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Advances in Biological Functions of STAT3
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Advances in Biological Functions of STAT3

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (30 August 2018) | Viewed by 109728

Special Issue Editor

Prof. Dr. Valeria Poli

E-Mail
Guest Editor
Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Turin, Via Nizza 52, 10126 Torino, Italy
Interests: JAK-STAT signalling; STAT3; cancer; breast cancer; inflammation; tumor microenvironment

Special Issue Information

Dear Colleagues,

Signal transducer and activator of transcription (STAT) 3 is a transcription factor activated by a wide variety of cytokine and growth factor receptors and oncogenes under both physiological and pathological conditions. Accordingly, its activities are involved in regulating many distinct processes including immune cells differentiation and function, embryonic stem cells pluripotency, proliferation, apoptosis and cell survival, autophagy, cell metabolism, migration and adhesion. Unrestrained STAT3 activity is often detected in tumors, driving multiple pro-oncogenic functions. Thus, STAT3 is considered as an oncogene and is the object of intense translational studies. On the other hand, one of STAT3 distinctive features is its ability to elicit different and sometimes opposite effects under different conditions. For example, STAT3 activities can be either pro-oncogenic or tumor-suppressive depending on tumor type and aetiology. The molecular bases underlining STAT3 multitasking features are still incompletely understood but include the interplay of different post-translational modifications, multiple and cell-specific interactors, and regulated sub-cellular localization and activities.

The aim of this Special Issue is to provide an updated vision of STAT3 biological functions as indicated, but not limited, by the keywords below. To this end, we welcome experts in the field to contribute research papers, review articles, theories, hypotheses, or commentaries on the various aspects of STAT3 function and regulation.

Prof. Dr. Valeria Poli
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

  • STAT3 functions under physiological and pathological conditions
  • STAT3 transcriptional activities
  • STAT3 non-canonical functions
  • STAT3 post-translational modifications
  • STAT3 mutations
  • STAT3 dysregulation
  • STAT3 as an oncogene or an oncosuppressor
  • Regulation of STAT3-mediated signaling
  • STAT3 as a drug target

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Published Papers (16 papers)

