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Thuya WL, Cao Y, Ho PCL, Wong ALA, Wang L, Zhou J, Nicot C, Goh BC. Insights into IL-6/JAK/STAT3 signaling in the tumor microenvironment: Implications for cancer therapy. Cytokine Growth Factor Rev 2025:S1359-6101(25)00003-6. [PMID: 39893129 DOI: 10.1016/j.cytogfr.2025.01.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2025] [Accepted: 01/13/2025] [Indexed: 02/04/2025]
Abstract
The IL-6/JAK/STAT3 signaling pathway is a key regulator of tumor progression, immune evasion, and therapy resistance in various cancers. Frequently dysregulated in malignancies, this pathway drives cancer cell growth, survival, angiogenesis, and metastasis by altering the tumor microenvironment (TME). IL-6 activates JAK kinases and STAT3 through its receptor complex, leading to the transcription of oncogenic genes and fostering an immunosuppressive TME. This environment recruits tumor-associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), and regulatory T cells (Tregs), collectively supporting immune evasion and tumor growth. IL-6/JAK/STAT3 axis also contributes to metabolic reprogramming, such as enhanced glycolysis and glutathione metabolism, helping cancer cells adapt to environmental stresses. Therapeutic targeting of this pathway has gained significant interest. Strategies include monoclonal antibodies against IL-6 or its receptor (e.g., Tocilizumab, Siltuximab), JAK inhibitors (e.g., Ruxolitinib), and STAT3-specific inhibitors (e.g., Napabucasin), which have exhibited promise in preclinical and initial clinical studies. These inhibitors can suppress tumor growth, reverse immune suppression, and enhance the efficacy of immunotherapies like immune checkpoint inhibitors. Combination therapies that integrate IL-6 pathway inhibitors with conventional treatments are particularly promising, addressing resistance mechanisms and improving patient outcomes. Advances in biomarker-driven patient selection, RNA-based therapies, and isoform-specific inhibitors pave the way for more precise interventions. This review delves into the diverse roles of IL-6/JAK/STAT3 signaling in cancer progression, therapeutic strategies targeting this pathway, and the potential for integrating these approaches into personalized medicine to enhance treatment outcomes.
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Affiliation(s)
- Win Lwin Thuya
- Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore
| | - Yang Cao
- Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore; Department of Laboratory Medicine, Lequn Brance, The First Hospital of Jilin University, Changchun, Jilin 130031, China
| | - Paul Chi-Lui Ho
- School of Pharmacy, Monash University Malaysia, Bandar Sunway, Jalan Lagoon, Selangor Darul Ehsan 47500, Malaysia
| | - Andrea Li-Ann Wong
- Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 119228, Singapore; NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, 117599, Singapore; Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, USA
| | - Lingzhi Wang
- Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore; NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, 117599, Singapore; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600, Singapore.
| | - Jianbiao Zhou
- Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 119228, Singapore; NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, 117599, Singapore.
| | - Christophe Nicot
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, USA
| | - Boon Cher Goh
- Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 119228, Singapore; NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, 117599, Singapore; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600, Singapore; Department of Haematology-Oncology, National University Cancer Institute, National University Health System, 119074, Singapore
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Rahbar Farzam O, Najafi S, Amini M, Rahimi Z, Dabbaghipour R, Zohdi O, Asemani Shahgoli G, Baradaran B, Akbari B. Interplay of miRNAs and lncRNAs in STAT3 signaling pathway in colorectal cancer progression. Cancer Cell Int 2024; 24:16. [PMID: 38185635 PMCID: PMC10771635 DOI: 10.1186/s12935-023-03202-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Accepted: 12/27/2023] [Indexed: 01/09/2024] Open
Abstract
In recent decades, colorectal cancer (CRC) has turned into one of the most widespread malignancies, and the incidence of this malignancy is expected to increase. Despite considerable improvements in therapeutic approaches, the prognosis, and the management of CRC face many problems. Likely, the main limitation in the successful treatment of CRC is the lack of appropriate clinical therapeutic targets. As an effective target, the signal transducer and activator of transcription 3 (STAT3) are regulated by a wide range of genes and involved in cellular processes, including cell growth, migration, invasion, immunosuppression, and angiogenesis. Aberrant regulation of STAT3 signaling leads to cellular dysfunction, diseases, and malignancies, including CRC. Consequently, targeting this signaling pathway is considered one of the therapeutic strategies used in CRC treatment. MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are non-coding RNA molecules with partial or no protein-coding activity that participate in gene regulation at epigenetic, transcriptional, and post-transcriptional levels and regulate multiple signaling pathways, including STAT3 signaling (especially JAK/STAT). Therefore, these regulatory molecules are suggested to be very promising targets to present new insights into overcoming the limitations of conventional therapeutic strategies. Therefore, the current review study aimed to summarize the therapeutic and diagnostic significance of miRNAs and lncRNAs and their therapeutic and diagnostic significance related to the expression and activity of STAT3 in CRC.
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Affiliation(s)
- Omid Rahbar Farzam
- Department of Medical Biotechnology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Souzan Najafi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Amini
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zohreh Rahimi
- Department of Clinical Biochemistry, Medical School, Daneshgah Avenue, Kermanshah, Iran
- Medical Biology Research Center, Daneshgah Avenue, Kermanshah, Iran
| | - Reza Dabbaghipour
- Department of Medical Genetics, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Omid Zohdi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Bahman Akbari
- Department of Medical Biotechnology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran.
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran.
