Special Issue "STAT3 Signalling in Cancer: Friend or Foe"

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A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (30 November 2013)

Special Issue Editor

Guest Editor
Prof. Dr. James Turkson

Cell and Molecular Biology Department, John A. Burns School of Medicine, University of Hawaii 701 Ilalo Street, Suite 344, Honolulu, HI 96813, USA
Website | E-Mail
Fax: +1-808-587-0742
Interests: STAT signaling; Stat3; tumorigenesis; small-molecules; peptides; peptidomimetics; inhibitors; computational modeling; natural products; rational drug design; signal transduction; tyrosine kinases; growth factor receptor signaling

Special Issue Information

Dear Colleague,

Aberrantly-active Signal Transducer and Activator of Transcription (STAT)3 has long been strongly implicated in malignant transformation and the development of human tumors, with the prevailing knowledge that it dysregulates cellular gene expression leading to uncontrolled cell growth and survival, and promotes tumor progression. Further, new mechanisms of STAT3-mediated oncogenesis that extend beyond the traditional transcriptional function have also been reported in recent years. Notwithstanding, evidence is also emerging that leads to the suggestion that STAT3 maintains contradictory functions, and that in certain contexts the protein might regulate cellular events that promote cell death and suppress cell proliferation. These data together indicate the biological functions of STAT3 are far more complex than presently known and that the overall responses to STAT3-inhibiting drugs are likely to be context dependent. In this Issue of Cancers, “STAT3 Signaling in Cancer: Friend or Foe”, experts are invited to contribute original research papers or review articles that will provide further insights on the seemingly divergent functions of STAT3 in cellular processes.

Prof. Dr. James Turkson
Guest Editor

Submission

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Keywords

  • STAT signaling
  • STAT3
  • malignant transformation
  • tumorigenesis
  • oncogenes
  • tumor suppressor function
  • cell proliferation
  • apoptosis
  • small-molecules inhibitors
  • tyrosine kinases
  • growth factor receptors

Published Papers (15 papers)