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Research

Jump to: Review, Other

15 pages, 2843 KiB  
Article
STAT3, a Hub Protein of Cellular Signaling Pathways, Is Triggered by β-Hexaclorocyclohexane
by Elisabetta Rubini, Fabio Altieri, Silvia Chichiarelli, Flavia Giamogante, Stefania Carissimi, Giuliano Paglia, Alberto Macone and Margherita Eufemi
Int. J. Mol. Sci. 2018, 19(7), 2108; https://doi.org/10.3390/ijms19072108 - 20 Jul 2018
Cited by 10 | Viewed by 6153
Abstract
Background: Organochlorine pesticides (OCPs) are widely distributed in the environment and their toxicity is mostly associated with the molecular mechanisms of endocrine disruption. Among OCPs, particular attention was focused on the effects of β-hexaclorocyclohexane (β-HCH), a widely common pollutant. A detailed epidemiological study [...] Read more.
Background: Organochlorine pesticides (OCPs) are widely distributed in the environment and their toxicity is mostly associated with the molecular mechanisms of endocrine disruption. Among OCPs, particular attention was focused on the effects of β-hexaclorocyclohexane (β-HCH), a widely common pollutant. A detailed epidemiological study carried out on exposed population in the “Valle del Sacco” found correlations between the incidence of a wide range of diseases and the occurrence of β-HCH contamination. Taking into account the pleiotropic role of the protein signal transducer and activator of transcription 3 (STAT3), its function as a hub protein in cellular signaling pathways triggered by β-HCH was investigated in different cell lines corresponding to tissues that are especially vulnerable to damage by environmental pollutants. Materials and Methods: Human prostate cancer (LNCaP), human breast cancer (MCF-7 and MDA-MB 468), and human hepatoma (HepG2) cell lines were treated with 10 μM β-HCH in the presence or absence of specific inhibitors for different receptors. All samples were subjected to analysis by immunoblotting and RT-qPCR. Results and Conclusions: The preliminary results allow us to hypothesize the involvement of STAT3, through both its canonical and non-canonical pathways, in response to β-HCH. Moreover, we ascertained the role of STAT3 as a master regulator of energy metabolism via the altered expression and localization of HIF-1α and PKM2, respectively, resulting in a Warburg-like effect. Full article
(This article belongs to the Special Issue Advances in Biological Functions of STAT3)
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15 pages, 5097 KiB  
Article
pSTAT3 Levels Have Divergent Expression Patterns and Associations with Survival in Squamous Cell Carcinoma and Adenocarcinoma of the Oesophagus
by Katie E. O’ Sullivan, Adriana J. Michielsen, Esther O’ Regan, Mary C. Cathcart, Gillian Moore, Eamon Breen, Ricardo Segurado, John V. Reynolds, Joanne Lysaght and Jacintha O’ Sullivan
Int. J. Mol. Sci. 2018, 19(6), 1720; https://doi.org/10.3390/ijms19061720 - 10 Jun 2018
Cited by 9 | Viewed by 3825
Abstract
Signal transducers and activator of transcription (STAT)-3 is activated in cancers, where it promotes growth, inflammation, angiogenesis, and inhibits apoptosis. Tissue microarrays were generated using tissues from 154 patients, with oesophageal adenocarcinoma (OAC) (n = 116) or squamous cell carcinoma (SCC) ( [...] Read more.
Signal transducers and activator of transcription (STAT)-3 is activated in cancers, where it promotes growth, inflammation, angiogenesis, and inhibits apoptosis. Tissue microarrays were generated using tissues from 154 patients, with oesophageal adenocarcinoma (OAC) (n = 116) or squamous cell carcinoma (SCC) (n = 38) tumours. The tissues were stained for pSTAT3 and IL-6R using immunohistochemistry. The OE33 (OAC) and OE21 (SCC) cell lines were treated with the STAT3 inhibitor, STATTIC. The Univariate cox regression analysis revealed that a positive pSTAT3 in SCC was adversely associated with survival (Hazard ratio (HR) 6.382, 95% CI 1.266–32.184), while a protective effect was demonstrated with the higher pSTAT3 levels in OAC epithelium (HR 0.74, 95% CI 0.574–0.953). The IL-6R intensity levels were higher in the SCC tumours compared with the OAC tumours for the core and leading edge tumour tissue. The pSTAT3 levels correlated positively with the IL-6R levels in both the OAC and SCC. The treatment of OE21 and OE33 cells with the STAT3 inhibitor STATTIC in vitro resulted in decreased survival, proliferation, migration, and increased apoptosis. The pSTAT3 expression was associated with adverse survival in SCC, but not in the OAC patients. The inhibition of STAT3 in both of the tumour subtypes resulted in alterations in the survival, proliferation, migration, and apoptosis, suggesting a potential role for therapeutically targeting STAT3. Full article
(This article belongs to the Special Issue Advances in Biological Functions of STAT3)
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11 pages, 1424 KiB  
Article
Biochemical Properties of a Decoy Oligodeoxynucleotide Inhibitor of STAT3 Transcription Factor
by David S. Lee, Rachel A. O’Keefe, Patrick K. Ha, Jennifer R. Grandis and Daniel E. Johnson
Int. J. Mol. Sci. 2018, 19(6), 1608; https://doi.org/10.3390/ijms19061608 - 30 May 2018
Cited by 12 | Viewed by 3975
Abstract
Cyclic STAT3 decoy (CS3D) is a second-generation, double-stranded oligodeoxynucleotide (ODN) that mimics a genomic response element for signal transducer and activator of transcription 3 (STAT3), an oncogenic transcription factor. CS3D competitively inhibits STAT3 binding to target gene promoters, resulting in decreased expression of [...] Read more.