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Kanno H, Matsumoto S, Yoshizumi T, Nakahara K, Kubo A, Murata H, Shuin T, U HS. Role of SOCS and VHL Proteins in Neuronal Differentiation and Development. Int J Mol Sci 2023; 24:ijms24043880. [PMID: 36835292 PMCID: PMC9960776 DOI: 10.3390/ijms24043880] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 02/08/2023] [Accepted: 02/09/2023] [Indexed: 02/17/2023] Open
Abstract
The basic helix-loop-helix factors play a central role in neuronal differentiation and nervous system development, which involve the Notch and signal transducer and activator of transcription (STAT)/small mother against decapentaplegic signaling pathways. Neural stem cells differentiate into three nervous system lineages, and the suppressor of cytokine signaling (SOCS) and von Hippel-Lindau (VHL) proteins are involved in this neuronal differentiation. The SOCS and VHL proteins both contain homologous structures comprising the BC-box motif. SOCSs recruit Elongin C, Elongin B, Cullin5(Cul5), and Rbx2, whereas VHL recruits Elongin C, Elongin B, Cul2, and Rbx1. SOCSs form SBC-Cul5/E3 complexes, and VHL forms a VBC-Cul2/E3 complex. These complexes degrade the target protein and suppress its downstream transduction pathway by acting as E3 ligases via the ubiquitin-proteasome system. The Janus kinase (JAK) is the main target protein of the E3 ligase SBC-Cul5, whereas hypoxia-inducible factor is the primary target protein of the E3 ligase VBC-Cul2; nonetheless, VBC-Cul2 also targets the JAK. SOCSs not only act on the ubiquitin-proteasome system but also act directly on JAKs to suppress the Janus kinase-signal transduction and activator of transcription (JAK-STAT) pathway. Both SOCS and VHL are expressed in the nervous system, predominantly in brain neurons in the embryonic stage. Both SOCS and VHL induce neuronal differentiation. SOCS is involved in differentiation into neurons, whereas VHL is involved in differentiation into neurons and oligodendrocytes; both proteins promote neurite outgrowth. It has also been suggested that the inactivation of these proteins may lead to the development of nervous system malignancies and that these proteins may function as tumor suppressors. The mechanism of action of SOCS and VHL involved in neuronal differentiation and nervous system development is thought to be mediated through the inhibition of downstream signaling pathways, JAK-STAT, and hypoxia-inducible factor-vascular endothelial growth factor pathways. In addition, because SOCS and VHL promote nerve regeneration, they are expected to be applied in neuronal regenerative medicine for traumatic brain injury and stroke.
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Affiliation(s)
- Hiroshi Kanno
- Department of Neurosurgery, School of Medicine, Yokohama City University, Yokohama 232-0024, Japan
- Department of Neurosurgery, Asahi Hospital, Tokyo 121-0078, Japan
- Correspondence: ; Tel.: +81-3-5242-5800
| | - Shutaro Matsumoto
- Department of Neurosurgery, School of Medicine, Yokohama City University, Yokohama 232-0024, Japan
- Department of Neurosurgery, Asahi Hospital, Tokyo 121-0078, Japan
| | - Tetsuya Yoshizumi
- Department of Neurosurgery, St. Mariannna Medical University, Kawasaki 216-8511, Japan
| | - Kimihiro Nakahara
- Department of Neurosurgery, International University of Health and Welfare, Atami 413-0012, Japan
| | | | - Hidetoshi Murata
- Department of Neurosurgery, St. Mariannna Medical University, Kawasaki 216-8511, Japan
| | - Taro Shuin
- Kochi Medical School Hospital, Nangoku 783-0043, Japan
| | - Hoi-Sang U
- Department of Electrical Engineering, University of California San Diego, San Diego, CA 92093, USA
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Fu W, Hou X, Dong L, Hou W. Roles of STAT3 in the pathogenesis and treatment of glioblastoma. Front Cell Dev Biol 2023; 11:1098482. [PMID: 36923251 PMCID: PMC10009693 DOI: 10.3389/fcell.2023.1098482] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 02/15/2023] [Indexed: 03/02/2023] Open
Abstract
Glioblastoma (GBM) is the most malignant of astrocytomas mainly involving the cerebral hemispheres and the cerebral cortex. It is one of the fatal and refractory solid tumors, with a 5-year survival rate of merely 5% among the adults. IL6/JAK/STAT3 is an important signaling pathway involved in the pathogenesis and progression of GBM. The expression of STAT3 in GBM tissues is substantially higher than that of normal brain cells. The abnormal activation of STAT3 renders the tumor microenvironment of GBM immunosuppression. Besides, blocking the STAT3 pathway can effectively inhibit the growth and metastasis of GBM. On this basis, inhibition of STAT3 may be a new therapeutic approach for GBM, and the combination of STAT3 targeted therapy and conventional therapies may improve the current status of GBM treatment. This review summarized the roles of STAT3 in the pathogenesis of GBM and the feasibility of STAT3 for GBM target therapy.
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Affiliation(s)
- Weijia Fu
- Department of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun, China.,Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun, China.,NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun, China
| | - Xue Hou
- Department of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun, China.,Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun, China.,NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun, China
| | - Lihua Dong
- Department of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun, China.,Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun, China.,NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun, China
| | - Wei Hou
- Department of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun, China.,Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun, China.,NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun, China
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Dewdney B, Ursich L, Fletcher EV, Johns TG. Anoctamins and Calcium Signalling: An Obstacle to EGFR Targeted Therapy in Glioblastoma? Cancers (Basel) 2022; 14:cancers14235932. [PMID: 36497413 PMCID: PMC9740065 DOI: 10.3390/cancers14235932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 11/28/2022] [Accepted: 11/28/2022] [Indexed: 12/05/2022] Open
Abstract
Glioblastoma is the most common form of high-grade glioma in adults and has a poor survival rate with very limited treatment options. There have been no significant advancements in glioblastoma treatment in over 30 years. Epidermal growth factor receptor is upregulated in most glioblastoma tumours and, therefore, has been a drug target in recent targeted therapy clinical trials. However, while many inhibitors and antibodies for epidermal growth factor receptor have demonstrated promising anti-tumour effects in preclinical models, they have failed to improve outcomes for glioblastoma patients in clinical trials. This is likely due to the highly plastic nature of glioblastoma tumours, which results in therapeutic resistance. Ion channels are instrumental in the development of many cancers and may regulate cellular plasticity in glioblastoma. This review will explore the potential involvement of a class of calcium-activated chloride channels called anoctamins in brain cancer. We will also discuss the integrated role of calcium channels and anoctamins in regulating calcium-mediated signalling pathways, such as epidermal growth factor signalling, to promote brain cancer cell growth and migration.
