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Biomedicines
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Role of STAT3 in Oncogenesis
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Role of STAT3 in Oncogenesis

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cell Biology and Pathology".

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 19744

Special Issue Editor

Prof. Dr. Kwang Seok Ahn

E-Mail Website
Guest Editor
Department of Science in Korean Medicine, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
Interests: chemoprevention; phytochemicals; signal transduction pathway; cancer cachexia; apoptosis; inflammation; autophagy

Special Issue Information

Dear Colleagues,

The signal transducer and activator of transcription 3 (STAT3) molecule plays a versatile role in numerous physiological processes. However, a number of studies have highlighted that this transcription factor may be deregulated in various malignancies, promoting tumor growth and metastasis. This Special Issue will highlight different mechanisms regulating STAT3 activation in tumor cells, its potential interaction with other signaling molecules, and pharmacological strategies to target its aberrant activation in tumor cells.

Prof. Dr. Kwang Seok Ahn
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. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). 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
  • cancer
  • metastasis
  • angiogenesis
  • pharmacological strategies

Published Papers (7 papers)

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Editorial

Jump to: Research, Review

3 pages, 176 KiB  
Editorial
Special Issue “Role of STAT3 in Oncogenesis”
by Kwang Seok Ahn
Biomedicines 2022, 10(11), 2689; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10112689 - 24 Oct 2022
Viewed by 799
Abstract
This Biomedicines Special Issue was designed to attract articles that focused on the pleiotropic role of the signal transducer and activator of transcription 3 (STAT3) transcription factor in different facets of tumorigenesis [...] Full article
(This article belongs to the Special Issue Role of STAT3 in Oncogenesis)
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Research