Cyclic STAT3 decoy (CS3D) is a second-generation, double-stranded oligodeoxynucleotide (ODN) that mimics a genomic response element for signal transducer and activator of transcription 3 (STAT3), an oncogenic transcription factor. CS3D competitively inhibits STAT3 binding to target gene promoters, resulting in decreased expression of proteins that promote cellular proliferation and survival. Previous studies have demonstrated antitumor activity of CS3D in preclinical models of solid tumors. However, prior to entering human clinical trials, the efficiency of generating the CS3D molecule and its stability in biological fluids should be determined. CS3D is synthesized as a single-stranded ODN and must have its free ends ligated to generate the final cyclic form. In this study, we report a ligation efficiency of nearly 95 percent. The ligated CS3D demonstrated a half-life of 7.9 h in human serum, indicating adequate stability for intravenous delivery. These results provide requisite biochemical characterization of CS3D that will inform upcoming clinical trials. Full article
(This article belongs to the Special Issue Advances in Biological Functions of STAT3)
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13 pages, 2810 KiB  
Article
Luteolin-Mediated Inhibition of Hepatic Stellate Cell Activation via Suppression of the STAT3 Pathway
by Claire B. Cummins, Xiaofu Wang, Omar Nunez Lopez, Gabriel Graham, Hong-Yan Tie, Jia Zhou and Ravi S. Radhakrishnan
Int. J. Mol. Sci. 2018, 19(6), 1567; https://doi.org/10.3390/ijms19061567 - 24 May 2018
Cited by 24 | Viewed by 4960
Abstract
Hepatic stellate cell (HSC) activation is responsible for hepatic fibrogenesis and is associated with an overexpression of transcription 3 (STAT3). Luteolin, a common dietary flavonoid with potent anti-inflammatory properties, has previously demonstrated antifibrogenic properties in HSCs but the mechanism has not been fully [...] Read more.
Hepatic stellate cell (HSC) activation is responsible for hepatic fibrogenesis and is associated with an overexpression of transcription 3 (STAT3). Luteolin, a common dietary flavonoid with potent anti-inflammatory properties, has previously demonstrated antifibrogenic properties in HSCs but the mechanism has not been fully elucidated. Activated human and rat hepatic stellate cell lines LX-2 and HSC-T6 were used to study the effects of luteolin on HSCs. Cellular proteins were determined by western blot and immunofluorescence. Cell proliferation was assessed with Alamar Blue assay. Luteolin significantly decreased LX-2 and HSC-T6 cell viability in a time-and-dose-dependent manner, as well as decreased HSC end-products α-smooth muscle actin (α-SMA), collagen I, and fibronectin. Luteolin decreased levels of total and phosphorylated STAT3, suppressed STAT3 nuclear translocation and transcriptional activity, and attenuated expression of STAT3-regulated proteins c-myc and cyclin D1. STAT3 specific inhibitors stattic and SH-4-54 demonstrated similar effects on HSC viability and α-SMA production. In LX-2 and HSC-T6 cells, luteolin demonstrates a potent ability to inhibit hepatic fibrogenesis via suppression of the STAT3 pathway. These results further elucidate the mechanism of luteolin as well as the effect of the STAT3 pathway on HSC activation. Full article
(This article belongs to the Special Issue Advances in Biological Functions of STAT3)
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14 pages, 47188 KiB  
Article
Genetic Variants in STAT3 Promoter Regions and Their Application in Molecular Breeding for Body Size Traits in Qinchuan Cattle
by Sen Wu, Yaning Wang, Yue Ning, Hongfang Guo, Xiaoyu Wang, Le Zhang, Rajwali Khan, Gong Cheng, Hongbao Wang and Linsen Zan
Int. J. Mol. Sci. 2018, 19(4), 1035; https://doi.org/10.3390/ijms19041035 - 29 Mar 2018
Cited by 31 | Viewed by 4676
Abstract
Signal transducer and activator of transcription 3 (STAT3) plays a critical role in leptin-mediated regulation of energy metabolism. This study investigated genetic variation in STAT3 promoter regions and verified their contribution to bovine body size traits. We first estimated the degree of conservation [...] Read more.
Signal transducer and activator of transcription 3 (STAT3) plays a critical role in leptin-mediated regulation of energy metabolism. This study investigated genetic variation in STAT3 promoter regions and verified their contribution to bovine body size traits. We first estimated the degree of conservation in STAT3, followed by measurements of its mRNA expression during fetal and adult stages of Qinchuan cattle. We then sequenced the STAT3 promoter region to determine genetic variants and evaluate their association with body size traits. From fetus to adult, STAT3 expression increased significantly in muscle, fat, heart, liver, and spleen tissues (p < 0.01), but decreased in the intestine, lung, and rumen (p < 0.01). We identified and named five single nucleotide polymorphisms (SNPs): SNP1-304A>C, SNP2-285G>A, SNP3-209A>C, SNP4-203A>G, and SNP5-188T>C. These five mutations fell significantly outside the Hardy–Weinberg equilibrium (HWE) (Chi-squared test, p < 0.05) and significantly associated with body size traits (p < 0.05). Individuals with haplotype H3H3 (CC-GG-CC-GG-CC) were larger in body size than other haplotypes. Therefore, variations in the STAT3 gene promoter regions, most notably haplotype H3H3, may benefit marker-assisted breeding of Qinchuan cattle. Full article
(This article belongs to the Special Issue Advances in Biological Functions of STAT3)
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Review

