecular mechanisms remain unclear. Here, we mimicked an inflammatory microenvironment both in vitro and in vivo and investigated its effects on the invasion and metastasis of colon cancer. Moreover, colon cancer patient samples were also analyzed statistically. Conditioned medium from the differentiated macrophages induced invasion and migration of colon cancer cells in vitro, which could be reversed by the treatment of a neutralizing anti-growth differentiation factor 15 (GDF15) antibody, indicating GDF15 involvement in inflammation-induced invasiveness. Also, we observed similar effects of human recombinant GDF15 on colon cancer cells. Mechanistically, GDF15 activated c-Fos by separating it from Lamin A/C, increasing transcriptional activity of c-Fos and regulating EMT gene expressions. However, c-Fos knockdown using lentivirus shRNA plasmid inhibited GDF15-triggered invasion and migration in vitro. In vivo, inflammation caused by lipopolysaccharides obviously increased GDF15 secretion, and c-Fos knockdown reduced the lung metastasis of colon cancer cells in mice model. In addition, c-Fos expressions in patient samples were found to be associated with colon cancer metastasis and TNM stages. Taken together, GDF15 in inflammatory microenvironment induces colon cancer invasion and metastasis by regulating EMT genes by activating c-Fos, which might be a potential therapeutic target for metastatic colon cancer. K E Y W O R D S EMT, Erk1/2, Lamin A/C/c-Fos signaling axis, macrophages-derived cytokine Abbreviations: CM, conditioned medium; DAPI, diamidinophenylindole; EMSA, electrophoretic mobility shift assays; EMT, epithelial-mesenchymal transition; GDF15, growth differentiation factor 15; H&E, hematoxylin and eosin; IH C, immunohistochemistry; LPS, lipopolysaccharides; PMA, phorbol 12-myristate 13-acetate; RM, regular medium; TAMs, tumor-associated macrophages. *Youxiang Ding and Kun Hao contributed equally to this work. SUPPORTING INFORMATIONAdditional supporting information may be found online in the Supporting Information section.How to cite this article: Ding Y, Hao K, Li Z, et al. c-Fos separation from Lamin A/C by GDF15 promotes colon cancer invasion and metastasis in inflammatory microenvironment.

Human Hox genes (Homeobox) have crucial roles in development and differentiation, regulating numerous processes including apoptosis, receptor signalling, differentiation, motility and angiogenesis. Aberrant expression of Hoxc6 gene has been reported in several tumor tissues and cancer cell lines. The prognostic significance of Hoxc6 in gastric cancer remains largely unknown.This study was aimed to investigate the clinical significance of Hoxc6 in gastric cancer.Total RNA of paired tissue samples (n=25) and a tissue microarray containing 161 paired tissues from patients with gastric cancers at different stages were collected. Quantitative real-time PCR and immunochemistry assay were carried out to investigate the expression of Hoxc6.Hoxc6 mRNA was increased in gastric cancer tissues ( 16 of 25) compared with the adjacent normal mucosa (P<0.05). Immunohistochemical detection showed that expression of Hoxc6 was associated with the depth of tumor invasion (P<0.05). Patients with higher expression levels of Hoxc6 had a shorter overall survival rate (P<0.05).Hoxc6 might contribute to the progression of gastric carcinogenesis and may be a significant predictor of poor survival in patients with gastric cancer after curative operations.

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