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15 pages, 2270 KiB  
Article
Antitumor Activity of Pulvomycin via Targeting Activated-STAT3 Signaling in Docetaxel-Resistant Triple-Negative Breast Cancer Cells
by Woong Sub Byun, Eun Seo Bae, Jinsheng Cui, Hyen Joo Park, Dong-Chan Oh and Sang Kook Lee
Biomedicines 2021, 9(4), 436; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9040436 - 17 Apr 2021
Cited by 11 | Viewed by 2697
Abstract
Although docetaxel-based regimens are common and effective for early-stage triple-negative breast cancer (TNBC) treatment, acquired drug resistance frequently occurs. Therefore, a novel therapeutic strategy for docetaxel-resistant TNBC is urgently required. Signal transducer and activator of transcription 3 (STAT3) plays a pivotal role in [...] Read more.
Although docetaxel-based regimens are common and effective for early-stage triple-negative breast cancer (TNBC) treatment, acquired drug resistance frequently occurs. Therefore, a novel therapeutic strategy for docetaxel-resistant TNBC is urgently required. Signal transducer and activator of transcription 3 (STAT3) plays a pivotal role in the tumorigenesis and metastasis of numerous cancers, and STAT3 signaling is aberrantly activated in TNBC cells. In this study, a docetaxel-resistant TNBC cell line (MDA-MB-231-DTR) was established, and mechanisms for the antitumor activity of pulvomycin, a novel STAT3 inhibitor isolated from marine-derived actinomycete, were investigated. Levels of activated STAT3 (p-STAT3 (Y705)) increased in docetaxel-resistant cells, and knockdown of STAT3 recovered the sensitivity to docetaxel in MDA-MB-231-DTR cells. Pulvomycin effectively inhibited the proliferation of both cell lines. In addition, pulvomycin suppressed the activation of STAT3 and subsequently induced G0/G1 cell cycle arrest and apoptosis. Pulvomycin also significantly inhibited the invasion and migration of MDA-MB-231-DTR cells through the modulation of epithelial-mesenchymal transition markers. In an MDA-MB-231-DTR-bearing xenograft mouse model, the combination of pulvomycin and docetaxel effectively inhibited tumor growth through STAT3 regulation. Thus, our findings demonstrate that the combination of docetaxel and STAT3 inhibitors is an effective strategy for overcoming docetaxel resistance in TNBC. Full article
(This article belongs to the Special Issue Role of STAT3 in Oncogenesis)
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15 pages, 4849 KiB  
Article
Albendazole Exhibits Anti-Neoplastic Actions against Gastric Cancer Cells by Affecting STAT3 and STAT5 Activation by Pleiotropic Mechanism(s)
by Min Hee Yang, In Jin Ha, Jae-Young Um and Kwang Seok Ahn
Biomedicines 2021, 9(4), 362; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9040362 - 31 Mar 2021
Cited by 11 | Viewed by 2418
Abstract
Albendazole (ABZ) has been reported to display anti-tumoral actions against various maliganncies, but possible impact of ABZ on gastric cancer has not been deciphered. As aberrant phosphorylation of STAT3 and STAT5 proteins can regulate the growth and progression of gastric cancer, we postulated [...] Read more.
Albendazole (ABZ) has been reported to display anti-tumoral actions against various maliganncies, but possible impact of ABZ on gastric cancer has not been deciphered. As aberrant phosphorylation of STAT3 and STAT5 proteins can regulate the growth and progression of gastric cancer, we postulated that ABZ may interrupt the activation of these oncogenic transcription factors. We found that ABZ exposure abrogated STAT3/5 activation, inhibited phosphorylation of Janus-activated kinases 1/2 and Src and enhanced the levels of SHP-1 protein. Silencing of SHP-1 gene by small interfering RNA (siRNA) reversed the ABZ-promoted attenuation of STAT3 as well as STAT5 activation and cellular apoptosis. In addition, these effects were noted to be driven by an augmented levels of reactive oxygen species caused by drug-induced GSH/GSSG imbalance. Thus, the data indicates that ABZ can modulate the activation of STAT3 and STAT5 by pleiotropic mechanisms in gastric cancer cells. Full article
(This article belongs to the Special Issue Role of STAT3 in Oncogenesis)
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15 pages, 1667 KiB  
Article
Activation of Interferon Signaling in Chronic Lymphocytic Leukemia Cells Contributes to Apoptosis Resistance via a JAK-Src/STAT3/Mcl-1 Signaling Pathway
by Brigitte Bauvois, Elodie Pramil, Ludovic Jondreville, Claire Quiney, Florence Nguyen-Khac and Santos A. Susin
Biomedicines 2021, 9(2), 188; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9020188 - 13 Feb 2021
Cited by 9 | Viewed by 2303
Abstract
Besides their antiviral and immunomodulatory functions, type I (α/β) and II (γ) interferons (IFNs) exhibit either beneficial or detrimental effects on tumor progression. Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of abnormal CD5+ B lymphocytes that escape death. Drug resistance [...] Read more.
Besides their antiviral and immunomodulatory functions, type I (α/β) and II (γ) interferons (IFNs) exhibit either beneficial or detrimental effects on tumor progression. Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of abnormal CD5+ B lymphocytes that escape death. Drug resistance and disease relapse still occur in CLL. The triggering of IFN receptors is believed to be involved in the survival of CLL cells, but the underlying molecular mechanisms are not yet characterized. We show here that both type I and II IFNs promote the survival of primary CLL cells by counteracting the mitochondrial (intrinsic) apoptosis pathway. The survival process was associated with the upregulation of signal transducer and activator of transcription-3 (STAT3) and its target anti-apoptotic Mcl-1. Furthermore, the blockade of the STAT3/Mcl-1 pathway by pharmacological inhibitors against STAT3, TYK2 (for type I IFN) or JAK2 (for type II IFN) markedly reduced IFN-mediated CLL cell survival. Similarly, the selective Src family kinase inhibitor PP2 notably blocked IFN-mediated CLL cell survival by downregulating the protein levels of STAT3 and Mcl-1. Our work reveals a novel mechanism of resistance to apoptosis promoted by IFNs in CLL cells, whereby JAKs (TYK2, JAK2) and Src kinases activate in concert a STAT3/Mcl-1 signaling pathway. In view of current clinical developments of potent STAT3 and Mcl-1 inhibitors, a combination of conventional treatments with these inhibitors might thus constitute a new therapeutic strategy in CLL. Full article
(This article belongs to the Special Issue Role of STAT3 in Oncogenesis)
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11 pages, 2471 KiB  
Article
IRE1 Alpha/XBP1 Axis Sustains Primary Effusion Lymphoma Cell Survival by Promoting Cytokine Release and STAT3 Activation
by Roberta Gonnella, Maria Saveria Gilardini Montani, Luisa Guttieri, Maria Anele Romeo, Roberta Santarelli and Mara Cirone
Biomedicines 2021, 9(2), 118; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9020118 - 27 Jan 2021
Cited by 19 | Viewed by 2737
Abstract
Primary Effusion Lymphoma (PEL) is a highly aggressive B cell lymphoma associated with Kaposi’s Sarcoma-associated Herpesvirus (KSHV). It is characterized by a high level of basal Endoplasmic Reticulum (ER) stress, Unfolded Protein Response (UPR) activation and constitutive phosphorylation of oncogenic pathways such as [...] Read more.
Primary Effusion Lymphoma (PEL) is a highly aggressive B cell lymphoma associated with Kaposi’s Sarcoma-associated Herpesvirus (KSHV). It is characterized by a high level of basal Endoplasmic Reticulum (ER) stress, Unfolded Protein Response (UPR) activation and constitutive phosphorylation of oncogenic pathways such as the Signal Transducer and activator of Transcription (STAT3). In this study, we found that the inositol requiring kinase (IRE) 1alpha/X-box binding protein (XBP1) axis of UPR plays a key role in the survival of PEL cells, while double stranded RNA-activated protein kinase-like ER kinase (PERK) and activating transcription factor (ATF) 6 slightly influence it, in correlation with the capacity of the IRE1alpha/XBP1 axis to induce the release of interleukin (IL)-6, IL-10 and Vascular-Endothelial Growth Factor (VEGF). Moreover, we found that IRE1alpha/XBP1 inhibition reduced STAT3 Tyr705 phosphorylation and induced a pro-survival autophagy in PEL cells. In conclusion, this study suggests that targeting the IRE1alpha/XBP1 axis represents a promising strategy against PEL cells and that the cytotoxic effect of this treatment may be potentiated by autophagy inhibition. Full article
(This article belongs to the Special Issue Role of STAT3 in Oncogenesis)
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15 pages, 4037 KiB  
Article
An Electrophilic Deguelin Analogue Inhibits STAT3 Signaling in H-Ras-Transformed Human Mammary Epithelial Cells: The Cysteine 259 Residue as a Potential Target
by Sung-Jun Hong, Jin-Tae Kim, Su-Jung Kim, Nam-Chul Cho, Kyeojin Kim, Seungbeom Lee, Young-Ger Suh, Kyung-Cho Cho, Kwang Pyo Kim and Young-Joon Surh
Biomedicines 2020, 8(10), 407; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines8100407 - 12 Oct 2020
Cited by 11 | Viewed by 2506
Abstract
Signal transducer and activator of transcription 3 (STAT3) is a point of convergence for numerous oncogenic signals that are often constitutively activated in many cancerous or transformed cells and some stromal cells in the tumor microenvironment. Persistent STAT3 activation in malignant cells stimulates [...] Read more.
Signal transducer and activator of transcription 3 (STAT3) is a point of convergence for numerous oncogenic signals that are often constitutively activated in many cancerous or transformed cells and some stromal cells in the tumor microenvironment. Persistent STAT3 activation in malignant cells stimulates proliferation, survival, angiogenesis, invasion, and tumor-promoting inflammation. STAT3 undergoes activation through phosphorylation on tyrosine 705, which facilitates its dimerization. Dimeric STAT3 translocates to the nucleus, where it regulates the transcription of genes involved in cell proliferation, survival, etc. In the present study, a synthetic deguelin analogue SH48, discovered by virtual screening, inhibited the phosphorylation, nuclear translocation, and transcriptional activity of STAT3 in H-ras transformed human mammary epithelial MCF-10A cells (MCF10A-ras). We speculated that SH48 bearing an α,β-unsaturated carbonyl group could interact with a thiol residue of STAT3, thereby inactivating this transcription factor. Non-electrophilic analogues of SH48 failed to inhibit STAT3 activation, lending support to the above supposition. By utilizing a biotinylated SH48, we were able to demonstrate the complex formation between SH48 and STAT3. SH48 treatment to MCF10A-ras cells induced autophagy, which was verified by staining with a fluorescent acidotropic probe, LysoTracker Red, as well as upregulating the expression of LC3II and p62. In conclusion, the electrophilic analogue of deguelin interacts with STAT3 and inhibits its activation in MCF10A-ras cells, which may account for its induction of autophagic death. Full article
(This article belongs to the Special Issue Role of STAT3 in Oncogenesis)
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Review