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Affiliation(s)
- Brittany Dewdney
- Cancer Centre, Telethon Kids Institute, Perth, WA 6009, Australia
- Centre for Child Health Research, University of Western Australia, Perth, WA 6009, Australia
- Correspondence: ; Tel.: +61-8-6319-1023
| | - Lauren Ursich
- Cancer Centre, Telethon Kids Institute, Perth, WA 6009, Australia
- School of Biomedical Sciences, University of Western Australia, Perth, WA 6009, Australia
| | - Emily V. Fletcher
- Cancer Centre, Telethon Kids Institute, Perth, WA 6009, Australia
- Centre for Child Health Research, University of Western Australia, Perth, WA 6009, Australia
| | - Terrance G. Johns
- Cancer Centre, Telethon Kids Institute, Perth, WA 6009, Australia
- Centre for Child Health Research, University of Western Australia, Perth, WA 6009, Australia
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6
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Potential role of Marine Bioactive Compounds targeting signaling pathways in cancer: A review. Eur J Pharmacol 2022; 936:175330. [DOI: 10.1016/j.ejphar.2022.175330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 10/12/2022] [Accepted: 10/13/2022] [Indexed: 11/23/2022]
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Genomic and Epigenomic Features of Glioblastoma Multiforme and its Biomarkers. JOURNAL OF ONCOLOGY 2022; 2022:4022960. [PMID: 36185622 PMCID: PMC9519330 DOI: 10.1155/2022/4022960] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 08/14/2022] [Accepted: 09/10/2022] [Indexed: 11/22/2022]
Abstract
Glioblastoma multiforme is a serious and life-threatening tumor of central nervous system, characterized by aggressive behavior, poor prognosis, and low survival rate. Despite of the availability of aggressive antitumor therapeutic regimen for glioblastoma (radiotherapy followed by chemotherapeutic dose), recovery rate, and patients' survival ratio is attributed to the lack of selectivity of therapeutic drugs and less advancement in cancer therapeutics over last decade. Moreover, tools employed in conventional diagnosis of glioblastoma are more invasive and painful, making the process excruciating for the patients. These challenges urge for the need of novel biomarkers for diagnosis, prognosis, and prediction purpose with less invasiveness and more patient compliance. This article will explore the genetic biomarkers isocitrate dehydrogenase mutation, MGMT mutations, and EGFR that can be deployed as an analytical tool in diagnosis of disease and prognosis of a therapeutic course. The review also highlights the importance of employing novel microRNAs as prognostic biomarkers. Recent clinical advancements to treat GBM and to prevent relapse of the disease are also discussed in this article in the hope of finding a robust and effective method to treat GBM.
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Yu J, Han L, Yang F, Zhao M, Zhou H, Hu L. SOCS5 contributes to temozolomide resistance in glioblastoma by regulating Bcl-2-mediated autophagy. Bioengineered 2022; 13:14125-14137. [PMID: 35730472 PMCID: PMC9342142 DOI: 10.1080/21655979.2022.2081463] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Temozolomide (TMZ) is the primary chemotherapeutic drug for treating glioblastoma (GBM); however, the final clinical outcome is considerably limited by the poor response and resistance to TMZ. Although autophagy is thought to be associated with chemotherapy resistance and cancer cell survival, the precise molecular mechanisms underlying this process remain elusive. The suppressor of cytokine signaling (SOCS) family is widely distributed in vivo and exerts a range of effects on tumors; however, the expression pattern and role of SOCS in GBM remains unknown. In this study, we determined that high SOCS5 expression level was associated with poor prognosis and TMZ resistance in GBM. TMZ induced an increase in SOCS5 expression level and upregulated autophagy during the acquisition of drug resistance. The observed increase in the extent of autophagy was mediated by SOCS5. Mechanistically, SOCS5 enhances the transcription of Bcl-2. Knockdown of SOCS5 inhibited TMZ chemoresistance in GBM cells through the inhibition of Bcl-2 recruited autophagy; upregulation of Bcl-2 blocked this effect. In summary, our findings revealed the involvement and underlying mechanism of SOCS5 in TMZ resistance. SOCS5 plays a critical role in GBM chemoresistance and may serve as a novel prognostic marker and therapeutic target for chemotherapeutically treating drug-resistant GBM.
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Affiliation(s)
- Jie Yu
- Department of Neurosurgery, Hunan Provincial People’s Hospital, Changsha, Hunan, China
| | - Lin Han
- Department of Neurosurgery, Tongji Hospital Affiliated to Tongji Medical College Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Feng Yang
- Department of Pharmacy, Hunan Provincial People’s Hospital, Changsha, Hunan, China
| | - Mingliang Zhao
- Chinese People’s Armed Police Force Characteristic Medical Center, Tianjin, Tianjin, China
| | - Hong Zhou
- Department of Neurosurgery, Hunan Provincial People’s Hospital, Changsha, Hunan, China
| | - Linwang Hu
- Department of Neurosurgery, Hunan Provincial People’s Hospital, Changsha, Hunan, China,CONTACT Linwang Hu Department of Neurosurgery, Hunan Provincial People’s Hospital, Changsha, Hunan Province410016, China
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SOCS3 gene silencing does not occur through methylation and mutations in gastric cancer. Hum Cell 2022; 35:1114-1125. [PMID: 35596898 DOI: 10.1007/s13577-022-00715-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 05/04/2022] [Indexed: 11/04/2022]
Abstract
Gastric cancer (GC) is ranked the third leading cause of cancer-related deaths worldwide. Mutations and epigenetic alterations in several essential genes, including p53, KRAS, PIK3CA, FAT4 and ARID1A, are often reported. Furthermore, loss of SOCS3 expression was reported in GC, suggesting its tumor suppressor role. To assess the mutational and methylation status of SOCS3, we performed gene panel exome sequencing on 47 human GC samples. The SOCS3 gene was rarely mutated, suggesting alternative regulation mechanisms, such as promoter hypermethylation and/or long non-coding RNAs (lncRNAs). We first explored SOCS3 promoter methylation status in 44 human GC samples by methylation-specific PCR (MS-PCR). Thirteen out of forty-four patients (29.5%) displayed a methylation pattern. Then, to see whether SOCS3 expression is silenced by CpG methylation, we examined publicly available databases (cbioportal and The Cancer Genome Atlas (TCGA)). The analysis revealed β values lower than 0.1, indicating hypo-methylation in healthy and GC samples. Moreover, moderate methylation (β < 0.4) and high methylation (β > 0.4) did not affect the free survival, suggesting that methylation is unlikely to be the mechanism ruling SOCS3 silencing in GC. Next, to assess the regulatory effects of lncRNAs on SOCS3, we silenced the AC125807.2-lncRNA and quantified the SOCS3 gene expression in AGS and NCI-N87 gastric cancer cell line. SOCS3 was found to be downregulated following AC125807.2-lncRNA silencing in AGS cells, suggesting the potential implication of lncRNA AC125807.2 in SOCS3 regulation. However, in NCI-N87 cells, there was no significant change in SOCS3 expression. In conclusion, neither mutations nor hypermethylation was associated with the SOCS3 downregulation in GC, and alternative mechanisms, including non-coding RNAs-mediated gene silencing, may be proposed.
