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The human fallopian tube harbors the cell of origin for the majority of high-grade serous "ovarian" cancers (HGSCs), but its cellular composition, particularly the epithelial component, is poorly characterized. We perform single-cell transcriptomic profiling of around 53,000 individual cells from 12 primary fallopian specimens to map their major cell types. We identify 10 epithelial subpopulations with diverse transcriptional programs. Based on transcriptional signatures, we reconstruct a trajectory whereby secretory cells differentiate into ciliated cells via a RUNX3high intermediate. Computational deconvolution of advanced HGSCs identifies the "early secretory" population as a likely precursor state for the majority of HGSCs. Its signature comprises both epithelial and mesenchymal features and is enriched in mesenchymal-type HGSCs (p = 6.7 × 10-27), a group known to have particularly poor prognoses. This cellular and molecular compendium of the human fallopian tube in cancer-free women is expected to advance our understanding of the earliest stages of fallopian epithelial neoplasia.

Objectives: Systemic sclerosis (SSc) is an autoimmune disease with unknown pathogenesis manifested by inflammation, vasculopathy and fibrosis in skin and internal organs. Type I interferon signature found in SSc propelled us to study plasmacytoid dendritic cells (pDCs) in this disease. We aimed to identify candidate pathways underlying pDC aberrancies in SSc and to validate its function on pDC biology. Methods: In total, 1193 patients with SSc were compared with 1387 healthy donors and 8 patients with localised scleroderma. PCR-based transcription factor profiling and methylation status analyses, single nucleotide polymorphism genotyping by sequencing and flow cytometry analysis were performed in pDCs isolated from the circulation of healthy controls or patients with SSc. pDCs were also cultured under hypoxia, inhibitors of methylation and hypoxia-inducible factors and runt-related transcription factor 3 (RUNX3) levels were determined. To study Runx3 function, Itgax-Cre:Runx3 mice were used in in vitro functional assay and bleomycin-induced SSc skin inflammation and fibrosis model. Results: Here, we show downregulation of transcription factor RUNX3 in SSc pDCs. A higher methylation status of the RUNX3 gene, which is associated with polymorphism rs6672420, correlates with lower RUNX3 expression and SSc susceptibility. Hypoxia is another factor that decreases RUNX3 level in pDC. Mouse pDCs deficient of Runx3 show enhanced maturation markers on CpG stimulation. In vivo, deletion of Runx3 in dendritic cell leads to spontaneous induction of skin fibrosis in untreated mice and increased severity of bleomycin-induced skin fibrosis. Conclusions: We show at least two pathways potentially causing low RUNX3 level in SSc pDCs, and we demonstrate the detrimental effect of loss of Runx3 in SSc model further underscoring the role of pDCs in this disease.

CD8+ T cells are essential for host protection against intracellular pathogens and tumors. During antigen-driven responses, CD8+ T cell fate is governed by transcriptional and epigenetic processes that allow naïve CD8+ T cells to develop into a wide range of effector and conventional memory cell subsets. Over the last decades, novel techniques and major efforts led to a better understanding of the origin, nature, and short- and long-term effects of these processes on individual CD8+ T cells. Under certain conditions, naïve CD8+ T cells can acquire memory phenotype and functions in an antigen-independent manner. Although homeostatic cytokines and initial activation pathways that drive the development of these unconventional memory cells had been identified, the ensuing transcriptional profile of these cells and their degree of similarity with conventional memory cells remained ill-defined. The epigenetic events that accompany unconventional memory formation were also not known.Here, we show that innate memory cells, a type of thymic unconventional memory cells, are transcriptionally close to conventional memory cells but only partially epigenetically programmed toward the full memory fate. We also show that the sole overexpression of the transcription factor Eomesodermin (EOMES), a master regulator of effector and conventional memory cells, is able to drive many of the phenotypical, functional, transcriptional, and epigenetic features of innate memory cells, and to induce the recruitment of BRG1, a member of chromatin remodeling complexes, to innate memory gene regulatory regions. We further show that the in vivo interleukine-4-dependent development of innate memory cells is largely dependent on BRG1. We bring to light that, in innate memory cells, EOMES is recruited in many instances to genomic regions previously bound by the transcription factor RUNX3. Overall, we provide insights into the mechanisms that allow memory cell formation and T cell receptor stimulation, Doctorat en Sciences médicales (Médecine), info:eu-repo/semantics/nonPublished

