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Paradoxical role of Id proteins in regulating tumorigenic potential of lymphoid cells
Sumedha Roy, Yuan Zhuang
Front. Med.. 2018, 12 (4 ): 374-386.
https://doi.org/10.1007/s11684-018-0652-x
A family of transcription factors known as Id proteins, or inhibitor of DNA binding and differentiation, is capable of regulating cell proliferation, survival and differentiation, and is often upregulated in multiple types of tumors. Due to their ability to promote self-renewal, Id proteins have been considered as oncogenes, and potential therapeutic targets in cancer models. On the contrary, certain Id proteins are reported to act as tumor suppressors in the development of Burkitt’s lymphoma in humans, and hepatosplenic and innate-like T cell lymphomas in mice. The contexts and mechanisms by which Id proteins can serve in such contradictory roles to determine tumor outcomes are still not well understood. In this review, we explore the roles of Id proteins in lymphocyte development and tumorigenesis, particularly with respect to inhibition of their canonical DNA binding partners known as E proteins. Transcriptional regulation by E proteins, and their antagonism by Id proteins, act as gatekeepers to ensure appropriate lymphocyte development at key checkpoints. We re-examine the derailment of these regulatory mechanisms in lymphocytes that facilitate tumor development. These mechanistic insights can allow better appreciation of the context-dependent roles of Id proteins in cancers and improve considerations for therapy.
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Intracellular and extracellular TGF-β signaling in cancer: some recent topics
Kohei Miyazono, Yoko Katsuno, Daizo Koinuma, Shogo Ehata, Masato Morikawa
Front. Med.. 2018, 12 (4 ): 387-411.
https://doi.org/10.1007/s11684-018-0646-8
Transforming growth factor (TGF)-β regulates a wide variety of cellular responses, including cell growth arrest, apoptosis, cell differentiation, motility, invasion, extracellular matrix production, tissue fibrosis, angiogenesis, and immune function. Although tumor-suppressive roles of TGF-β have been extensively studied and well-characterized in many cancers, especially at early stages, accumulating evidence has revealed the critical roles of TGF-β as a pro-tumorigenic factor in various types of cancer. This review will focus on recent findings regarding epithelial-mesenchymal transition (EMT) induced by TGF-β, in relation to crosstalk with some other signaling pathways, and the roles of TGF-β in lung and pancreatic cancers, in which TGF-β has been shown to be involved in cancer progression. Recent findings also strongly suggested that targeting TGF-β signaling using specific inhibitors may be useful for the treatment of some cancers. TGF-β plays a pivotal role in the differentiation and function of regulatory T cells (Tregs). TGF-β is produced as latent high molecular weight complexes, and the latent TGF-β complex expressed on the surface of Tregs contains glycoprotein A repetitions predominant (GARP, also known as leucine-rich repeat containing 32 or LRRC32). Inhibition of the TGF-β activities through regulation of the latent TGF-β complex activation will be discussed.
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The MYC transcription factor network: balancing metabolism, proliferation and oncogenesis
Patrick A. Carroll, Brian W. Freie, Haritha Mathsyaraja, Robert N. Eisenman
Front. Med.. 2018, 12 (4 ): 412-425.
https://doi.org/10.1007/s11684-018-0650-z
Transcription factor networks have evolved in order to control, coordinate, and separate, the functions of distinct network modules spatially and temporally. In this review we focus on the MYC network (also known as the MAX-MLX Network), a highly conserved super-family of related basic-helix-loop-helix-zipper (bHLHZ) proteins that functions to integrate extracellular and intracellular signals and modulate global gene expression. Importantly the MYC network has been shown to be deeply involved in a broad spectrum of human and other animal cancers. Here we summarize molecular and biological properties of the network modules with emphasis on functional interactions among network members. We suggest that these network interactions serve to modulate growth and metabolism at the transcriptional level in order to balance nutrient demand with supply, to maintain growth homeostasis, and to influence cell fate. Moreover, oncogenic activation of MYC and/or loss of a MYC antagonist, results in an imbalance in the activity of the network as a whole, leading to tumor initiation, progression and maintenance.
