scholarly journals The Multifaced Role of STAT3 in Cancer and Its Implication for Anticancer Therapy

2021 ◽  
Vol 22 (2) ◽  
pp. 603
Author(s):  
Manlio Tolomeo ◽  
Antonio Cascio
Keyword(s):  
Tumor Promoter ◽  
Tumor Type ◽  
Signal Transducer ◽  
Suppressor Factor ◽  
Specific Tumor ◽  
Cytokine Stimulation ◽  
Pleiotropic Functions ◽  
Stat3 Mutations ◽  
Potent Tumor

Signal transducer and activator of transcription (STAT) 3 is one of the most complex regulators of transcription. Constitutive activation of STAT3 has been reported in many types of tumors and depends on mechanisms such as hyperactivation of receptors for pro-oncogenic cytokines and growth factors, loss of negative regulation, and excessive cytokine stimulation. In contrast, somatic STAT3 mutations are less frequent in cancer. Several oncogenic targets of STAT3 have been recently identified such as c-myc, c-Jun, PLK-1, Pim1/2, Bcl-2, VEGF, bFGF, and Cten, and inhibitors of STAT3 have been developed for cancer prevention and treatment. However, despite the oncogenic role of STAT3 having been widely demonstrated, an increasing amount of data indicate that STAT3 functions are multifaced and not easy to classify. In fact, the specific cellular role of STAT3 seems to be determined by the integration of multiple signals, by the oncogenic environment, and by the alternative splicing into two distinct isoforms, STAT3α and STAT3β. On the basis of these different conditions, STAT3 can act both as a potent tumor promoter or tumor suppressor factor. This implies that the therapies based on STAT3 modulators should be performed considering the pleiotropic functions of this transcription factor and tailored to the specific tumor type.

scholarly journals Somatic mutations activating STAT3 in human inflammatory hepatocellular adenomas

2011 ◽  
Vol 208 (7) ◽  
pp. 1359-1366 ◽  
Author(s):  
Camilla Pilati ◽  
Mohamed Amessou ◽  
Michel P. Bihl ◽  
Charles Balabaud ◽  
Jeanne Tran Van Nhieu ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Liver Tumors ◽  
Sh2 Domain ◽  
Signal Transducer ◽  
Somatic Signal ◽  
First Time ◽  
Transcription 3 ◽  
Stat3 Mutations ◽  
Hepatocellular Adenomas

Inflammatory hepatocellular adenomas (IHCAs) are benign liver tumors. 60% of these tumors have IL-6 signal transducer (IL6ST; gp130) mutations that activate interleukin 6 (IL-6) signaling. Here, we report that 12% of IHCA subsets lacking IL6ST mutations harbor somatic signal transducer and activator of transcription 3 (STAT3) mutations (6/49). Most of these mutations are amino acid substitutions in the SH2 domain that directs STAT3 dimerization. In contrast to wild-type STAT3, IHCA STAT3 mutants constitutively activated the IL-6 signaling pathway independent of ligand in hepatocellular cells. Indeed, the IHCA STAT3 Y640 mutant homodimerized independent of IL-6 and was hypersensitive to IL-6 stimulation. This was associated with phosphorylation of tyrosine 705, a residue required for IL-6–induced STAT3 activation. Silencing or inhibiting the tyrosine kinases JAK1 or Src, which phosphorylate STAT3, impaired constitutive activity of IHCA STAT3 mutants in hepatocellular cells. Thus, we identified for the first time somatic STAT3 mutations in human tumors, revealing a new mechanism of recurrent STAT3 activation and underscoring the role of the IL-6–STAT3 pathway in benign hepatocellular tumorigenesis.

scholarly journals Cystatin M/E (Cystatin 6): A Janus-Faced Cysteine Protease Inhibitor with Both Tumor-Suppressing and Tumor-Promoting Functions

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1877
Author(s):  
Gilles Lalmanach ◽  
Mariana Kasabova-Arjomand ◽  
Fabien Lecaille ◽  
Ahlame Saidi
Keyword(s):  
Prognostic Significance ◽  
Tight Binding ◽  
Cysteine Protease Inhibitor ◽  
Tumor Promoter ◽  
Regulatory Mechanisms ◽  
Placental Development ◽  
Cysteine Cathepsins ◽  
Cystatin M