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29 pages, 1783 KiB  
Review
Effects of Cardiovascular Risk Factors on Cardiac STAT3
by Márton Pipicz, Virág Demján, Márta Sárközy and Tamás Csont
Int. J. Mol. Sci. 2018, 19(11), 3572; https://doi.org/10.3390/ijms19113572 - 12 Nov 2018
Cited by 35 | Viewed by 5779
Abstract
Nuclear, mitochondrial and cytoplasmic signal transducer and activator of transcription 3 (STAT3) regulates many cellular processes, e.g., the transcription or opening of mitochondrial permeability transition pore, and its activity depends on the phosphorylation of Tyr705 and/or Ser727 sites. In the heterogeneous network of [...] Read more.
Nuclear, mitochondrial and cytoplasmic signal transducer and activator of transcription 3 (STAT3) regulates many cellular processes, e.g., the transcription or opening of mitochondrial permeability transition pore, and its activity depends on the phosphorylation of Tyr705 and/or Ser727 sites. In the heterogeneous network of cardiac cells, STAT3 promotes cardiac muscle differentiation, vascular element formation and extracellular matrix homeostasis. Overwhelming evidence suggests that STAT3 is beneficial for the heart, plays a role in the prevention of age-related and postpartum heart failure, protects the heart against cardiotoxic doxorubicin or ischaemia/reperfusion injury, and is involved in many cardioprotective strategies (e.g., ischaemic preconditioning, perconditioning, postconditioning, remote or pharmacological conditioning). Ischaemic heart disease is still the leading cause of death worldwide, and many cardiovascular risk factors contribute to the development of the disease. This review focuses on the effects of various cardiovascular risk factors (diabetes, aging, obesity, smoking, alcohol, depression, gender, comedications) on cardiac STAT3 under non-ischaemic baseline conditions, and in settings of ischaemia/reperfusion injury with or without cardioprotective strategies. Full article
(This article belongs to the Special Issue Advances in Biological Functions of STAT3)
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16 pages, 2456 KiB  
Review
Nucleus, Mitochondrion, or Reticulum? STAT3 à La Carte
by Lidia Avalle and Valeria Poli
Int. J. Mol. Sci. 2018, 19(9), 2820; https://doi.org/10.3390/ijms19092820 - 18 Sep 2018
Cited by 55 | Viewed by 6541
Abstract
The transcription factor signal transducer and activator of transcription (STAT)3 mediates the functions of cytokines, growth factors, and oncogenes under both physiological and pathological conditions. Uncontrolled/constitutive STAT3 activity is often detected in tumors of different types, where its role is mostly that of [...] Read more.
The transcription factor signal transducer and activator of transcription (STAT)3 mediates the functions of cytokines, growth factors, and oncogenes under both physiological and pathological conditions. Uncontrolled/constitutive STAT3 activity is often detected in tumors of different types, where its role is mostly that of an oncogene, contributing in multiple ways to tumor transformation, growth, and progression. For this reason, many laboratories and pharmaceutical companies are making efforts to develop specific inhibitors. However, STAT3 has also been shown to act as a tumor suppressor in a number of cases, suggesting that its activity is strongly context-specific. Here, we discuss the bases that can explain the multiple roles of this factor in both physiological and pathological contexts. In particular, we focus on the following four features: (i) the distinct properties of the STAT3α and β isoforms; (ii) the multiple post-translational modifications (phosphorylation on tyrosine or serine, acetylation and methylation on different residues, and oxidation and glutathionylation) that can affect its activities downstream of multiple different signals; (iii) the non-canonical functions in the mitochondria, contributing to the maintenance of energy homeostasis under stress conditions; and (iv) the recently discovered functions in the endoplasmic reticulum, where STAT3 contributes to the regulation of calcium homeostasis, energy production, and apoptosis. Full article
(This article belongs to the Special Issue Advances in Biological Functions of STAT3)
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19 pages, 1567 KiB  
Review
Protein Tyrosine Phosphatases as Potential Regulators of STAT3 Signaling
by Mihwa Kim, Liza D. Morales, Ik-Soon Jang, Yong-Yeon Cho and Dae Joon Kim
Int. J. Mol. Sci. 2018, 19(9), 2708; https://doi.org/10.3390/ijms19092708 - 11 Sep 2018
Cited by 115 | Viewed by 10465
Abstract