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Dai L, Tao Y, Shi Z, Liang W, Hu W, Xing Z, Zhou S, Guo X, Fu X, Wang X. SOCS3 Acts as an Onco-immunological Biomarker With Value in Assessing the Tumor Microenvironment, Pathological Staging, Histological Subtypes, Therapeutic Effect, and Prognoses of Several Types of Cancer. Front Oncol 2022; 12:881801. [PMID: 35600392 PMCID: PMC9122507 DOI: 10.3389/fonc.2022.881801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 03/28/2022] [Indexed: 12/03/2022] Open
Abstract
The suppressor of cytokine signaling (SOCS) family contains eight members, including SOCS1–7 and CIS, and SOCS3 has been shown to inhibit cytokine signal transduction in various signaling pathways. Although several studies have currently shown the correlations between SOCS3 and several types of cancer, no pan-cancer analysis is available to date. We used various computational tools to explore the expression and pathogenic roles of SOCS3 in several types of cancer, assessing its potential role in the pathogenesis of cancer, in tumor immune infiltration, tumor progression, immune evasion, therapeutic response, and prognostic. The results showed that SOCS3 was downregulated in most The Cancer Genome Atlas (TCGA) cancer datasets but was highly expressed in brain tumors, breast cancer, esophageal cancer, colorectal cancer, and lymphoma. High SOCS3 expression in glioblastoma multiforme (GBM) and brain lower-grade glioma (LGG) were verified through immunohistochemical experiments. GEPIA and Kaplan–Meier Plotter were used, and this bioinformatics analysis showed that high SOCS3 expression was associated with a poor prognosis in the majority of cancers, including LGG and GBM. Our analysis also indicated that SOCS3 may be involved in tumor immune evasion via immune cell infiltration or T-cell exclusion across different types of cancer. In addition, SOCS3 methylation was negatively correlated with mRNA expression levels, worse prognoses, and dysfunctional T-cell phenotypes in various types of cancer. Next, different analytical methods were used to select genes related to SOCS3 gene alterations and carcinogenic characteristics, such as STAT3, SNAI1, NFKBIA, BCL10, TK1, PGS1, BIRC5, TMC8, and AFMID, and several biological functions were identified between them. We found that SOCS3 was involved in cancer development primarily through the JAK/STAT signaling pathway and cytokine receptor activity. Furthermore, SOCS3 expression levels were associated with immunotherapy or chemotherapy for numerous types of cancer. In conclusion, this study showed that SOCS3 is an immune-oncogenic molecule that may possess value as a biomarker for diagnosis, treatment, and prognosis of several types of cancer in the future.
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Affiliation(s)
- Lirui Dai
- Institute of Neuroscience, Zhengzhou University, Zhengzhou, China
- Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Henan International Joint Laboratory of Glioma Metabolism and Microenvironment Research, Zhengzhou, China
| | - Yiran Tao
- Institute of Neuroscience, Zhengzhou University, Zhengzhou, China
- Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Henan International Joint Laboratory of Glioma Metabolism and Microenvironment Research, Zhengzhou, China
| | - Zimin Shi
- Institute of Neuroscience, Zhengzhou University, Zhengzhou, China
- Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Henan International Joint Laboratory of Glioma Metabolism and Microenvironment Research, Zhengzhou, China
| | - Wulong Liang
- Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Henan International Joint Laboratory of Glioma Metabolism and Microenvironment Research, Zhengzhou, China
| | - Weihua Hu
- Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Henan International Joint Laboratory of Glioma Metabolism and Microenvironment Research, Zhengzhou, China
| | - Zhe Xing
- Institute of Neuroscience, Zhengzhou University, Zhengzhou, China
- Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Henan International Joint Laboratory of Glioma Metabolism and Microenvironment Research, Zhengzhou, China
| | - Shaolong Zhou
- Institute of Neuroscience, Zhengzhou University, Zhengzhou, China
- Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Xuyang Guo
- Institute of Neuroscience, Zhengzhou University, Zhengzhou, China
- Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Henan International Joint Laboratory of Glioma Metabolism and Microenvironment Research, Zhengzhou, China
| | - Xudong Fu
- Institute of Neuroscience, Zhengzhou University, Zhengzhou, China
- Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Henan International Joint Laboratory of Glioma Metabolism and Microenvironment Research, Zhengzhou, China
| | - Xinjun Wang
- Institute of Neuroscience, Zhengzhou University, Zhengzhou, China
- Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Henan International Joint Laboratory of Glioma Metabolism and Microenvironment Research, Zhengzhou, China
- *Correspondence: Xinjun Wang,
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Magnolol Induces the Extrinsic/Intrinsic Apoptosis Pathways and Inhibits STAT3 Signaling-Mediated Invasion of Glioblastoma Cells. Life (Basel) 2021; 11:life11121399. [PMID: 34947930 PMCID: PMC8706091 DOI: 10.3390/life11121399] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 12/05/2021] [Accepted: 12/06/2021] [Indexed: 11/16/2022] Open
Abstract
Glioblastoma multiforme (GBM) is the most common form of malignant brain tumor, with poor prognosis; the efficacy of current standard therapy for GBM remains unsatisfactory. Magnolol, an herbal medicine from Magnolia officinalis, exhibited anticancer properties against many types of cancers. However, whether magnolol suppresses GBM progression as well as its underlying mechanism awaits further investigation. In this study, we used the MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) assay, apoptosis marker analysis, transwell invasion and wound-healing assays to identify the effects of magnolol on GBM cells. We also validated the potential targets of magnolol on GBM with the GEPIA (Gene Expression Profiling Interactive Analysis) and Western blotting assay. Magnolol was found to trigger cytotoxicity and activate extrinsic/intrinsic apoptosis pathways in GBM cells. Both caspase-8 and caspase-9 were activated by magnolol. In addition, GEPIA data indicated the PKCδ (Protein kinase C delta)/STAT3 (Signal transducer and activator of transcription 3) signaling pathway as a potential target of GBM. Magnolol effectively suppressed the phosphorylation and nuclear translocation of STAT3 in GBM cells. Meanwhile, tumor invasion and migration ability and the associated genes, including MMP-9 (Matrix metalloproteinase-9) and uPA (Urokinase-type plasminogen activator), were all diminished by treatment with magnolol. Taken together, our results suggest that magnolol-induced anti-GBM effect may be associated with the inactivation of PKCδ/STAT3 signaling transduction.