BACKGROUND/AIM: In genetically engineered murine models of pancreatic ductal adenocarcinomas (PDAC), high levels of Runx3 increase the metastatic potential of cancer cells. In this study we evaluated the role of Runx3 in human pancreatic cancer. MATERIALS AND METHODS: Runx3 was retrospectively assessed by immunohistochemistry in seventy-eight tumor samples of patients who underwent surgical resection for PDCA and were followed at least for 24 months. RESULTS: Thirty-two cases resulted completely negative for Runx3; forty-six showed highly variable expression. We established an optimal cut-off value of Runx3 in predicting distant metastasis equal to 0.04. The odds ratio (ORs) for development of distant metastases at multivariate analysis for patients having Runx3 ≥0.04 was 4.26 (p=0.043) and 4.68 (p=0.032) after adjusting for residual tumor and treatment, respectively; OR for development of metastases in multiple sites was 4.28 (p=0.025) for Runx3 ≥0.04. CONCLUSION: Our results support the ability of Runx3 to contribute to the dissemination of human PDAC thus confirming the observations from murine models.

Thrombospondin-1 (TSP-1), a matricellular protein widely acclaimed to be involved in the inhibition of angiogenesis and tumorigenesis, is synthesized and secreted by many cell types, including osteoblast and cancer cells. TSP-1 is highly upregulated during early stage of osteogenesis, whereas it inhibits terminal osteoblast differentiation. Expression of TSP-1 is downregulated in cancer cells, and its ectopic expression has been shown to restrain tumor growth. Transcriptional regulation of TSP-1 in osteogenesis and cancer is poorly understood; this prompted us to study its regulation by the two key regulators of the aforementioned processes: Runx2 and Runx3. Through a PCR-based cDNA subtraction technique, we identified and cloned a cDNA fragment for mouse TSP-1, whose expression was dramatically upregulated in response to Runx2 expression in mesenchymal stem cells. Moreover, TSP-1 expression was considerably reduced in the lung of Runx2 knockout mouse. On the other hand, TSP-1 gene expression drastically increased at both the transcriptional and translational levels in response to Runx3 expression in B16-F10 melanoma cells. In line with this, Runx2 and Runx3 bound to the TSP-1 promoter and stimulated its activity. Hence, these results provide first line of evidence that TSP-1 is a transcriptional target gene of Runx2 and Runx3., International Journal of Molecular Sciences, 14(7), pp.14321-14332; 2013

Cumulative evidences show that Runt-related transcription factor 3 (RUNX3) has a tumor suppressive role in various cancers. In particular, RUNX3 appears to be an important component of the transforming growth factor-beta (TGF-ß)-induced tumor suppression pathway. Contrary to reports on this tumor suppressive role of RUNX3, RUNX3 can also function as an oncogene when overexpressed. Recently, we found that RUNX3 overexpression was frequently observed and was well correlated with malignant behaviors in head and neck cancer, which is one of the most common types of human cancer. Moreover, it has been revealed that RUNX3 overexpression promoted cell growth and inhibited apoptosis in head and neck cancer cells. This review introduces the oncogenic role of RUNX3 in certain types of cancer including head and neck cancer.

Bone morphogenetic proteins (BMPs), members of the transforming growth factor-beta (TGF-beta) superfamily, are multifunctional cytokines regulating a broad spectrum of biological functions. Recent studies show the presence of BMP receptor 1a mutations in juvenile polyposis and frequent Smad4 mutations in colon cancer, suggesting that aberrations in BMP signaling play an important role in intestinal cancer pathogenesis. However, the exact molecular mechanisms remain poorly understood. The Runt domain transcription factor RUNX3 is an integral component of signaling pathways mediated by TGF-beta and BMPs. RUNX3 is a gastric and colon tumor suppressor, functioning downstream of TGF-beta. Recently, we showed the tumor-suppressive effects of RUNX3 by its ability to attenuate beta-catenin/T-cell factors (TCFs) transactivation in intestinal tumorigenesis. Here, we explore the molecular basis of the tumor-suppressive function of the BMP pathway through RUNX3 in colorectal carcinogenesis. BMP exerted a growth-suppressive effect in HT-29, a human colorectal cancer cell line. c-Myc oncogene was found to be downregulated by BMP and/or RUNX3. We show that upregulation of RUNX3 by BMP reduces c-Myc expression. Evidence is presented suggesting that RUNX3 downregulates c-Myc expression by two parallel pathways-directly at the transcriptional level and through attenuation of beta-catenin/TCFs, downstream of BMPs in colorectal cancer cells., Cancer Research, 70(10), pp.4243-4252; 2010