The signal transducer and activator of transcription 3 (STAT3) protein is a major transcription factor involved in many cellular processes, such as cell growth and proliferation, differentiation, migration, and cell death or cell apoptosis. It is activated in response to a variety of [...] Read more.
The signal transducer and activator of transcription 3 (STAT3) protein is a major transcription factor involved in many cellular processes, such as cell growth and proliferation, differentiation, migration, and cell death or cell apoptosis. It is activated in response to a variety of extracellular stimuli including cytokines and growth factors. The aberrant activation of STAT3 contributes to several human diseases, particularly cancer. Consequently, STAT3-mediated signaling continues to be extensively studied in order to identify potential targets for the development of new and more effective clinical therapeutics. STAT3 activation can be regulated, either positively or negatively, by different posttranslational mechanisms including serine or tyrosine phosphorylation/dephosphorylation, acetylation, or demethylation. One of the major mechanisms that negatively regulates STAT3 activation is dephosphorylation of the tyrosine residue essential for its activation by protein tyrosine phosphatases (PTPs). There are seven PTPs that have been shown to dephosphorylate STAT3 and, thereby, regulate STAT3 signaling: PTP receptor-type D (PTPRD), PTP receptor-type T (PTPRT), PTP receptor-type K (PTPRK), Src homology region 2 (SH-2) domain-containing phosphatase 1(SHP1), SH-2 domain-containing phosphatase 2 (SHP2), MEG2/PTP non-receptor type 9 (PTPN9), and T-cell PTP (TC-PTP)/PTP non-receptor type 2 (PTPN2). These regulators have great potential as targets for the development of more effective therapies against human disease, including cancer. Full article
(This article belongs to the Special Issue Advances in Biological Functions of STAT3)
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30 pages, 686 KiB  
Review
Contribution of STAT3 to Inflammatory and Fibrotic Diseases and Prospects for its Targeting for Treatment
by Moses M. Kasembeli, Uddalak Bharadwaj, Prema Robinson and David J. Tweardy
Int. J. Mol. Sci. 2018, 19(8), 2299; https://doi.org/10.3390/ijms19082299 - 05 Aug 2018
Cited by 120 | Viewed by 7879
Abstract
Signal transducer and activator of transcription (STAT) 3 plays a central role in the host response to injury. It is activated rapidly within cells by many cytokines, most notably those in the IL-6 family, leading to pro-proliferative and pro-survival programs that assist the [...] Read more.
Signal transducer and activator of transcription (STAT) 3 plays a central role in the host response to injury. It is activated rapidly within cells by many cytokines, most notably those in the IL-6 family, leading to pro-proliferative and pro-survival programs that assist the host in regaining homeostasis. With persistent activation, however, chronic inflammation and fibrosis ensue, leading to a number of debilitating diseases. This review summarizes advances in our understanding of the role of STAT3 and its targeting in diseases marked by chronic inflammation and/or fibrosis with a focus on those with the largest unmet medical need. Full article
(This article belongs to the Special Issue Advances in Biological Functions of STAT3)
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16 pages, 809 KiB  
Review
STAT3 in Skeletal Muscle Function and Disorders
by Eleonora Guadagnin, Davi Mázala and Yi-Wen Chen
Int. J. Mol. Sci. 2018, 19(8), 2265; https://doi.org/10.3390/ijms19082265 - 02 Aug 2018
Cited by 54 | Viewed by 8455
Abstract
Signal transducer and activator of transcription 3 (STAT3) signaling plays critical roles in regulating skeletal muscle mass, repair, and diseases. In this review, we discuss the upstream activators of STAT3 in skeletal muscles, with a focus on interleukin 6 (IL6) and transforming growth [...] Read more.
Signal transducer and activator of transcription 3 (STAT3) signaling plays critical roles in regulating skeletal muscle mass, repair, and diseases. In this review, we discuss the upstream activators of STAT3 in skeletal muscles, with a focus on interleukin 6 (IL6) and transforming growth factor beta 1 (TGF-β1). We will also discuss the double-edged effect of STAT3 activation in the muscles, including the role of STAT3 signaling in muscle hypertrophy induced by exercise training or muscle wasting in cachectic diseases and muscular dystrophies. STAT3 is a critical regulator of satellite cell self-renewal after muscle injury. STAT3 knock out affects satellite cell myogenic progression by impairing proliferation and inducing premature differentiation. Recent studies in STAT3 signaling demonstrated its direct role in controlling myogenic capacity of myoblasts and satellite cells, as well as the potential benefit in using STAT3 inhibitors to treat muscle diseases. However, prolonged STAT3 activation in muscles has been shown to be responsible for muscle wasting by activating protein degradation pathways. It is important to balance the extent of STAT3 activation and the duration and location (cell types) of the STAT3 signaling when developing therapeutic interventions. STAT3 signaling in other tissues and organs that can directly or indirectly affects skeletal muscle health are also discussed. Full article