Alongside its contribution in maintaining skin homeostasis and its probable involvement in fetal and placental development, cystatin M/E (also known as cystatin 6) was first described as a tumor suppressor of breast cancer. This review aims to provide an update on cystatin M/E with particular attention paid to its role during tumorigenesis. Cystatin M/E, which is related to type 2 cystatins, displays the unique property of being a dual tight-binding inhibitor of both legumain (also known as asparagine endopeptidase) and cysteine cathepsins L, V and B, while its expression level is epigenetically regulated via the methylation of the CST6 promoter region. The tumor-suppressing role of cystatin M/E was further reported in melanoma, cervical, brain, prostate, gastric and renal cancers, and cystatin M/E was proposed as a biomarker of prognostic significance. Contrariwise, cystatin M/E could have an antagonistic function, acting as a tumor promoter (e.g., oral, pancreatic cancer, thyroid and hepatocellular carcinoma). Taking into account these apparently divergent functions, there is an urgent need to decipher the molecular and cellular regulatory mechanisms of the expression and activity of cystatin M/E associated with the safeguarding homeostasis of the proteolytic balance as well as its imbalance in cancer.

scholarly journals Genetic Suppressor Element 1 (GSE1) Promotes the Oncogenic and Recurrent Phenotypes of Castration-Resistant Prostate Cancer by Targeting Tumor-Associated Calcium Signal Transducer 2 (TACSTD2)

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 3959
Author(s):  
Oluwaseun Adebayo Bamodu ◽  
Yuan-Hung Wang ◽  
Chen-Hsun Ho ◽  
Su-Wei Hu ◽  
Chia-Da Lin ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Disease Progression ◽  
Therapy Resistance ◽  
Calcium Signal ◽  
Signal Transducer ◽  
Castration Resistance ◽  
Castration Resistant

Background: prostate cancer (PCa) is a principal cause of cancer-related morbidity and mortality. Castration resistance and metastasis are clinical challenges and continue to impede therapeutic success, despite diagnostic and therapeutic advances. There are reports of the oncogenic activity of genetic suppressor element (GSE)1 in breast and gastric cancers; however, its role in therapy resistance, metastasis, and susceptibility to disease recurrence in PCa patients remains unclear. Objective: this study investigated the role of aberrantly expressed GSE1 in the metastasis, therapy resistance, relapse, and poor prognosis of advanced PCa. Methods: we used a large cohort of multi-omics data and in vitro, ex vivo, and in vivo assays to investigate the potential effect of altered GSE1 expression on advanced/castration-resistant PCa (CRPC) treatment responses, disease progression, and prognosis. Results: using a multi-cohort approach, we showed that GSE1 is upregulated in PCa, while tumor-associated calcium signal transducer 2 (TACSTD2) is downregulated. Moreover, the direct, but inverse, correlation interaction between GSE1 and TACSTD2 drives metastatic disease, castration resistance, and disease progression and modulates the clinical and immune statuses of patients with PCa. Patients with GSE1highTACSTD2low expression are more prone to recurrence and disease-specific death than their GSE1lowTACSTD2high counterparts. Interestingly, we found that the GSE1–TACSTD2 expression profile is associated with the therapy responses and clinical outcomes in patients with PCa, especially those with metastatic/recurrent disease. Furthermore, we demonstrate that the shRNA-mediated targeting of GSE1 (shGSE1) significantly inhibits cell proliferation and attenuates cell migration and tumorsphere formation in metastatic PC3 and DU145 cell lines, with an associated suppression of VIM, SNAI2, and BCL2 and the concomitant upregulation of TACSTD2 and BAX. Moreover, shGSE1 enhances sensitivity to the antiandrogens abiraterone and enzalutamide in vitro and in vivo. Conclusion: these data provide preclinical evidence of the oncogenic role of dysregulated GSE1–TACSTD2 signaling and show that the molecular or pharmacological targeting of GSE1 is a workable therapeutic strategy for inhibiting androgen-driven oncogenic signals, re-sensitizing CRPC to treatment, and repressing the metastatic/recurrent phenotypes of patients with PCa.