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Research

Jump to: Review

Open AccessArticle Stat5 Exerts Distinct, Vital Functions in the Cytoplasm and Nucleus of Bcr-Abl+ K562 and Jak2(V617F)+ HEL Leukemia Cells
Cancers 2015, 7(1), 503-537; doi:10.3390/cancers7010503
Received: 16 December 2014 / Revised: 9 March 2015 / Accepted: 12 March 2015 / Published: 19 March 2015
Cited by 3 | PDF Full-text (3516 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Signal transducers and activators of transcription (Stats) play central roles in the conversion of extracellular signals, e.g., cytokines, hormones and growth factors, into tissue and cell type specific gene expression patterns. In normal cells, their signaling potential is strictly limited in extent and
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Signal transducers and activators of transcription (Stats) play central roles in the conversion of extracellular signals, e.g., cytokines, hormones and growth factors, into tissue and cell type specific gene expression patterns. In normal cells, their signaling potential is strictly limited in extent and duration. The persistent activation of Stat3 or Stat5 is found in many human tumor cells and contributes to their growth and survival. Stat5 activation plays a pivotal role in nearly all hematological malignancies and occurs downstream of oncogenic kinases, e.g., Bcr-Abl in chronic myeloid leukemias (CML) and Jak2(V617F) in other myeloproliferative diseases (MPD). We defined the mechanisms through which Stat5 affects growth and survival of K562 cells, representative of Bcr-Abl positive CML, and HEL cells, representative for Jak2(V617F) positive acute erythroid leukemia. In our experiments we suppressed the protein expression levels of Stat5a and Stat5b through shRNA mediated downregulation and demonstrated the dependence of cell survival on the presence of Stat5. Alternatively, we interfered with the functional capacities of the Stat5 protein through the interaction with a Stat5 specific peptide ligand. This ligand is a Stat5 specific peptide aptamer construct which comprises a 12mer peptide integrated into a modified thioredoxin scaffold, S5-DBD-PA. The peptide sequence specifically recognizes the DNA binding domain (DBD) of Stat5. Complex formation of S5-DBD-PA with Stat5 causes a strong reduction of P-Stat5 in the nuclear fraction of Bcr-Abl-transformed K562 cells and a suppression of Stat5 target genes. Distinct Stat5 mediated survival mechanisms were detected in K562 and Jak2(V617F)-transformed HEL cells. Stat5 is activated in the nuclear and cytosolic compartments of K562 cells and the S5-DBD-PA inhibitor most likely affects the viability of Bcr-Abl+ K562 cells through the inhibition of canonical Stat5 induced target gene transcription. In HEL cells, Stat5 is predominantly present in the cytoplasm and the survival of the Jak2(V617F)+ HEL cells is impeded through the inhibition of the cytoplasmic functions of Stat5. Full article
(This article belongs to the Special Issue STAT3 Signalling in Cancer: Friend or Foe)
Open AccessArticle STAT3 Activities and Energy Metabolism: Dangerous Liaisons
Cancers 2014, 6(3), 1579-1596; doi:10.3390/cancers6031579
Received: 13 May 2014 / Revised: 3 July 2014 / Accepted: 16 July 2014 / Published: 31 July 2014
Cited by 5 | PDF Full-text (1526 KB) | HTML Full-text | XML Full-text
Abstract
STAT3 mediates cytokine and growth factor receptor signalling, becoming transcriptionally active upon tyrosine 705 phosphorylation (Y-P). Constitutively Y-P STAT3 is observed in many tumors that become addicted to its activity, and STAT3 transcriptional activation is required for tumor transformation downstream of several oncogenes.
[...] Read more.
STAT3 mediates cytokine and growth factor receptor signalling, becoming transcriptionally active upon tyrosine 705 phosphorylation (Y-P). Constitutively Y-P STAT3 is observed in many tumors that become addicted to its activity, and STAT3 transcriptional activation is required for tumor transformation downstream of several oncogenes. We have recently demonstrated that constitutively active STAT3 drives a metabolic switch towards aerobic glycolysis through the transcriptional induction of Hif-1α and the down-regulation of mitochondrial activity, in both MEF cells expressing constitutively active STAT3 (Stat3C/C) and STAT3-addicted tumor cells. This novel metabolic function is likely involved in mediating pre-oncogenic features in the primary Stat3C/C MEFs such as resistance to apoptosis and senescence and rapid proliferation. Moreover, it strongly contributes to the ability of primary Stat3C/C MEFs to undergo malignant transformation upon spontaneous immortalization, a feature that may explain the well known causative link between STAT3 constitutive activity and tumor transformation under chronic inflammatory conditions. Taken together with the recently uncovered role of STAT3 in regulating energy metabolism from within the mitochondrion when phosphorylated on Ser 727, these data place STAT3 at the center of a hub regulating energy metabolism under different conditions, in most cases promoting cell survival, proliferation and malignant transformation even though with distinct mechanisms. Full article
(This article belongs to the Special Issue STAT3 Signalling in Cancer: Friend or Foe)
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Open AccessArticle Loss of STAT3 in Lymphoma Relaxes NK Cell-Mediated Tumor Surveillance
Cancers 2014, 6(1), 193-210; doi:10.3390/cancers6010193
Received: 2 December 2013 / Revised: 8 January 2014 / Accepted: 16 January 2014 / Published: 27 January 2014
Cited by 4 | PDF Full-text (764 KB) | HTML Full-text | XML Full-text
Abstract
The transcription factors and proto-oncogenes STAT3 and STAT5 are highly activated in hematological malignancies and represent promising therapeutic targets. Whereas the importance of STAT5 as tumor promoter is beyond doubt, the role of STAT3 in hematological cancers is less well understood. Both, enforced
[...] Read more.
The transcription factors and proto-oncogenes STAT3 and STAT5 are highly activated in hematological malignancies and represent promising therapeutic targets. Whereas the importance of STAT5 as tumor promoter is beyond doubt, the role of STAT3 in hematological cancers is less well understood. Both, enforced as well as attenuated expression of STAT3 were reported in hematopoietic malignancies. Recent evidence implicates STAT3 as key player for tumor immune surveillance as it both mediates the production of and response to inflammatory cytokines. Here we investigated the effects of STAT3 deletion in a BCR/ABL-induced lymphoma model, which is tightly controlled by natural killer (NK) cells in vivo. Upon STAT3 deletion tumor growth is significantly enhanced when compared to STAT3-expressing controls. The increased tumor size upon loss of STAT3 was accompanied by reduced NK cell infiltration and decreased levels of the cytokine IFN-γ and the chemokine RANTES. Upon transplantation into NK cell-deficient mice differences in lymphoma size were abolished indicating that STAT3 expression in the tumor cells controls NK cell-dependent tumor surveillance. Our findings indicate that STAT3 inhibition in lymphoma patients will impair NK cell-mediated tumor surveillance, which needs to be taken into account when testing STAT3 inhibitors in preclinical or clinical trials. Full article
(This article belongs to the Special Issue STAT3 Signalling in Cancer: Friend or Foe)
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Review