(This article belongs to the Special Issue Advances in Biological Functions of STAT3)
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14 pages, 1127 KiB  
Review
STAT3 in Tumor-Associated Myeloid Cells: Multitasking to Disrupt Immunity
by Yu-Lin Su, Shuvomoy Banerjee, Seok Voon White and Marcin Kortylewski
Int. J. Mol. Sci. 2018, 19(6), 1803; https://doi.org/10.3390/ijms19061803 - 19 Jun 2018
Cited by 70 | Viewed by 7609
Abstract
Myeloid immune cells, such as dendritic cells, monocytes, and macrophages, play a central role in the generation of immune responses and thus are often either disabled or even hijacked by tumors. These new tolerogenic activities of tumor-associated myeloid cells are controlled by an [...] Read more.
Myeloid immune cells, such as dendritic cells, monocytes, and macrophages, play a central role in the generation of immune responses and thus are often either disabled or even hijacked by tumors. These new tolerogenic activities of tumor-associated myeloid cells are controlled by an oncogenic transcription factor, signal transducer and activator of transcription 3 (STAT3). STAT3 multitasks to ensure tumors escape immune detection by impairing antigen presentation and reducing production of immunostimulatory molecules while augmenting the release of tolerogenic mediators, thereby reducing innate and adaptive antitumor immunity. Tumor-associated myeloid cells and STAT3 signaling in this compartment are now commonly recognized as an attractive cellular target for improving efficacy of standard therapies and immunotherapies. Hereby, we review the importance and functional complexity of STAT3 signaling in this immune cell compartment as well as potential strategies for cancer therapy. Full article
(This article belongs to the Special Issue Advances in Biological Functions of STAT3)
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21 pages, 775 KiB  
Review
STAT3 Interactors as Potential Therapeutic Targets for Cancer Treatment
by Federica Laudisi, Fabio Cherubini, Giovanni Monteleone and Carmine Stolfi
Int. J. Mol. Sci. 2018, 19(6), 1787; https://doi.org/10.3390/ijms19061787 - 16 Jun 2018
Cited by 108 | Viewed by 8496
Abstract
Signal transducers and activators of transcription (STATs) mediate essential signaling pathways in different biological processes, including immune responses, hematopoiesis, and neurogenesis. Among the STAT members, STAT3 plays crucial roles in cell proliferation, survival, and differentiation. While STAT3 activation is transient in physiological conditions, [...] Read more.
Signal transducers and activators of transcription (STATs) mediate essential signaling pathways in different biological processes, including immune responses, hematopoiesis, and neurogenesis. Among the STAT members, STAT3 plays crucial roles in cell proliferation, survival, and differentiation. While STAT3 activation is transient in physiological conditions, STAT3 becomes persistently activated in a high percentage of solid and hematopoietic malignancies (e.g., melanoma, multiple myeloma, breast, prostate, ovarian, and colon cancers), thus contributing to malignant transformation and progression. This makes STAT3 an attractive therapeutic target for cancers. Initial strategies aimed at inhibiting STAT3 functions have focused on blocking the action of its activating kinases or sequestering its DNA binding ability. More recently, the diffusion of proteomic-based techniques, which have allowed for the identification and characterization of novel STAT3-interacting proteins able to modulate STAT3 activity via its subcellular localization, interact with upstream kinases, and recruit transcriptional machinery, has raised the possibility to target such cofactors to specifically restrain STAT3 oncogenic functions. In this article, we summarize the available data about the function of STAT3 interactors in malignant cells and discuss their role as potential therapeutic targets for cancer treatment. Full article
(This article belongs to the Special Issue Advances in Biological Functions of STAT3)
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14 pages, 17326 KiB  
Review