RUNX proteins are heterodimeric factors that play crucial roles during development and differentiation of cells of the immune system. The RUNX3 transcription factor controls lineage decisions during thymopoiesis and T-cell differentiation, and modulates myeloid cell effector functions. We now report the characterization of the human RUNX3/p33 isoform, generated by splicing out a Runt DNA-binding domain-encoding exon, and whose transcriptional activities differ from those of the prototypic RUNX3/p44 molecule. Unlike RUNX3/p44, RUNX3/p33 is induced upon maturation of monocyte-derived dendritic cells (MDDC), and is unable to transactivate the regulatory regions of the CD11a, CD11c and CD49e integrin genes. Overexpression of RUNX3/p33 in myeloid cell lines led to diminished expression of genes involved in inflammatory responses. Moreover, overexpression of RUNX3/p33 down-modulated the basal level of IL-8 production from immature monocyte-derived dendritic cells (MDDC). Besides, siRNA-mediated knock-down of RUNX3 led to diminished levels of IL-8 RNA in immature MDDC, and modulated the neutrophil-recruiting capacity of myeloid cell line supernatants. Since IL-8 promotes neutrophil chemotaxis and degranulation during inflammatory responses, and exerts mitogenic and angiogenic actions within tumor microenvironment, our results imply that myeloid RUNX3 expression regulates the recruitment of leukocytes towards inflammatory foci and might also contribute to human cancer progression.

A major goal of molecular biology is to elucidate the mechanisms underlying cancer development and progression in order to achieve early detection, better diagnosis and staging and novel preventive and therapeutic strategies. We feel that an understanding of Runt-related transcription factor 3 (RUNX3)-regulated biological pathways will directly impact our knowledge of these areas of human carcinogenesis. The RUNX3 transcription factor is a downstream effector of the transforming growth factor-beta (TGF-beta) signaling pathway, and has a critical role in the regulation of cell proliferation and cell death by apoptosis, and in angiogenesis, cell adhesion and invasion. We previously identified RUNX3 as a major gastric tumor suppressor by establishing a causal relationship between loss of function and gastric carcinogenesis. More recently, we showed that RUNX3 functions as a bona fide initiator of colonic carcinogenesis by linking the Wnt oncogenic and TGF-beta tumor suppressive pathways. Apart from gastric and colorectal cancers, a multitude of epithelial cancers exhibit inactivation of RUNX3, thereby making it a putative tumor suppressor in human neoplasia. This review highlights our current understanding of the molecular mechanisms of RUNX3 inactivation in the context of cancer development and progression., Biochimica et Biophysica Acta - Reviews on Cancer, 1796(2), pp.315-331; 2009

type:text, Runx2 is a transcription factor that belongs to Runx family (Runx1, Runx2, and Runx3). Runx2 interacts with many other transcription factors and co-regulators in the transcriptional regulation of its target genes. Cbfb is one of the co-regulators, forms heterodimers with Runx2, and is required for Runx2-dependent transcriptional regulation. Runx2 is essential for the commitment of multipotent mesenchymal cells into the osteoblastic lineage, because Runx2-deficient mice show complete lack of bone formation due to the absence of osteoblasts. Further, Runx2 inhibits adipocyte differentiation, because Runx2-deficient calvarial cells spontaneously differentiate into adipocytes. Overexpression of Runx2 in osteoblasts inhibits osteoblast maturation but decreased the expression of major bone matrix protein genes. Therefore, Runx2 triggers the gene expression of bone matrix proteins, while keeping the osteoblastic cells in an immature stage. Moreover, Runx2 strongly inhibits the transition of osteoblasts into osteocytes. Runx2 and Runx3 double knockout mice showed that Runx2 and Runx3 have redundant functions in chondrocytes, and that they are essential for chondrocyte maturation. Runx2 directly induces Ihh expression and coordinates the proliferation and differentiation of chondrocytes. Therefore, Runx2 regulates bone formation by regulating osteoblast differentiation as well as chondrocyte maturation.