Jump to: Research

Open AccessReview STAT3: A Novel Molecular Mediator of Resistance to Chemoradiotherapy
Cancers 2014, 6(4), 1986-2011; doi:10.3390/cancers6041986
Received: 30 May 2014 / Revised: 28 August 2014 / Accepted: 4 September 2014 / Published: 29 September 2014
Cited by 15 | PDF Full-text (905 KB) | HTML Full-text | XML Full-text
Abstract
Chemoradiotherapy (CRT) represents a standard treatment for many human cancers, frequently combined with radical surgical resection. However, a considerable percentage of primary cancers are at least partially resistant to CRT, which represents a substantial clinical problem, because it exposes cancer patients to the
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Chemoradiotherapy (CRT) represents a standard treatment for many human cancers, frequently combined with radical surgical resection. However, a considerable percentage of primary cancers are at least partially resistant to CRT, which represents a substantial clinical problem, because it exposes cancer patients to the potential side effects of both irradiation and chemotherapy. It is therefore exceedingly important to determine the molecular characteristics underlying CRT-resistance and to identify novel molecular targets that can be manipulated to re-sensitize resistant tumors to CRT. In this review, we highlight much of the recent evidence suggesting that the signal transducer and activator of transcription 3 (STAT3) plays a prominent role in mediating CRT-resistance, and we outline why inhibition of STAT3 holds great promise for future multimodal treatment concepts in oncology. Full article
(This article belongs to the Special Issue STAT3 Signalling in Cancer: Friend or Foe)
Open AccessReview STAT3: An Anti-Invasive Factor in Colorectal Cancer?
Cancers 2014, 6(3), 1394-1407; doi:10.3390/cancers6031394
Received: 5 March 2014 / Revised: 13 June 2014 / Accepted: 20 June 2014 / Published: 3 July 2014
Cited by 7 | PDF Full-text (414 KB) | HTML Full-text | XML Full-text
Abstract
Signal Transducer and Activator of Transcription 3 (STAT3) is activated in a majority of cancers, and promotes tumorigenesis and even metastasis through transcriptional activation of its target genes. Recently, we discovered that STAT3 suppresses epithelial-to-mesenchymal transition (EMT) and thus metastasis in a mouse
[...] Read more.
Signal Transducer and Activator of Transcription 3 (STAT3) is activated in a majority of cancers, and promotes tumorigenesis and even metastasis through transcriptional activation of its target genes. Recently, we discovered that STAT3 suppresses epithelial-to-mesenchymal transition (EMT) and thus metastasis in a mouse model of colorectal cancer (CRC), while it did not affect the overall tumor burden. Furthermore, we found that STAT3 in intestinal epithelial cells (IEC) suppresses EMT by regulating stability of an EMT inducer, SNAI-1 (Snail-1). Here, STAT3 functions as an adaptor rather than a transcription factor in the post-translational modification of SNAI-1. In this review, we discuss the unexpected and contradictory role of STAT3 in metastasis of CRC and its clinical implications. Full article
(This article belongs to the Special Issue STAT3 Signalling in Cancer: Friend or Foe)
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Open AccessReview STAT3 in Cancer—Friend or Foe?
Cancers 2014, 6(3), 1408-1440; doi:10.3390/cancers6031408
Received: 17 April 2014 / Revised: 19 June 2014 / Accepted: 20 June 2014 / Published: 3 July 2014
Cited by 16 | PDF Full-text (1314 KB) | HTML Full-text | XML Full-text
Abstract
The roles and significance of STAT3 in cancer biology have been extensively studied for more than a decade. Mounting evidence has shown that constitutive activation of STAT3 is a frequent biochemical aberrancy in cancer cells, and this abnormality directly contributes to tumorigenesis and