The Multifaceted Role of STAT3 in Mammary Gland Involution and Breast Cancer
by Katherine Hughes and Christine J. Watson
Int. J. Mol. Sci. 2018, 19(6), 1695; https://doi.org/10.3390/ijms19061695 - 07 Jun 2018
Cited by 49 | Viewed by 9292
Abstract
Since seminal descriptions of signal transducer and activator of transcription 3 (STAT3) as a signal transducer and transcriptional regulator, which is most usually activated by phosphorylation of a specific tyrosine residue, a staggering wealth of research has delineated the key role of this [...] Read more.
Since seminal descriptions of signal transducer and activator of transcription 3 (STAT3) as a signal transducer and transcriptional regulator, which is most usually activated by phosphorylation of a specific tyrosine residue, a staggering wealth of research has delineated the key role of this transcription factor as a mediator of mammary gland postlactational regression (involution), and paradoxically, a pro-survival factor in breast cancer and some breast cancer cell lines. STAT3 is a critical regulator of lysosomal-mediated programmed cell death (LM-PCD) during mammary gland involution, where uptake of milk fat globules, and consequent high levels of free fatty acids, cause permeabilisation of lysosomal vesicle membranes, in turn leading to cathepsin protease leakage and cell death. A recent proteomic screen of STAT3-induced changes in lysosomal membrane protein components has highlighted wide-ranging effects of STAT3, which may coordinate LM-PCD via the stimulation of endocytosis, intracellular trafficking, and lysosome biogenesis. In parallel, STAT3 regulates the acute phase response during the first phase of involution, and it contributes to shaping the pro-tumourigenic ‘wound healing’ signature of the gland during the second phase of this process. STAT3 activation during involution is important across species, although some differences exist in the progression of involution in dairy cows. In breast cancer, a number of upstream regulators can lead to STAT3 activation and the effects of phosphorylation of STAT3 are equally wide-ranging. Recent studies have implicated microRNAs in some regulatory pathways. In this review, we will examine the multifaceted role of STAT3 in mammary gland involution and tumourigenesis, incorporating a review of these fundamental processes in tandem with a discussion of recent developments in this field. Full article
(This article belongs to the Special Issue Advances in Biological Functions of STAT3)
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14 pages, 598 KiB  
Review
A New Perspective: Mitochondrial Stat3 as a Regulator for Lymphocyte Function
by Mercedes Rincon and Felipe Valença Pereira
Int. J. Mol. Sci. 2018, 19(6), 1656; https://doi.org/10.3390/ijms19061656 - 04 Jun 2018
Cited by 37 | Viewed by 8348
Abstract
Stat3 as a transcription factor regulating gene expression in lymphocytes during the immune response is well known. However, since the pioneering studies discovering the presence of Stat3 in mitochondria and its role in regulating mitochondrial metabolism, only a few studies have investigated this [...] Read more.
Stat3 as a transcription factor regulating gene expression in lymphocytes during the immune response is well known. However, since the pioneering studies discovering the presence of Stat3 in mitochondria and its role in regulating mitochondrial metabolism, only a few studies have investigated this non-conventional function of Stat3 in lymphocytes. From this perspective, we review what is known about Stat3 as a transcription factor and what is known and unknown about mitochondrial Stat3 (mitoStat3) in lymphocytes. We also provide a framework to consider how some of the functions previously assigned to Stat3 as regulator of gene transcription could be mediated by mitoStat3 in lymphocytes. The goal of this review is to stimulate interest for future studies investigating mitoStat3 in the immune response that could lead to the generation of alternative pharmacological inhibitors of mitoStat3 for the treatment of chronic inflammatory diseases. Full article
(This article belongs to the Special Issue Advances in Biological Functions of STAT3)
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14 pages, 2449 KiB  
Review
Structural Biology of STAT3 and Its Implications for Anticancer Therapies Development
by Jacopo Sgrignani, Maura Garofalo, Milos Matkovic, Jessica Merulla, Carlo V. Catapano and Andrea Cavalli
Int. J. Mol. Sci. 2018, 19(6), 1591; https://doi.org/10.3390/ijms19061591 - 28 May 2018
Cited by 88 | Viewed by 8203
Abstract