The Role of Signal Transducer and Activator of Transcription 3 (Stat3) in Stretch Injury to Bladder Smooth Muscle Cells

2007 ◽  
Vol 3 ◽  
pp. S35
Author(s):  
Sarel Halachmi ◽  
Karen Aitken ◽  
Martha Szybowska ◽  
Nesrin Sabha ◽  
Shariff Dessouki ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Signal Transducer ◽  
Bladder Smooth Muscle ◽  
Stretch Injury ◽  
Transcription 3

scholarly journals Regulation of Jak2 Function by Phosphorylation of Tyr317 and Tyr637 during Cytokine Signaling

2009 ◽  
Vol 29 (12) ◽  
pp. 3367-3378 ◽  
Author(s):  
Scott A. Robertson ◽  
Rositsa I. Koleva ◽  
Lawrence S. Argetsinger ◽  
Christin Carter-Su ◽  
Jarrod A. Marto ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Activity ◽  
Feedback Inhibition ◽  
Dominant Role ◽  
Kinase Domain ◽  
Cytokine Signaling ◽  
Tyrosine Kinase Domain ◽  
Phosphorylation Sites ◽  
Cytokine Stimulation

ABSTRACT Jak2, the cognate tyrosine kinase for numerous cytokine receptors, undergoes multisite phosphorylation during cytokine stimulation. To understand the role of phosphorylation in Jak2 regulation, we used mass spectrometry to identify numerous Jak2 phosphorylation sites and characterize their significance for Jak2 function. Two sites outside of the tyrosine kinase domain, Tyr317 in the FERM domain and Tyr637 in the JH2 domain, exhibited strong regulation of Jak2 activity. Mutation of Tyr317 promotes increased Jak2 activity, and the phosphorylation of Tyr317 during cytokine signaling requires prior activation loop phosphorylation, which is consistent with a role for Tyr317 in the feedback inhibition of Jak2 kinase activity after receptor stimulation. Comparison to several previously identified regulatory phosphorylation sites on Jak2 revealed a dominant role for Tyr317 in the attenuation of Jak2 signaling. In contrast, mutation of Tyr637 decreased Jak2 signaling and activity and partially suppressed the activating JH2 V617F mutation, suggesting a role for Tyr637 phosphorylation in the release of JH2 domain-mediated suppression of Jak2 kinase activity during cytokine stimulation. The phosphorylation of Tyr317 and Tyr637 act in concert with other regulatory events to maintain appropriate control of Jak2 activity and cytokine signaling.

A common epitope is shared by activated signal transducer and activator of transcription-5 (STAT5) and the phosphorylated erythropoietin receptor: implications for the docking model of STAT activation

Blood ◽  
2001 ◽  
Vol 97 (8) ◽  
pp. 2230-2237 ◽  
Author(s):  
Dwayne L. Barber ◽  
Bryan K. Beattie ◽  
Jacqueline M. Mason ◽  
Melody H.-H. Nguyen ◽  
Monique Yoakim ◽  
...  
Keyword(s):  
Structural Features ◽  
Sh2 Domain ◽  
Erythropoietin Receptor ◽  
Janus Kinase ◽  
Signal Transducer ◽  
Specific Antibodies ◽  
Docking Model ◽  
Receptor Interactions ◽  
Cytokine Stimulation ◽  
Carboxy Terminal

Abstract Erythropoietin (EPO) specifically activates the Janus kinase JAK2 and the transcription factor signal transducer and activator of transcription-5 (STAT5). All members of the STAT family are tyrosine phosphorylated in response to cytokine stimulation at a conserved carboxy-terminal tyrosine, Y694, in the case of STAT5. To determine structural features important for STAT signaling, we generated an activation-specific STAT5 antibody using a phosphopeptide containing amino acids 687 to 698 of STAT5 as antigen. This antibody specifically recognizes tyrosine- phosphorylated STAT5 but not nonphosphorylated STAT5. In immunoprecipitation reactions from cell lines and primary erythroblasts, 2 distinct polyclonal activation-specific STAT5 antibodies selectively immunoprecipitate the tyrosine phosphorylated EPO receptor (EPO-R) in addition to STAT5 under native and denaturing conditions. We propose that the activation-specific STAT5 antibody recognizes the 2 substrates to which the STAT5 SH2 domain interacts, namely, the tyrosine- phosphorylated EPO-R and STAT5 itself. Several studies have implicated EPO-R Y343, Y401, Y431, and Y479 in the recruitment of STAT5. Using a series of EPO-R tyrosine mutants expressed in Ba/F3 cells, we have shown that the activation-specific STAT5 antibody immunoprecipitates an EPO-R containing only 2 tyrosines at positions 343 and 401, confirming the importance of these tyrosines in STAT5 recruitment. These data uncover a novel aspect of STAT SH2 domain recognition and demonstrate the utility of activation-specific antibodies for examining the specificity of STAT–cytokine receptor interactions.