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The roles and significance of STAT3 in cancer biology have been extensively studied for more than a decade. Mounting evidence has shown that constitutive activation of STAT3 is a frequent biochemical aberrancy in cancer cells, and this abnormality directly contributes to tumorigenesis and shapes many malignant phenotypes in cancer cells. Nevertheless, results from more recent experimental and clinicopathologic studies have suggested that STAT3 also can exert tumor suppressor effects under specific conditions. Importantly, some of these studies have demonstrated that STAT3 can function either as an oncoprotein or a tumor suppressor in the same cell type, depending on the specific genetic background or presence/absence of specific coexisting biochemical defects. Thus, in the context of cancer biology, STAT3 can be a friend or foe. In the first half of this review, we will highlight the “evil” features of STAT3 by summarizing its oncogenic functions and mechanisms. The differences between the canonical and non-canonical pathway will be highlighted. In the second half, we will summarize the evidence supporting that STAT3 can function as a tumor suppressor. To explain how STAT3 may mediate its tumor suppressor effects, we will discuss several possible mechanisms, one of which is linked to the role of STAT3β, one of the two STAT3 splicing isoforms. Taken together, it is clear that the roles of STAT3 in cancer are multi-faceted and far more complicated than one appreciated previously. The new knowledge has provided us with new approaches and strategies when we evaluate STAT3 as a prognostic biomarker or therapeutic target. Full article
(This article belongs to the Special Issue STAT3 Signalling in Cancer: Friend or Foe)
Open AccessReview STAT3 Activity and Function in Cancer: Modulation by STAT5 and miR-146b
Cancers 2014, 6(2), 958-968; doi:10.3390/cancers6020958
Received: 24 January 2014 / Revised: 19 March 2014 / Accepted: 28 March 2014 / Published: 23 April 2014
Cited by 8 | PDF Full-text (513 KB) | HTML Full-text | XML Full-text
Abstract
The transcription factor STAT3 regulates genes that control critical cellular processes such as proliferation, survival, pluripotency, and motility. Thus, under physiological conditions, the transcriptional function of STAT3 is tightly regulated as one part of a complex signaling matrix. When these processes are subverted
[...] Read more.
The transcription factor STAT3 regulates genes that control critical cellular processes such as proliferation, survival, pluripotency, and motility. Thus, under physiological conditions, the transcriptional function of STAT3 is tightly regulated as one part of a complex signaling matrix. When these processes are subverted through mutation or epigenetic events, STAT3 becomes highly active and drives elevated expression of genes underlying these phenotypes, leading to malignant cellular behavior. However, even in the presence of activated STAT3, other cellular modulators can have a major impact on the biological properties of a cancer cell, which is reflected in the clinical behavior of a tumor. Recent evidence has suggested that two such key modulators are the activation status of other STAT family members, particularly STAT5, and the expression of STAT3-regulated genes that are part of negative feedback circuits, including microRNAs such as miR-146b. With attention to these newly emerging areas, we will gain greater insight into the consequence of STAT3 activation in the biology of human cancers. In addition, understanding these subtleties of STAT3 signaling in cancer pathogenesis will allow the development of more rational molecular approaches to cancer therapy. Full article
(This article belongs to the Special Issue STAT3 Signalling in Cancer: Friend or Foe)
Open AccessReview STAT3 Target Genes Relevant to Human Cancers
Cancers 2014, 6(2), 897-925; doi:10.3390/cancers6020897
Received: 3 January 2014 / Revised: 22 March 2014 / Accepted: 28 March 2014 / Published: 16 April 2014
Cited by 50 | PDF Full-text (708 KB) | HTML Full-text | XML Full-text
Abstract
Since its discovery, the STAT3 transcription factor has been extensively studied for its function as a transcriptional regulator and its role as a mediator of development, normal physiology, and pathology of many diseases, including cancers. These efforts have uncovered an array of genes
[...] Read more.
Since its discovery, the STAT3 transcription factor has been extensively studied for its function as a transcriptional regulator and its role as a mediator of development, normal physiology, and pathology of many diseases, including cancers. These efforts have uncovered an array of genes that can be positively and negatively regulated by STAT3, alone and in cooperation with other transcription factors. Through regulating gene expression, STAT3 has been demonstrated to play a pivotal role in many cellular processes including oncogenesis, tumor growth and progression, and stemness. Interestingly, recent studies suggest that STAT3 may behave as a tumor suppressor by activating expression of genes known to inhibit tumorigenesis. Additional evidence suggested that STAT3 may elicit opposing effects depending on cellular context and tumor types. These mixed results signify the need for a deeper understanding of STAT3, including its upstream regulators, parallel transcription co-regulators, and downstream target genes. To help facilitate fulfilling this unmet need, this review will be primarily focused on STAT3 downstream target genes that have been validated to associate with tumorigenesis and/or malignant biology of human cancers. Full article