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Challenges of NK cell-based immunotherapy in the new era
Fang Fang, Weihua Xiao, Zhigang Tian
Front. Med.. 2018, 12 (4 ): 440-450.
https://doi.org/10.1007/s11684-018-0653-9
Natural killer cells (NKs) have a great potential for cancer immunotherapy because they can rapidly and directly kill transformed cells in the absence of antigen presensitization. Various cellular sources, including peripheral blood mononuclear cells (PBMCs), stem cells, and NK cell lines, have been used for producing NK cells. In particular, NK cells that expanded from allogeneic PBMCs exhibit better efficacy than those that did not. However, considering the safety, activities, and reliability of the cell products, researchers must develop an optimal protocol for producing NK cells from PBMCs in the manufacture setting and clinical therapeutic regimen. In this review, the challenges on NK cell-based therapeutic approaches and clinical outcomes are discussed.
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Regulation of T cell immunity by cellular metabolism
Zhilin Hu, Qiang Zou, Bing Su
Front. Med.. 2018, 12 (4 ): 463-472.
https://doi.org/10.1007/s11684-018-0668-2
T cells are an important adaptive immune response arm that mediates cell-mediated immunity. T cell metabolism plays a central role in T cell activation, proliferation, differentiation, and effector function. Specific metabolic programs are tightly controlled to mediate T cell immune responses, and alterations in T cell metabolism may result in many immunological disorders. In this review, we will summarize the main T cell metabolic pathways and the important factors participating in T cell metabolic programming during T cell homeostasis, differentiation, and function.
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Activation of phagocytosis by immune checkpoint blockade
Chia-Wei Li, Yun-Ju Lai, Jennifer L. Hsu, Mien-Chie Hung
Front. Med.. 2018, 12 (4 ): 473-480.
https://doi.org/10.1007/s11684-018-0657-5
Inhibition of macrophage-mediated phagocytosis has emerged as an essential mechanism for tumor immune evasion. One mechanism inhibiting the innate response is the presence of the macrophage inhibitory molecule, signal regulatory protein-α (SIRPα), on tumor-associated macrophages (TAMs) and its cognate ligand cluster of differentiation 47 (CD47) on tumor cells in the tumor microenvironment. On the basis of a recently discovered programmed death protein 1 (PD-1) in TAMs, we discuss the potential inhibitory receptors that possess new functions beyond T cell exhaustion in this review. As more and more immune receptors are found to be expressed on TAMs, the corresponding therapies may also stimulate macrophages for phagocytosis and thereby provide extra anti-tumor benefits in cancer therapy. Therefore, identification of biomarkers and combinatorial therapeutic strategies, have the potential to improve the efficacy and safety profiles of current immunotherapies.
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RNA m6 A modification and its function in diseases
Jiyu Tong, Richard A. Flavell, Hua-Bing Li
Front. Med.. 2018, 12 (4 ): 481-489.
https://doi.org/10.1007/s11684-018-0654-8
N 6 -methyladenosine (m6 A) is the most common post-transcriptional RNA modification throughout the transcriptome, affecting fundamental aspects of RNA metabolism. m6 A modification could be installed by m6 A “writers” composed of core catalytic components (METTL3/METTL14/WTAP) and newly defined regulators and removed by m6 A “erasers” (FTO and ALKBH5). The function of m6 A is executed by m6 A “readers” that bind to m6 A directly (YTH domain-containing proteins, eIF3 and IGF2BPs) or indirectly (HNRNPA2B1). In the past few years, advances in m6 A modulators (“writers,” “erasers,” and “readers”) have remarkably renewed our understanding of the function and regulation of m6 A in different cells under normal or disease conditions. However, the mechanism and the regulatory network of m6 A are still largely unknown. Moreover, investigations of the m6 A physiological roles in human diseases are limited. In this review, we summarize the recent advances in m6 A research and highlight the functional relevance and importance of m6 A modification in in vitro cell lines, in physiological contexts, and in cancers.
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