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Microglial Cytokines Induce Invasiveness and Proliferation of Human Glioblastoma through Pyk2 and FAK Activation. Cancers (Basel) 2021; 13:cancers13246160. [PMID: 34944779 PMCID: PMC8699228 DOI: 10.3390/cancers13246160] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 11/29/2021] [Accepted: 12/03/2021] [Indexed: 12/25/2022] Open
Abstract
Simple Summary Microglia infiltrate most gliomas and have been demonstrated to promote tumor growth, invasion, and treatment resistance. To develop improved treatment methods, that take into consideration the supporting role of microglia in tumor progression, the functional and mechanistic pathways of glioma–microglia interactions need to be identified and experimentally dissected. Our recent studies and literature reports revealed the overexpression of Pyk2 and FAK in glioblastomas. Pyk2 and FAK signaling pathways have been shown to regulate migration and proliferation in glioma cells, including microglia-promoted glioma cell migration. However, the specific factors released by microglia that modulate Pyk2 and FAK to promote glioma invasiveness and proliferation are poorly understood. The aim of this study was to identify key microglia-derived signaling molecules that induce the activation of Pyk2- and FAK-dependent glioma cell proliferation and invasiveness. Abstract Glioblastoma is the most aggressive brain tumor in adults. Multiple lines of evidence suggest that microglia create a microenvironment favoring glioma invasion and proliferation. Our previous studies and literature reports indicated the involvement of focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (Pyk2) in glioma cell proliferation and invasion, stimulated by tumor-infiltrating microglia. However, the specific microglia-released factors that modulate Pyk2 and FAK signaling in glioma cells are unknown. In this study, 20 human glioblastoma specimens were evaluated with the use of RT-PCR and western blotting. A Pierson correlation test demonstrated a correlation (0.6–1.0) between the gene expression levels for platelet-derived growth factor β(PDGFβ), stromal-derived factor 1α (SDF-1α), IL-6, IL-8, and epidermal growth factor (EGF) in tumor-purified microglia and levels of p-Pyk2 (Y579/Y580) and p-FAK(Y925) in glioma cells. siRNA knockdown against Pyk2 or FAK in three primary glioblastoma cell lines, developed from the investigated specimens, in combination with the cytokine receptor inhibitors gefitinib (1 μM), DMPQ (200 nM), and burixafor (1 μM) identified EGF, PDGFβ, and SDF-1α as key extracellular factors in the Pyk2- and FAK-dependent activation of invadopodia formation and the migration of glioma cells. EGF and IL-6 were identified as regulators of the Pyk2- and FAK-dependent activation of cell viability and mitosis.
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Dai L, Li Z, Liang W, Hu W, Zhou S, Yang Z, Tao Y, Hou X, Xing Z, Mao J, Shi Z, Wang X. SOCS proteins and their roles in the development of glioblastoma. Oncol Lett 2021; 23:5. [PMID: 34820004 PMCID: PMC8607235 DOI: 10.3892/ol.2021.13123] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 10/11/2021] [Indexed: 12/13/2022] Open
Abstract
Glioblastoma multiforme (GBM) is the most common type of primary brain tumor in adults. GBM is characterized by a high degree of malignancy and aggressiveness, as well as high morbidity and mortality rates. GBM is currently treatable via surgical resection, chemotherapy and radiotherapy, but the prognosis of patients with GBM is poor. The suppressor of cytokine signaling (SOCS) protein family comprises eight members, including SOCS1-SOCS7 and cytokine-inducible SH2-containing protein. SOCS proteins regulate the biogenesis of GBM via the JAK/STAT and NF-κB signaling pathways. Driven by NF-κB, the expression of SOCS proteins can serve as a negative regulator of the JAK/STAT signaling pathway and exerts a potential inhibitory effect on GBM. In GBM, E3 ubiquitin ligase is involved in the regulation of cellular functions, such as the receptor tyrosine kinase (RTK) survival signal, in which SOCS proteins negatively regulate RTK signaling, and kinase overexpression or mutation can lead to the development of malignancies. Moreover, SOCS proteins affect the proliferation and differentiation of GBM cells by regulating the tumor microenvironment. SOCS proteins also serve specific roles in GBM of different grades and different isocitrate dehydrogenase mutation status. The aim of the present review was to describe the biogenesis and function of the SOCS protein family, the roles of SOCS proteins in the microenvironment of GBM, as well as the role of this protein family and E3 ubiquitin ligases in GBM. Furthermore, the role of SOCS proteins as diagnostic and prognostic markers in GBM and their potential role as GBM therapeutics were explored.
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Affiliation(s)
- Lirui Dai
- Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan 450052, P.R. China.,Department of Science and Technology of Henan Province, Henan International Joint Laboratory of Glioma Metabolism and Microenvironment Research, Zhengzhou, Henan 450052, P.R. China
| | - Zian Li
- Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan 450052, P.R. China.,Department of Science and Technology of Henan Province, Henan International Joint Laboratory of Glioma Metabolism and Microenvironment Research, Zhengzhou, Henan 450052, P.R. China
| | - Wulong Liang
- Department of Science and Technology of Henan Province, Henan International Joint Laboratory of Glioma Metabolism and Microenvironment Research, Zhengzhou, Henan 450052, P.R. China
| | - Weihua Hu
- Department of Science and Technology of Henan Province, Henan International Joint Laboratory of Glioma Metabolism and Microenvironment Research, Zhengzhou, Henan 450052, P.R. China
| | - Shaolong Zhou
- Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan 450052, P.R. China.,Department of Science and Technology of Henan Province, Henan International Joint Laboratory of Glioma Metabolism and Microenvironment Research, Zhengzhou, Henan 450052, P.R. China
| | - Zhuo Yang
- Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan 450052, P.R. China.,Department of Science and Technology of Henan Province, Henan International Joint Laboratory of Glioma Metabolism and Microenvironment Research, Zhengzhou, Henan 450052, P.R. China
| | - Yiran Tao
- Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan 450052, P.R. China.,Department of Science and Technology of Henan Province, Henan International Joint Laboratory of Glioma Metabolism and Microenvironment Research, Zhengzhou, Henan 450052, P.R. China
| | - Xuelei Hou
- Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan 450052, P.R. China.,Department of Science and Technology of Henan Province, Henan International Joint Laboratory of Glioma Metabolism and Microenvironment Research, Zhengzhou, Henan 450052, P.R. China
| | - Zhe Xing
- Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan 450052, P.R. China.,Department of Science and Technology of Henan Province, Henan International Joint Laboratory of Glioma Metabolism and Microenvironment Research, Zhengzhou, Henan 450052, P.R. China
| | - Jianchao Mao
- Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan 450052, P.R. China.,Department of Science and Technology of Henan Province, Henan International Joint Laboratory of Glioma Metabolism and Microenvironment Research, Zhengzhou, Henan 450052, P.R. China
| | - Zimin Shi
- Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan 450052, P.R. China.,Department of Science and Technology of Henan Province, Henan International Joint Laboratory of Glioma Metabolism and Microenvironment Research, Zhengzhou, Henan 450052, P.R. China
| | - Xinjun Wang
- Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan 450052, P.R. China.,Department of Science and Technology of Henan Province, Henan International Joint Laboratory of Glioma Metabolism and Microenvironment Research, Zhengzhou, Henan 450052, P.R. China
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14
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Yu Y, Sung SK, Lee CH, Ha M, Kang J, Kwon EJ, Kang JW, Kim Y, Kim GH, Heo HJ, Lee H, Kim TW, Lee Y, Myung K, Oh CK, Kim YH. SOCS3 is Related to Cell Proliferation in Neuronal Tissue: An Integrated Analysis of Bioinformatics and Experiments. Front Genet 2021; 12:743786. [PMID: 34646310 PMCID: PMC8502821 DOI: 10.3389/fgene.2021.743786] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 09/02/2021] [Indexed: 12/13/2022] Open
Abstract
Glioma is the most common primary malignant tumor that occurs in the central nervous system. Gliomas are subdivided according to a combination of microscopic morphological, molecular, and genetic factors. Glioblastoma (GBM) is the most aggressive malignant tumor; however, efficient therapies or specific target molecules for GBM have not been developed. We accessed RNA-seq and clinical data from The Cancer Genome Atlas, the Chinese Glioma Genome Atlas, and the GSE16011 dataset, and identified differentially expressed genes (DEGs) that were common to both GBM and lower-grade glioma (LGG) in three independent cohorts. The biological functions of common DEGs were examined using NetworkAnalyst. To evaluate the prognostic performance of common DEGs, we performed Kaplan-Meier and Cox regression analyses. We investigated the function of SOCS3 in the central nervous system using three GBM cell lines as well as zebrafish embryos. There were 168 upregulated genes and 50 downregulated genes that were commom to both GBM and LGG. Through survival analyses, we found that SOCS3 was the only prognostic gene in all cohorts. Inhibition of SOCS3 using siRNA decreased the proliferation of GBM cell lines. We also found that the zebrafish ortholog, socs3b, was associated with brain development through the regulation of cell proliferation in neuronal tissue. While additional mechanistic studies are necessary, our results suggest that SOCS3 is an important biomarker for glioma and that SOCS3 is related to the proliferation of neuronal tissue.