(This article belongs to the Special Issue STAT3 Signalling in Cancer: Friend or Foe)
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Open AccessReview Transcription Factor STAT3 as a Novel Molecular Target for Cancer Prevention
Cancers 2014, 6(2), 926-957; doi:10.3390/cancers6020926
Received: 13 December 2013 / Revised: 11 March 2014 / Accepted: 18 March 2014 / Published: 16 April 2014
Cited by 42 | PDF Full-text (1068 KB) | HTML Full-text | XML Full-text
Abstract
Signal Transducers and Activators of Transcription (STATs) are a family of transcription factors that regulate cell proliferation, differentiation, apoptosis, immune and inflammatory responses, and angiogenesis. Cumulative evidence has established that STAT3 has a critical role in the development of multiple cancer types. Because
[...] Read more.
Signal Transducers and Activators of Transcription (STATs) are a family of transcription factors that regulate cell proliferation, differentiation, apoptosis, immune and inflammatory responses, and angiogenesis. Cumulative evidence has established that STAT3 has a critical role in the development of multiple cancer types. Because it is constitutively activated during disease progression and metastasis in a variety of cancers, STAT3 has promise as a drug target for cancer therapeutics. Recently, STAT3 was found to have an important role in maintaining cancer stem cells in vitro and in mouse tumor models, suggesting STAT3 is integrally involved in tumor initiation, progression and maintenance. STAT3 has been traditionally considered as nontargetable or undruggable, and the lag in developing effective STAT3 inhibitors contributes to the current lack of FDA-approved STAT3 inhibitors. Recent advances in cancer biology and drug discovery efforts have shed light on targeting STAT3 globally and/or specifically for cancer therapy. In this review, we summarize current literature and discuss the potential importance of STAT3 as a novel target for cancer prevention and of STAT3 inhibitors as effective chemopreventive agents. Full article
(This article belongs to the Special Issue STAT3 Signalling in Cancer: Friend or Foe)
Open AccessReview The Multifaceted Roles of STAT3 Signaling in the Progression of Prostate Cancer
Cancers 2014, 6(2), 829-859; doi:10.3390/cancers6020829
Received: 8 February 2014 / Revised: 11 March 2014 / Accepted: 17 March 2014 / Published: 9 April 2014
Cited by 26 | PDF Full-text (504 KB) | HTML Full-text | XML Full-text
Abstract
The signal transducer and activator of transcription (STAT)3 governs essential functions of epithelial and hematopoietic cells that are often dysregulated in cancer. While the role for STAT3 in promoting the progression of many solid and hematopoietic malignancies is well established, this review will
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The signal transducer and activator of transcription (STAT)3 governs essential functions of epithelial and hematopoietic cells that are often dysregulated in cancer. While the role for STAT3 in promoting the progression of many solid and hematopoietic malignancies is well established, this review will focus on the importance of STAT3 in prostate cancer progression to the incurable metastatic castration-resistant prostate cancer (mCRPC). Indeed, STAT3 integrates different signaling pathways involved in the reactivation of androgen receptor pathway, stem like cells and the epithelial to mesenchymal transition that drive progression to mCRPC. As equally important, STAT3 regulates interactions between tumor cells and the microenvironment as well as immune cell activation. This makes it a major factor in facilitating prostate cancer escape from detection of the immune response, promoting an immunosuppressive environment that allows growth and metastasis. Based on the multifaceted nature of STAT3 signaling in the progression to mCRPC, the promise of STAT3 as a therapeutic target to prevent prostate cancer progression and the variety of STAT3 inhibitors used in cancer therapies is discussed. Full article
