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TGF-β Signaling in Human Disease
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TGF-β Signaling in Human Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 5014

Special Issue Editor

Dr. Jun-ichi Hanai

E-Mail Website
Guest Editor
Department of Medicine, Massachusetts General Hospital, Center for Cancer Research, Harvard Medical School, Boston, MA 02215, USA
Interests: pathological stem cells; cancer biology; fibrosis and cellular plasticity; EMT; TGF-b signaling; epigenetics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

TGF-β superfamily ligands signal via cell-surface serine/threonine kinase receptors to intracellular Smad proteins, which in turn accumulate in the nucleus to regulate gene expression. Smad-independent pathways are also employed in a cell-specific manner to transduce TGF-β signals. Ligand access to the signaling receptors is regulated by numerous secreted agonists and antagonists and by membrane-associated co-receptors that act in a context-dependent manner.

TGF-β superfamily members play key roles throughout development and later in adult homeostasis to orchestrate complex processes. Consistent with their diverse functions, aberrant signaling by members of the TGF-β superfamily is associated with a wide range of human pathologies, including immune system compromise, cardiovascular and fibrotic diseases, aging processes and, critically, cancer. The knowledge of this superfamily is expanding into previously uncharted areas of biology and human pathogenesis. This Special Issue will focused on the mechanisms of aberrations in this signaling pathway that lead to development of human disease pathologies.

Dr. Jun-ichi Hanai
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • signaling crosstalk
  • EMT
  • EndoMT
  • tissue morphogenesis and plasticity
  • oncogenic stem cells (cancer initiating cells)
  • tissue microenvironment dynamics
  • epigenetic regulation
  • aging

Published Papers (3 papers)

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Research

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13 pages, 3466 KiB  
Article
The TGF-β/UCHL5/Smad2 Axis Contributes to the Pathogenesis of Placenta Accreta
by Kei Hashimoto, Yuko Miyagawa, Saya Watanabe, Kazuki Takasaki, Miki Nishizawa, Keita Yatsuki, Yuko Takahashi, Hideo Kamata, Chikara Kihira, Haruko Hiraike, Yukifumi Sasamori, Koichiro Kido, Eiji Ryo and Kazunori Nagasaka
Int. J. Mol. Sci. 2023, 24(18), 13706; https://doi.org/10.3390/ijms241813706 - 5 Sep 2023
Cited by 2 | Viewed by 1071
Abstract
Placenta accreta is a high-risk condition causing obstetric crisis and hemorrhage; however, its pathogenesis remains unknown. We aimed to identify the factors contributing to trophoblast invasiveness and angiogenic potential, which in turn drive the pathogenesis of placenta accreta. We focused on the transforming [...] Read more.
Placenta accreta is a high-risk condition causing obstetric crisis and hemorrhage; however, its pathogenesis remains unknown. We aimed to identify the factors contributing to trophoblast invasiveness and angiogenic potential, which in turn drive the pathogenesis of placenta accreta. We focused on the transforming growth factor (TGF)-β1-Smad pathway and investigated the intrinsic relationship between the time- and dose-dependent inhibition of the ubiquitinating enzyme UCHL5 using bAP15, a deubiquitinase inhibitor, after TGF-β1 stimulation and the invasive and angiogenic potential of two cell lines, gestational choriocarcinoma cell line JEG-3 and trophoblast cell line HTR-8/SVneo. UCHL5 inhibition negatively regulated TGF-β1-induced Smad2 activation, decreasing extravillous trophoblast invasiveness. Smad1/5/9 and extracellular signal-regulated kinase (ERK) were simultaneously activated, and vascular endothelial growth factor was secreted into the trophoblast medium. However, extravillous trophoblast culture supernatant severely impaired the vasculogenic potential of human umbilical vein endothelial cells. These results suggest that the downstream ERK pathway and Smad1/5/9 potentially regulate the TGF-β1-Smad pathway in extravillous trophoblasts, whereas Smad2 contributes to their invasiveness. The abnormal invasive and angiogenic capacities of extravillous cells, likely driven by the interaction between TGF-β1-Smad and ERK pathways, underlie the pathogenesis of placenta accreta. Full article
(This article belongs to the Special Issue TGF-β Signaling in Human Disease)
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13 pages, 6299 KiB  
Article
TGF-β-3 Induces Different Effects from TGF-β-1 and -2 on Cellular Metabolism and the Spatial Properties of the Human Trabecular Meshwork Cells
by Megumi Watanabe, Tatsuya Sato, Yuri Tsugeno, Megumi Higashide, Masato Furuhashi and Hiroshi Ohguro
Int. J. Mol. Sci. 2023, 24(4), 4181; https://doi.org/10.3390/ijms24044181 - 20 Feb 2023
Cited by 5 | Viewed by 1534
Abstract
To compare the effects among three TGF-β isoforms (TGF-β-1, TGF-β-2, and TGF-β-3) on the human trabecular meshwork (HTM), two-dimensional (2D) and three-dimensional (3D) cultures of commercially available certified immortalized HTM cells were used, and the following analyses were conducted: (1) trans-endothelial electrical resistance [...] Read more.
To compare the effects among three TGF-β isoforms (TGF-β-1, TGF-β-2, and TGF-β-3) on the human trabecular meshwork (HTM), two-dimensional (2D) and three-dimensional (3D) cultures of commercially available certified immortalized HTM cells were used, and the following analyses were conducted: (1) trans-endothelial electrical resistance (TEER) and FITC dextran permeability measurements (2D); (2) a real-time cellular metabolic analysis (2D); (3) analysis of the physical property of the 3D HTM spheroids; and (4) an assessment of the gene expression levels of extracellular matrix (ECM) components (2D and 3D). All three TGF-β isoforms induced a significant increase in TEER values and a relative decrease in FITC dextran permeability in the 2D-cultured HTM cells, but these effects were the most potent in the case of TGF-β-3. The findings indicated that solutions containing 10 ng/mL of TGF-β-1, 5 ng/mL of TGF-β-2, and 1 ng/mL of TGF-β-3 had nearly comparable effects on TEER measurements. However, a real-time cellular metabolic analysis of the 2D-cultured HTM cells under these concentrations revealed that TGF-3-β induced quite different effects on the metabolic phenotype, with a decreased ATP-linked respiration, increased proton leakage, and decreased glycolytic capacity compared with TGF-β-1 and TGF-β-2. In addition, the concentrations of the three TGF-β isoforms also caused diverse effects on the physical properties of 3D HTM spheroids and the mRNA expression of ECMs and their modulators, in many of which, the effects of TGF-β-3 were markedly different from TGF-β-1 and TGF-β-2. The findings presented herein suggest that these diverse efficacies among the TGF-β isoforms, especially the unique action of TGF-β-3 toward HTM, may induce different effects within the pathogenesis of glaucoma. Full article
(This article belongs to the Special Issue TGF-β Signaling in Human Disease)
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Review