Runx2 is a transcription factor that belongs to Runx family (Runx1, Runx2, and Runx3). Runx2 interacts with many other transcription factors and co-regulators in the transcriptional regulation of its target genes. Cbfb is one of the co-regulators, forms heterodimers with Runx2, and is required for Runx2-dependent transcriptional regulation. Runx2 is essential for the commitment of multipotent mesenchymal cells into the osteoblastic lineage, because Runx2-deficient mice show complete lack of bone formation due to the absence of osteoblasts. Further, Runx2 inhibits adipocyte differentiation, because Runx2-deficient calvarial cells spontaneously differentiate into adipocytes. Overexpression of Runx2 in osteoblasts inhibits osteoblast maturation but decreased the expression of major bone matrix protein genes. Therefore, Runx2 triggers the gene expression of bone matrix proteins, while keeping the osteoblastic cells in an immature stage. Moreover, Runx2 strongly inhibits the transition of osteoblasts into osteocytes. Runx2 and Runx3 double knockout mice showed that Runx2 and Runx3 have redundant functions in chondrocytes, and that they are essential for chondrocyte maturation. Runx2 directly induces Ihh expression and coordinates the proliferation and differentiation of chondrocytes. Therefore, Runx2 regulates bone formation by regulating osteoblast differentiation as well as chondrocyte maturation.

Sexual dimorphism is an emerging feature of ankylosing spondylitis (AS), a chronic rheumatic condition affecting up to three times more men than women. Using 691 individuals from a Swedish case-control cohort, we revealed that sex biases are also a hallmark of AS genetic predisposition, and that this multifactorial disease is in part driven by both rare and common variants. We identified SNPs via the targeted re-sequencing of 7 270 coding and non-coding loci, and assessed novel patterns of association with both single marker and aggregate loci SKAT tests. The male specific RUNX3 locus (including rs7414934, OR=2.58, p=1.7x10-5) and female specific MICB SKAT locus (27 variants, p=1.2x10-6; rs3828903, OR=4.62, p=6.2x10-13) exceeded discovery thresholds. Multiple risk variants from each locus were shown to be functionally active in immune (Jurkat), skin (HaCat) and bone (SaOS-2) cell lines. Differential patterns of genetic predisposition may point to alternative disease mechanisms in male and female patients. Genetic and functional analyses demonstrated that risk alleles should not be considered in isolation and that associated variants would likely affect gene regulation across multiple tissues. This work illustrates the need to consider the contribution of sex to the genetics of AS and the duality that individual loci may play in the key clinical outcomes of disease.

Runx2 is a transcription factor that belongs to Runx family (Runx1, Runx2, and Runx3). Runx2 interacts with many other transcription factors and co-regulators in the transcriptional regulation of its target genes. Cbfb is one of the co-regulators, forms heterodimers with Runx2, and is required for Runx2-dependent transcriptional regulation. Runx2 is essential for the commitment of multipotent mesenchymal cells into the osteoblastic lineage, because Runx2-deficient mice show complete lack of bone formation due to the absence of osteoblasts. Further, Runx2 inhibits adipocyte differentiation, because Runx2-deficient calvarial cells spontaneously differentiate into adipocytes. Overexpression of Runx2 in osteoblasts inhibits osteoblast maturation but decreased the expression of major bone matrix protein genes. Therefore, Runx2 triggers the gene expression of bone matrix proteins, while keeping the osteoblastic cells in an immature stage. Moreover, Runx2 strongly inhibits the transition of osteoblasts into osteocytes. Runx2 and Runx3 double knockout mice showed that Runx2 and Runx3 have redundant functions in chondrocytes, and that they are essential for chondrocyte maturation. Runx2 directly induces Ihh expression and coordinates the proliferation and differentiation of chondrocytes. Therefore, Runx2 regulates bone formation by regulating osteoblast differentiation as well as chondrocyte maturation.