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24 pages, 1187 KiB  
Review
STAT3 and p53: Dual Target for Cancer Therapy
by Thu-Huyen Pham, Hyo-Min Park, Jinju Kim, Jin Tae Hong and Do-Young Yoon
Biomedicines 2020, 8(12), 637; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines8120637 - 21 Dec 2020
Cited by 34 | Viewed by 5068
Abstract
The tumor suppressor p53 is considered the “guardian of the genome” that can protect cells against cancer by inducing cell cycle arrest followed by cell death. However, STAT3 is constitutively activated in several human cancers and plays crucial roles in promoting cancer cell [...] Read more.
The tumor suppressor p53 is considered the “guardian of the genome” that can protect cells against cancer by inducing cell cycle arrest followed by cell death. However, STAT3 is constitutively activated in several human cancers and plays crucial roles in promoting cancer cell proliferation and survival. Hence, STAT3 and p53 have opposing roles in cellular pathway regulation, as activation of STAT3 upregulates the survival pathway, whereas p53 triggers the apoptotic pathway. Constitutive activation of STAT3 and gain or loss of p53 function due to mutations are the most frequent events in numerous cancer types. Several studies have reported the association of STAT3 and/or p53 mutations with drug resistance in cancer treatment. This review discusses the relationship between STAT3 and p53 status in cancer, the molecular mechanism underlying the negative regulation of p53 by STAT3, and vice versa. Moreover, it underlines prospective therapies targeting both STAT3 and p53 to enhance chemotherapeutic outcomes. Full article
(This article belongs to the Special Issue Role of STAT3 in Oncogenesis)
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