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Affiliation(s)
- Yeuni Yu
- Department of Biomedical Informatics, School of Medicine, Pusan National University, Busan, South Korea
| | - Soon Ki Sung
- Department of Neurosurgery, Pusan National University Yangsan Hospital, Yangsan, South Korea
| | - Chi Hyung Lee
- Department of Neurosurgery, Pusan National University Yangsan Hospital, Yangsan, South Korea
| | - Mihyang Ha
- Interdisciplinary Program of Genomic Science, Pusan National University, Yangsan, South Korea
| | - Junho Kang
- Department of Biomedical Informatics, School of Medicine, Pusan National University, Busan, South Korea
| | - Eun Jung Kwon
- Interdisciplinary Program of Genomic Science, Pusan National University, Yangsan, South Korea
| | - Ji Wan Kang
- Interdisciplinary Program of Genomic Science, Pusan National University, Yangsan, South Korea
| | - Youngjoo Kim
- Interdisciplinary Program of Genomic Science, Pusan National University, Yangsan, South Korea
| | - Ga Hyun Kim
- Interdisciplinary Program of Genomic Science, Pusan National University, Yangsan, South Korea
| | - Hye Jin Heo
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan, South Korea
| | - Hansong Lee
- Department of Biomedical Informatics, School of Medicine, Pusan National University, Busan, South Korea
| | - Tae Woo Kim
- Department of Orthopaedic Surgery, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan, South Korea
| | - Yoonsung Lee
- Center for Genomic Integrity, Institute for Basic Science (IBS), Ulsan, South Korea.,Department of Core Research Laboratory, Clinical Research Institute, Kyung Hee University Hospital at Gangdong, Seoul, South Korea
| | - Kyungjae Myung
- Center for Genomic Integrity, Institute for Basic Science (IBS), Ulsan, South Korea
| | - Chang-Kyu Oh
- Center for Genomic Integrity, Institute for Basic Science (IBS), Ulsan, South Korea.,Department of Anatomy, College of Medicine, Inje University, Busan, South Korea
| | - Yun Hak Kim
- Department of Biomedical Informatics, School of Medicine, Pusan National University, Busan, South Korea.,Department of Anatomy, School of Medicine, Pusan National University, Yangsan, South Korea
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15
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Dai L, Li Z, Tao Y, Liang W, Hu W, Zhou S, Fu X, Wang X. Emerging roles of suppressor of cytokine signaling 3 in human cancers. Biomed Pharmacother 2021; 144:112262. [PMID: 34607102 DOI: 10.1016/j.biopha.2021.112262] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 09/22/2021] [Accepted: 09/26/2021] [Indexed: 02/07/2023] Open
Abstract
As a member of the suppressor of cytokine signaling (SOCS) family, SOCS3 is a cytokine-inducible protein that inhibits cytokine signaling in a variety of signaling pathways. Increasing evidence shows that SOCS3 regulates tumor development through multiple pathological and physiological processes. It is worth mentioning that SOCS3 negatively regulates JAK/STAT signaling by binding to JAK/cytokine receptors or phosphorylation docking sites on STAT receptors, thus preventing tumor cell proliferation and inhibiting tumor cell invasion and metastasis. The kinase inhibitory region KIR of SOCS3 is the key to JAK inhibition. In addition, SOCS3 may also regulate tumor progression through other molecules or signaling pathways, such as microRNAs (miRNAs), IL-6 and NF-κB signaling pathway. MicroRNAs inhibit SOCS3 expression by binding to the 3' untranslated region of SOCS3 mRNA, thus regulating tumor development processes, including tumor cell proliferation, invasion, metastasis, differentiation, cell cycle and apoptosis, as well as tumor metastasis and chemotherapy resistance. On the whole, SOCS3 acts as an inhibitor of the majority of tumors through various pathways. In the present review, the role of SOCS3 in multitudinous tumors was comprehensively summarized, the molecular mechanisms and modes of action of SOCS3 in tumors were discussed, and the association between SOCS3 expression and the clinical characteristics of patients with cancer were emphasized.
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Affiliation(s)
- Lirui Dai
- Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450052, China; Henan International Joint Laboratory of Glioma Metabolism and Microenvironment Research, Zhengzhou, Henan, China
| | - Zian Li
- Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450052, China; Henan International Joint Laboratory of Glioma Metabolism and Microenvironment Research, Zhengzhou, Henan, China
| | - Yiran Tao
- Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450052, China; Henan International Joint Laboratory of Glioma Metabolism and Microenvironment Research, Zhengzhou, Henan, China
| | - Wulong Liang
- Henan International Joint Laboratory of Glioma Metabolism and Microenvironment Research, Zhengzhou, Henan, China
| | - Weihua Hu
- Henan International Joint Laboratory of Glioma Metabolism and Microenvironment Research, Zhengzhou, Henan, China
| | - Shaolong Zhou
- Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450052, China; Henan International Joint Laboratory of Glioma Metabolism and Microenvironment Research, Zhengzhou, Henan, China
| | - Xudong Fu
- Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450052, China; Henan International Joint Laboratory of Glioma Metabolism and Microenvironment Research, Zhengzhou, Henan, China
| | - Xinjun Wang
- Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450052, China; Henan International Joint Laboratory of Glioma Metabolism and Microenvironment Research, Zhengzhou, Henan, China.