scholarly journals Genetic Evidence for an Essential Role of Neuronally Expressed IL-6 Signal Transducer gp130 in the Induction and Maintenance of Experimentally Induced Mechanical Hypersensitivityin vivoandin vitro

2011 ◽  
Vol 7 ◽  
pp. 1744-8069-7-73 ◽  
Author(s):  
Serena Quarta ◽  
Christian Vogl ◽  
Cristina E Constantin ◽  
Nurcan Üçeyler ◽  
Claudia Sommer ◽  
...  
Keyword(s):  
Essential Role ◽  
Genetic Evidence ◽  
Signal Transducer ◽  
Experimentally Induced

scholarly journals The Role of Non-Coding RNAs in the Regulation of the Proto-Oncogene MYC in Different Types of Cancer

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 921
Author(s):  
Ekaterina Mikhailovna Stasevich ◽  
Matvey Mikhailovich Murashko ◽  
Lyudmila Sergeevna Zinevich ◽  
Denis Eriksonovich Demin ◽  
Anton Markovich Schwartz
Keyword(s):  
Malignant Tumors ◽  
Current Data ◽  
Cellular Processes ◽  
Cell Divisions ◽  
Specific Tumor ◽  
Different Types ◽  
Myc Gene ◽  
Non Coding Rnas ◽  
Tumor Types

Alterations in the expression level of the MYC gene are often found in the cells of various malignant tumors. Overexpressed MYC has been shown to stimulate the main processes of oncogenesis: uncontrolled growth, unlimited cell divisions, avoidance of apoptosis and immune response, changes in cellular metabolism, genomic instability, metastasis, and angiogenesis. Thus, controlling the expression of MYC is considered as an approach for targeted cancer treatment. Since c-Myc is also a crucial regulator of many cellular processes in healthy cells, it is necessary to find ways for selective regulation of MYC expression in tumor cells. Many recent studies have demonstrated that non-coding RNAs play an important role in the regulation of the transcription and translation of this gene and some RNAs directly interact with the c-Myc protein, affecting its stability. In this review, we summarize current data on the regulation of MYC by various non-coding RNAs that can potentially be targeted in specific tumor types.

Expression of Activated and Latent Signal Transducer and Activator of Transcription 3 in 303 Non–Small Cell Lung Carcinomas and 44 Malignant Mesotheliomas: Possible Role for Chemotherapeutic Intervention

2007 ◽  
Vol 131 (9) ◽  
pp. 1350-1360 ◽  
Author(s):  
Rosanede Oliveira Duarte Achcar ◽  
Philip T. Cagle ◽  
Jaishree Jagirdar
Keyword(s):  
Therapeutic Target ◽  
Critical Role ◽  
Active Form ◽  
Small Cell ◽  
Tumor Type ◽  
Signal Transducer ◽  
Small Cell Lung ◽  
Cell Lung Carcinoma ◽  
Transcription 3 ◽  
Mib 1

Abstract Context.—Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in diverse human cancers and plays a critical role in tumor cell survival, proliferation, migration, invasion, angiogenesis, and inhibition of apoptosis. The phosphorylated active form of STAT3 (pSTAT3) mediates its effects via nuclear transcriptional activity. However, it was recently observed that the nonphosphorylated, cytoplasmic, inactive form of STAT3 is involved in cell motility and consequently tumor invasion. It appears that, although STAT3 is not absolutely required for tumor formation, tumors that develop in the presence of STAT3 become dependent on its expression for their survival, making it a potential therapeutic target. Objective.—To investigate the possible utility of STAT3 as a future therapeutic target in non–small cell lung carcinoma (NSCLC) and malignant mesothelioma (MM). Design.—Immunohistochemical expression of MIB-1, STAT3, and pSTAT3 was assessed in 303 NSCLC and 44 MM archival cases. Results.—A more conspicuous expression of inactive STAT3 (91.44% in NSCLC and 79.5% in MM cases) was present compared with the nuclear activated form pSTAT3 (60.53% in NSCLC and 61.4% in MM cases). MIB-1 did not correlate with the expression of STAT3 or pSTAT3. Conclusions.—The strong expression of cytoplasmic inactive STAT3 in NSCLC and MM cases implies a major role for STAT3 in tumor motility, invasion, and metastasis via a nontranscriptional pathway. We conclude that STAT3 and pSTAT3 are up-regulated in a high percentage of NSCLCs and MMs, regardless of tumor type, age, sex, smoking status, stage and grade of tumor, or survival, providing a basis for therapeutic intervention.

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