(This article belongs to the Special Issue STAT3 Signalling in Cancer: Friend or Foe)
Open AccessReview The Role of STAT3 in Non-Small Cell Lung Cancer
Cancers 2014, 6(2), 708-722; doi:10.3390/cancers6020708
Received: 5 December 2013 / Revised: 23 February 2014 / Accepted: 7 March 2014 / Published: 26 March 2014
Cited by 22 | PDF Full-text (495 KB) | HTML Full-text | XML Full-text
Abstract
Persistent phosphorylation of signal transducer and activator of transcription 3 (STAT3) has been demonstrated in 22%~65% of non-small cell lung cancers (NSCLC). STAT3 activation is mediated by receptor tyrosine kinases, such as epidermal growth factor receptor (EGFR) and MET, cytokine receptors, such as
[...] Read more.
Persistent phosphorylation of signal transducer and activator of transcription 3 (STAT3) has been demonstrated in 22%~65% of non-small cell lung cancers (NSCLC). STAT3 activation is mediated by receptor tyrosine kinases, such as epidermal growth factor receptor (EGFR) and MET, cytokine receptors, such as IL-6, and non-receptor kinases, such as Src. Overexpression of total or phosphorylated STAT3 in resected NSCLC leads to poor prognosis. In a preclinical study, overexpression of STAT3 was correlated with chemoresistance and radioresistance in NSCLC cells. Here, we review the role of STAT3 and the mechanisms of treatment resistance in malignant diseases, especially NSCLC. As STAT3 is a critical mediator of the oncogenic effects of EGFR mutations, we discuss STAT3 pathways in EGFR-mutated NSCLC, referring to mechanisms of EGFR tyrosine kinase inhibitor resistance. Full article
(This article belongs to the Special Issue STAT3 Signalling in Cancer: Friend or Foe)
Open AccessReview Stat3 and Gap Junctions in Normal and Lung Cancer Cells
Cancers 2014, 6(2), 646-662; doi:10.3390/cancers6020646
Received: 14 November 2013 / Revised: 11 February 2014 / Accepted: 27 February 2014 / Published: 25 March 2014
Cited by 4 | PDF Full-text (3176 KB) | HTML Full-text | XML Full-text
Abstract
Gap junctions are channels linking the interiors of neighboring cells. A reduction in gap junctional intercellular communication (GJIC) correlates with high cell proliferation, while oncogene products such as Src suppress GJIC, through the Ras/Raf/Erk and other effector pathways. High Src activity was found
[...] Read more.
Gap junctions are channels linking the interiors of neighboring cells. A reduction in gap junctional intercellular communication (GJIC) correlates with high cell proliferation, while oncogene products such as Src suppress GJIC, through the Ras/Raf/Erk and other effector pathways. High Src activity was found to correlate with high levels of the Src effector, Signal Transducer and Activator of Transcription-3 (Stat3) in its tyrosine-705 phosphorylated, i.e., transcriptionally activated form, in the majority of Non-Small Cell Lung Cancer lines examined. However, Stat3 inhibition did not restore GJIC in lines with high Src activity. In the contrary, Stat3 inhibition in normal cells or in lines with low Src activity and high GJIC eliminated gap junctional communication. Therefore, despite the fact that Stat3 is growth promoting and in an activated form acts like an oncogene, it is actually required for junctional permeability. Full article
(This article belongs to the Special Issue STAT3 Signalling in Cancer: Friend or Foe)
Open AccessReview Genetic Interactions of STAT3 and Anticancer Drug Development
Cancers 2014, 6(1), 494-525; doi:10.3390/cancers6010494
Received: 13 November 2013 / Revised: 18 February 2014 / Accepted: 20 February 2014 / Published: 6 March 2014
Cited by 6 | PDF Full-text (629 KB) | HTML Full-text | XML Full-text
Abstract
Signal transducer and activator of transcription 3 (STAT3) plays critical roles in tumorigenesis and malignant evolution and has been intensively studied as a therapeutic target for cancer. A number of STAT3 inhibitors have been evaluated for their antitumor activity in vitro and in
[...] Read more.