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16
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Bian Z, Ji W, Xu B, Huo Z, Huang H, Huang J, Jiao J, Shao J, Zhang X. Noncoding RNAs involved in the STAT3 pathway in glioma. Cancer Cell Int 2021; 21:445. [PMID: 34425834 PMCID: PMC8381529 DOI: 10.1186/s12935-021-02144-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Accepted: 08/11/2021] [Indexed: 01/03/2023] Open
Abstract
Glioma is the most common malignant primary brain tumour in adults. Despite improvements in neurosurgery and radiotherapy, the prognosis of glioma patients remains poor. One of the main limitations is that there are no proper clinical therapeutic targets for glioma. Therefore, it is crucial to find one or more effective targets. Signal transducer and activator of transcription 3 (STAT3) is a member of the STAT family of genes. Abnormal expression of STAT3 is involved in the process of cell proliferation, migration, invasion, immunosuppression, angiogenesis, dryness maintenance, and resistance to radiotherapy and chemotherapy in glioma. Therefore, STAT3 has been considered an ideal therapeutic target in glioma. Noncoding RNAs (ncRNAs) are a group of genes with limited or no protein-coding capacity that can regulate gene expression at the epigenetic, transcriptional and posttranscriptional level. In this review, we summarized the ncRNAs that are correlated with the ectopic expression of STAT3 in glioma.
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Affiliation(s)
- Zheng Bian
- Department of Neurosurgery, Wuxi People's Hospital of Nanjing Medical University, Wuxi, People's Republic of China
| | - Wei Ji
- Department of Neurosurgery, Wuxi People's Hospital of Nanjing Medical University, Wuxi, People's Republic of China
| | - Bin Xu
- Department of Neurosurgery, Wuxi People's Hospital of Nanjing Medical University, Wuxi, People's Republic of China
| | - Zhengyuan Huo
- Department of Neurosurgery, Wuxi People's Hospital of Nanjing Medical University, Wuxi, People's Republic of China
| | - Hui Huang
- Department of Neurosurgery, Wuxi People's Hospital of Nanjing Medical University, Wuxi, People's Republic of China
| | - Jin Huang
- Department of Neurosurgery, Wuxi People's Hospital of Nanjing Medical University, Wuxi, People's Republic of China
| | - Jiantong Jiao
- Department of Neurosurgery, Wuxi People's Hospital of Nanjing Medical University, Wuxi, People's Republic of China
| | - Junfei Shao
- Department of Neurosurgery, Wuxi People's Hospital of Nanjing Medical University, Wuxi, People's Republic of China.
| | - Xiaolu Zhang
- Department of Neurosurgery, Wuxi People's Hospital of Nanjing Medical University, Wuxi, People's Republic of China.
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17
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Wang Y, Lou N, Zuo M, Zhu F, He Y, Cheng Z, Wang X. STAT3-induced ZBED3-AS1 promotes the malignant phenotypes of melanoma cells by activating PI3K/AKT signaling pathway. RNA Biol 2021; 18:355-368. [PMID: 34241580 DOI: 10.1080/15476286.2021.1950463] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Melanoma is considered as the most frequent primary malignancy occurring in skin. Accumulating studies have suggested that long non-coding RNAs (lncRNAs) play critical parts in multiple cancers. In this study, we explored the molecular mechanism of ZBED3 antisense RNA 1 (ZBED3-AS1) in melanoma. We observed that ZBED3-AS1 expression was remarkably up-regulated in melanoma tissues, and high ZBED3-AS1 level was linked to unsatisfactory survival of melanoma patients. Then, we discovered that ZBED3-AS1 was overexpressed in melanoma cells compared with human epidermal melanocytes. In addition, loss-of-function assays verified that ZBED3-AS1 knockdown restrained cell proliferation, migration, epithelial-mesenchymal transition (EMT), and stemness in melanoma. In addition, signal transducer and activator of transcription 3 (STAT3), which also showed tumour-facilitating functions in melanoma, was confirmed as a transcriptional activator of ZBED3-AS1. Moreover, ZBED3-AS1 enhanced the expression of AT-rich interaction domain 4B (ARID4B) through sequestering miR-381-3p. Importantly, we further confirmed that ZBED3-AS1 promoted the malignant progression of melanoma by regulating miR-381-3p/ARID4B axis to activate the phosphatidylinositol 3-kinase/AKT serine/threonine kinase (PI3K/AKT) signalling pathway. In a word, our research might provide a novel therapeutic target for melanoma.
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Affiliation(s)
- Yang Wang
- Department of Pathology, Shenzhen People's Hospital, The Second Clinical Medical College, Jinan University, Shenzhen, Guangdong, China
| | - Nan Lou
- Department of Joint Replacement Surgery, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Min Zuo
- Department of Pathology, Shenzhen People's Hospital, The Second Clinical Medical College, Jinan University, Shenzhen, Guangdong, China
| | - Fuqiang Zhu
- Department of Pathology, Shenzhen People's Hospital, The Second Clinical Medical College, Jinan University, Shenzhen, Guangdong, China
| | - Yan He
- Department of Pathology, Longgang Center Hospital of Shenzhen, Guangdong, China
| | - Zhiqiang Cheng
- Department of Pathology, Shenzhen People's Hospital, The Second Clinical Medical College, Jinan University, Shenzhen, Guangdong, China
| | - Xiaomei Wang
- Department of Pathology, Shenzhen People's Hospital, The Second Clinical Medical College, Jinan University, Shenzhen, Guangdong, China
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18
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Gao AH, Hu YR, Zhu WP. IFN-γ inhibits ovarian cancer progression via SOCS1/JAK/STAT signaling pathway. Clin Transl Oncol 2021; 24:57-65. [PMID: 34275119 DOI: 10.1007/s12094-021-02668-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Accepted: 06/08/2021] [Indexed: 12/12/2022]
Abstract
PURPOSE Ovarian cancer (OC) is a common malignancy, and IFN-γ, a multifunctional cytokine, is unveiled to impede the multiplication and enhance apoptosis in diverse tumor cells in previous research. Nonetheless, its function and mechanism in OC are blurred. METHODS OC cell lines SKOV3 and OVCAR3 were dealt with different concentrations (0-40 ng/ml) of IFN-γ. CCK-8 experiment was utilized to examine cell multiplication; Flow cytometry was executed to detect apoptosis and cell cycle; Wound healing assay was utilized to detect cell migration; and Transwell experiment was implemented to examine cell invasion. qRT-PCR analysis was applied to detect STAT5, STAT3, JAK2 and JAK3 mRNA expression in OC cell lines. Western blot experiment was applied to detect the protein and phosphorylation levels of SOCS1, STAT5 and STAT3. RESULTS IFN-γ suppressed OC cell multiplication in a concentration-dependent manner. Relative to the control group, IFN-γ restrained OC cell migration, invasion, enhanced apoptosis and prevented cell transformation from G0/G1 to S phase. Further analysis revealed that IFN-γ up-modulated SOCS1 expression and impeded STAT5 and STAT3 protein phosphorylation levels, and knockdown of SOCS1 partially counteracted the inhibitory effect of IFN-γ on STAT5 and STAT3 protein phosphorylation levels. CONCLUSION IFN-γ represses OC progression by facilitating SOCS1 to suppress STAT3 and STAT5 protein phosphorylation.