Transcription factors are proteins able to bind DNA and induce the transcription of specific genes. Consequently, they play a pivotal role in multiple cellular pathways and are frequently over-expressed or dysregulated in cancer. Here, we will focus on a specific “signal transducer and [...] Read more.
Transcription factors are proteins able to bind DNA and induce the transcription of specific genes. Consequently, they play a pivotal role in multiple cellular pathways and are frequently over-expressed or dysregulated in cancer. Here, we will focus on a specific “signal transducer and activator of transcription” (STAT3) factor that is involved in several pathologies, including cancer. For long time, the mechanism by which STAT3 exerts its cellular functions has been summarized by a three steps process: (1) Protein phosphorylation by specific kinases, (2) dimerization promoted by phosphorylation, (3) activation of gene expression by the phosphorylated dimer. Consequently, most of the inhibitors reported in literature aimed at blocking phosphorylation and dimerization. However, recent observations reopened the debate and the entire functional mechanism has been revisited stimulating the scientific community to pursue new inhibition strategies. In particular, the dimerization of the unphosphorylated species has been experimentally demonstrated and specific roles proposed also for these dimers. Despite difficulties in the expression and purification of the full length STAT3, structural biology investigations allowed the determination of atomistic structures of STAT3 dimers and several protein domains. Starting from this information, computational methods have been used both to improve the understanding of the STAT3 functional mechanism and to design new inhibitors to be used as anticancer drugs. In this review, we will focus on the contribution of structural biology to understand the roles of STAT3, to design new inhibitors and to suggest new strategies of pharmacological intervention. Full article
(This article belongs to the Special Issue Advances in Biological Functions of STAT3)
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Commentary
STAT3 in Breast Cancer Onset and Progression: A Matter of Time and Context
by Ilenia Segatto, Gustavo Baldassarre and Barbara Belletti
Int. J. Mol. Sci. 2018, 19(9), 2818; https://doi.org/10.3390/ijms19092818 - 18 Sep 2018
Cited by 29 | Viewed by 3942
Abstract
Signal transducer and activator of transcription 3 (STAT3) is responsible for mediating the transcriptional programs downstream of several cytokine, growth factor, and oncogenic stimuli. Its expression and activity are consistently linked to cellular transformation, as well as tumor initiation and progression. Due to [...] Read more.
Signal transducer and activator of transcription 3 (STAT3) is responsible for mediating the transcriptional programs downstream of several cytokine, growth factor, and oncogenic stimuli. Its expression and activity are consistently linked to cellular transformation, as well as tumor initiation and progression. Due to this central role, STAT3 is widely considered a good target for anti-cancer therapy; however, the success of these approaches has been, so far, very limited. Notably, on one side, STAT3 is aberrantly active in many breast cancers, on the other, at the physiological level, it is the main mediator of epithelial cell death during post-lactation mammary-gland involution, thus strongly suggesting that its biological functions are highly context-specific. One of the most peculiar features of STAT3 is that it can act both in cell-autonomous and non-cell-autonomous manners, simultaneously modulating the phenotypes of the tumor cells and their microenvironment. Here, we focus on the role of STAT3 in breast cancer progression, discussing the potential contrasting roles of STAT3 activation in the establishment of locally recurrent and distant metastatic disease. Based on the most recent literature, depending on the tumor cell type, the local microenvironment status, and the stage of the disease, either STAT3 activation or inactivation can support disease progression. Accordingly, cancer cells dynamically exploit STAT3 activity to carry out transcriptional programs somehow contrasting and complementary, such as supporting survival and growth, dormancy and awakening, stem cell-like features, and inflammation, immune response, and immune evasion. As a consequence, to achieve clinical efficacy, the conception and testing of anti-STAT3 targeted therapies will need a very careful evaluation of these opposing roles and of the most appropriate tumor context, disease stage and patient population to treat. Full article
(This article belongs to the Special Issue Advances in Biological Functions of STAT3)
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