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16 pages, 1407 KiB  
Review
TGF-β Signaling in Progression of Oral Cancer
by Yuanyuan Guo, Tiansong Xu, Yujuan Chai and Feng Chen
Int. J. Mol. Sci. 2023, 24(12), 10263; https://doi.org/10.3390/ijms241210263 - 17 Jun 2023
Cited by 5 | Viewed by 1981
Abstract
Oral cancer is a common malignancy worldwide, accounting for 1.9% to 3.5% of all malignant tumors. Transforming growth factor β (TGF-β), as one of the most important cytokines, is found to play complex and crucial roles in oral cancers. It may act in [...] Read more.
Oral cancer is a common malignancy worldwide, accounting for 1.9% to 3.5% of all malignant tumors. Transforming growth factor β (TGF-β), as one of the most important cytokines, is found to play complex and crucial roles in oral cancers. It may act in a pro-tumorigenic and tumor-suppressive manner; activities of the former include cell cycle progression inhibition, tumor microenvironment preparation, apoptosis promotion, stimulation of cancer cell invasion and metastasis, and suppression of immune surveillance. However, the triggering mechanisms of these distinct actions remain unclear. This review summarizes the molecular mechanisms of TGF-β signal transduction, focusing on oral squamous cell and salivary adenoid systemic carcinomas as well as keratocystic odontogenic tumors. Both the supporting and contrary evidence of the roles of TGF-β is discussed. Importantly, the TGF-β pathway has been the target of new drugs developed in the past decade, some having demonstrated promising therapeutic effects in clinical trials. Therefore, the achievements of TGF-β pathway-based therapeutics and their challenges are also assessed. The summarization and discussion of the updated knowledge of TGF-β signaling pathways will provide insight into the design of new strategies for oral cancer treatment, leading to an improvement in oral cancer outcomes. Full article
(This article belongs to the Special Issue TGF-β Signaling in Human Disease)
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