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      Research progress on the forkhead box C1

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          Abstract

          FOXC1 is a vital member of FOX families which play important roles in biological processes including proliferation, differentiation, apoptosis, migration, invasion, metabolism, and longevity. Here we are focusing on roles of FOXC1 and their mechanisms in cancers. FOXC1 promoted progress of many cancers, such as breast cancer (especially basal-like breast cancer), hepatocellular carcinoma, gastric cancer and so on. FOXC1 was also found to be associated with drug resistance of cancers. FOXC1 promoted metastasis of cancers by increasing expression of MMP7, NEDD9 and Snail. Proliferation and invasion of cancers were increased by FOXC1 by mediating NF-κB, MST1R and KLF4 expression. FOXC1 was associated with development by regulating expression of FGF19 and MSX1. Recently, FOXC1 was found to be required for niche of stem cells or development of stem cells by mediating expression of Gli2, CXCL12, SCF, NFATC1, BMP and Myh7. Overall, FOXC1 exerts its functions by many mechanisms and may be used as a potential biomarker for diseases.

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          Forkhead transcription factors: key players in health and disease.

          Reiner Veitia, Bérénice A Benayoun, Sandrine Caburet (2011)
          Forkhead box (FOX) proteins constitute an evolutionarily conserved family of transcription factors with a central role not only during development, but also in the adult organism. Thus, the misregulation and/or mutation of FOX genes often induce human genetic diseases, promote cancer or deregulate ageing. Indeed, germinal FOX gene mutations cause diseases ranging from infertility to language and/or speech disorders and immunological defects. Moreover, because of their central role in signalling pathways and in the regulation of homeostasis, somatic misregulation and/or mutation of FOX genes are associated with cancer. FOX proteins have undergone diversification in terms of their sequence, regulation and function. In addition to dedicated roles, evidence suggests that Forkhead factors have retained some functional redundancy. Thus, combinations of slightly defective alleles might induce disease phenotypes in humans, acting as quantitative trait loci. Uncovering such variants would be a big step towards understanding the functional interdependencies of different FOX members and their implications in complex pathologies. Copyright © 2011 Elsevier Ltd. All rights reserved.
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            Foxc1 is a critical regulator of haematopoietic stem/progenitor cell niche formation.

            Yoshiki Omatsu, Masanari Seike, Tatsuki Sugiyama … (2014)
            Haematopoietic stem and progenitor cells are maintained by special microenvironments known as niches in bone marrow. Many studies have identified diverse candidate cells that constitute niches for haematopoietic stem cells in the marrow, including osteoblasts, endothelial cells, Schwann cells, α-smooth muscle actin-expressing macrophages and mesenchymal progenitors such as CXC chemokine ligand (CXCL)12-abundant reticular (CAR) cells, stem cell factor-expressing cells, nestin-expressing cells and platelet-derived growth factor receptor-α (PDGFR-α)(+)Sca-1(+)CD45(-)Ter119(-) (PαS) cells. However, the molecular basis of the formation of the niches remains unclear. Here we find that the transcription factor Foxc1 is preferentially expressed in the adipo-osteogenic progenitor CAR cells essential for haematopoietic stem and progenitor cell maintenance in vivo in the developing and adult bone marrow. When Foxc1 was deleted in all marrow mesenchymal cells or CAR cells, from embryogenesis onwards, osteoblasts appeared normal, but haematopoietic stem and progenitor cells were markedly reduced and marrow cavities were occupied by adipocytes (yellow adipose marrow) with reduced CAR cells. Inducible deletion of Foxc1 in adult mice depleted haematopoietic stem and progenitor cells and reduced CXCL12 and stem cell factor expression in CAR cells but did not induce a change to yellow marrow. These data suggest a role for Foxc1 in inhibiting adipogenic processes in CAR progenitors. Foxc1 might also promote CAR cell development, upregulating CXCL12 and stem cell factor expression. This study identifies Foxc1 as a specific transcriptional regulator essential for development and maintenance of the mesenchymal niches for haematopoietic stem and progenitor cells.
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              Interleukin-8 Induces Expression of FOXC1 to Promote Transactivation of CXCR1 and CCL2 in Hepatocellular Carcinoma Cell Lines and Formation of Metastases in Mice.

              Wenjie Huang, Zhangqian Chen, Lin Zhang … (2015)
              Inflammation regulated by interleukin (IL) 8 promotes metastasis of hepatocellular carcinoma (HCC). The transcription factor forkhead box C1 (FOXC1) promotes metastasis by activating the epithelial to mesenchymal transition; its levels in liver tumors have been associated with shorter survival times of patients. We investigated whether FOXC1 activates inflammation signaling pathways in HCC cell lines.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Oncotarget
                Journal ID (iso-abbrev): Oncotarget
                Journal ID (publisher-id): Oncotarget
                Journal ID (publisher-id): ImpactJ
                Title: Oncotarget
                Publisher: Impact Journals LLC
                ISSN (Electronic): 1949-2553
                Publication date Collection: 23 February 2018
                Publication date (Electronic): 20 November 2017
                Volume: 9
                Issue: 15
                Pages: 12471-12478
                Affiliations
                1 The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing 100050, China
                2 Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China
                Author notes
                Correspondence to: Jinhua Wang, wjh@ 123456imm.ac.cn
                Article
                Publisher ID: 22527
                DOI: 10.18632/oncotarget.22527
                PMC ID: 5844762
                PubMed ID: 29552326
                SO-VID: 796a6446-f630-4671-b9b3-53c525908f13
                Copyright © Copyright: © 2018 Wang et al.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 29 July 2017
                Date accepted : 1 November 2017
                Categories
                Subject: Review

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: fox family,foxc1,cancer,drug resistance,stem cell
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: fox family, foxc1, cancer, drug resistance, stem cell

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