Signal transducer and activator of transcription 3 (STAT3) plays critical roles in tumorigenesis and malignant evolution and has been intensively studied as a therapeutic target for cancer. A number of STAT3 inhibitors have been evaluated for their antitumor activity in vitro and in vivo in experimental tumor models and several approved therapeutic agents have been reported to function as STAT3 inhibitors. Nevertheless, most STAT3 inhibitors have yet to be translated to clinical evaluation for cancer treatment, presumably because of pharmacokinetic, efficacy, and safety issues. In fact, a major cause of failure of anticancer drug development is lack of efficacy. Genetic interactions among various cancer-related pathways often provide redundant input from parallel and/or cooperative pathways that drives and maintains survival environments for cancer cells, leading to low efficacy of single-target agents. Exploiting genetic interactions of STAT3 with other cancer-related pathways may provide molecular insight into mechanisms of cancer resistance to pathway-targeted therapies and strategies for development of more effective anticancer agents and treatment regimens. This review focuses on functional regulation of STAT3 activity; possible interactions of the STAT3, RAS, epidermal growth factor receptor, and reduction-oxidation pathways; and molecular mechanisms that modulate therapeutic efficacies of STAT3 inhibitors. Full article
(This article belongs to the Special Issue STAT3 Signalling in Cancer: Friend or Foe)
Open AccessReview The Role of STAT3 in Thyroid Cancer
Cancers 2014, 6(1), 526-544; doi:10.3390/cancers6010526
Received: 16 December 2013 / Revised: 15 February 2014 / Accepted: 27 February 2014 / Published: 6 March 2014
Cited by 5 | PDF Full-text (403 KB) | HTML Full-text | XML Full-text
Abstract
Thyroid cancer is the most common endocrine malignancy and its global incidence rates are rapidly increasing. Although the mortality of thyroid cancer is relatively low, its rate of recurrence or persistence is relatively high, contributing to incurability and morbidity of the disease. Thyroid
[...] Read more.
Thyroid cancer is the most common endocrine malignancy and its global incidence rates are rapidly increasing. Although the mortality of thyroid cancer is relatively low, its rate of recurrence or persistence is relatively high, contributing to incurability and morbidity of the disease. Thyroid cancer is mainly treated by surgery and radioiodine remnant ablation, which is effective only for non-metastasized primary tumors. Therefore, better understanding of the molecular targets available in this tumor is necessary. Similarly to many other tumor types, oncogenic molecular alterations in thyroid epithelium include aberrant signal transduction of the mitogen-activated protein kinase, phosphatidylinositol 3-kinase/AKT (also known as protein kinase B), NF-кB, and WNT/β-catenin pathways. However, the role of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT3) pathway, a well-known mediator of tumorigenesis in different tumor types, is relatively less understood in thyroid cancer. Intriguingly, recent studies have demonstrated that, in thyroid cancer, the JAK/STAT3 pathway may function in the context of tumor suppression rather than promoting tumorigenesis. In this review, we provide an update of STAT3 function in thyroid cancer and discuss some of the evidences that support this hypothesis. Full article
(This article belongs to the Special Issue STAT3 Signalling in Cancer: Friend or Foe)
Open AccessReview STAT3 Activation in Glioblastoma: Biochemical and Therapeutic Implications
Cancers 2014, 6(1), 376-395; doi:10.3390/cancers6010376
Received: 16 December 2013 / Revised: 19 January 2014 / Accepted: 29 January 2014 / Published: 10 February 2014
Cited by 20 | PDF Full-text (398 KB) | HTML Full-text | XML Full-text
Abstract
Signal transducer and activator of transcription 3 (STAT3) is a potent regulator of gliomagenesis through its induction of angiogenesis, host immunosuppression, and tumor invasion. Gain of function mutations result in constitutive activation of STAT3 in glioma cells, making STAT3 an attractive target for
[...] Read more.
Signal transducer and activator of transcription 3 (STAT3) is a potent regulator of gliomagenesis through its induction of angiogenesis, host immunosuppression, and tumor invasion. Gain of function mutations result in constitutive activation of STAT3 in glioma cells, making STAT3 an attractive target for inhibition in cancer therapy. Nevertheless, some studies show that STAT3 also participates in terminal differentiation and apoptosis of various cell lines and in glioma with phosphatase and tensin homolog (PTEN)-deficient genetic backgrounds. In light of these findings, the utility of STAT3 as a prognostic indicator and as a target of drug therapies will be contingent on a more nuanced understanding of its pro- and anti-tumorigenic effects. Full article
(This article belongs to the Special Issue STAT3 Signalling in Cancer: Friend or Foe)

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