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Affiliation(s)
- A H Gao
- Department of Gynaecology and Obstetrics, The Second Affiliated Hospital of Soochow University, No.1055 sanxiang road, Suzhou, 215004, China
| | - Y R Hu
- Department of Scientific Research Management, Zhuhai People's Hospital (Zhuhai Hospital Affiliated With Jinan University), Zhuhai, 519000, Guangdong, China.
| | - W P Zhu
- Department of Gynaecology and Obstetrics, The Second Affiliated Hospital of Soochow University, No.1055 sanxiang road, Suzhou, 215004, China.
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Chaudhary R, Morris RJ, Steinson E. The multifactorial roles of microglia and macrophages in the maintenance and progression of glioblastoma. J Neuroimmunol 2021; 357:577633. [PMID: 34153803 DOI: 10.1016/j.jneuroim.2021.577633] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 05/26/2021] [Accepted: 06/11/2021] [Indexed: 01/18/2023]
Abstract
The functional characteristics of glial cells, in particular microglia, have attained considerable importance in several diseases, including glioblastoma, the most hostile and malignant type of intracranial tumor. Microglia performs a highly significant role in the brain's inflammatory response mechanism. They exhibit anti-tumor properties via phagocytosis and the activation of a number of different cytotoxic substances. Some tumor-derived factors, however, transform these microglial cells into immunosuppressive and tumor-supportive, facilitating survival and progression of tumorigenic cells. Glioma-associated microglia and/or macrophages (GAMs) accounts for a large proportion of glioma infiltrating cells. Once within the tumor, GAMs exhibit a distinct phenotype of initiation that subsequently supports the growth and development of tumorigenic cells, angiogenesis and stimulates the infiltration of healthy brain regions. Interventions that suppress or prohibit the induction of GAMs at the tumor site or attenuate their immunological activities accommodating anti-tumor actions are likely to exert positive impact on glioblastoma treatment. In the present paper, we aim to summarize the most recent knowledge of microglia and its physiology, as well as include a very brief description of different molecular factors involved in microglia and glioblastoma interplay. We further address some of the major signaling pathways that regulate the baseline motility of glioblastoma progression. Finally, we discussed a number of therapeutic approaches regarding glioblastoma treatment.
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Affiliation(s)
- Rishabh Chaudhary
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow, India.
| | - Rhianna J Morris
- Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, United Kingdom
| | - Emma Steinson
- School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, QLD, Australia
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20
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Ou A, Ott M, Fang D, Heimberger AB. The Role and Therapeutic Targeting of JAK/STAT Signaling in Glioblastoma. Cancers (Basel) 2021; 13:437. [PMID: 33498872 PMCID: PMC7865703 DOI: 10.3390/cancers13030437] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 01/19/2021] [Accepted: 01/21/2021] [Indexed: 12/17/2022] Open
Abstract
Glioblastoma remains one of the deadliest and treatment-refractory human malignancies in large part due to its diffusely infiltrative nature, molecular heterogeneity, and capacity for immune escape. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway contributes substantively to a wide variety of protumorigenic functions, including proliferation, anti-apoptosis, angiogenesis, stem cell maintenance, and immune suppression. We review the current state of knowledge regarding the biological role of JAK/STAT signaling in glioblastoma, therapeutic strategies, and future directions for the field.
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Affiliation(s)
- Alexander Ou
- Department of Neuro-Oncology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA;
| | - Martina Ott
- Department of Neurosurgery, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA; (M.O.); (D.F.)
| | - Dexing Fang
- Department of Neurosurgery, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA; (M.O.); (D.F.)
| | - Amy B. Heimberger
- Department of Neurosurgery, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA; (M.O.); (D.F.)
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21
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Liu H, Wang W, Liu C. Increased expression of IFN-γ in preeclampsia impairs human trophoblast invasion via a SOCS1/JAK/STAT1 feedback loop. Exp Ther Med 2020; 21:112. [PMID: 33335575 PMCID: PMC7739872 DOI: 10.3892/etm.2020.9544] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Accepted: 08/11/2020] [Indexed: 12/12/2022] Open
Abstract
The weakening of extravillous trophoblast (EVT) invasion results in shallow placenta implantation. In HTR8/SVneo cells, IFN-γ can activate STAT1 and reduce cell invasion, and suppressor of cytokine signaling (SOCS) is an important negative regulatory protein in the Janus kinase (JAK)/STAT activator pathway and has a negative feedback function on JAK/STAT1. The aim of the present study was to elucidate how SOCS1 feedback regulates JAK/STAT1 and affects EVT cell invasion, which in turn affects the development of preeclampsia (PE). MTT and Annexin V/phosphatidylserine (PS) assays were performed to evaluate the viability and apoptosis of HTR8/SVneo cells treated with IFN-γ, respectively. Wound healing and invasion assays were also conducted to measure the migratory and invasive abilities of IFN-γ-treated HTR8/SVneo cells. The mRNA and protein expression levels of genes were detected using reverse transcription-quantitative PCR and western blot analysis. Small interfering RNA knockdown of SOCS1 was used to verify the role of feedback regulation in the IFN-γ-activated JAK/STAT1 signaling pathway. IFN-γ can inhibit HTR8/SVneo migration and invasion, and promote apoptosis by increasing the expression of phosphorylated (p)-JAK, p-STAT1 and caspase3, and reducing the expression of platelet-derived growth factor receptor A and Ezrin. Furthermore, SOCS1 may negatively regulate JAK/STAT1 and affect HTR-8/SVneo invasiveness. Evaluation of clinical samples demonstrated that the expression levels of SOCS1 and IFN-γ were higher in patients with PE compared with the healthy group. Collectively, the present results indicated that IFN-γ reduced the invasion of HTR-8/SVneo cells by activating JAK/STAT1, concurrently leading to an increase in SOCS1, which negatively regulates JAK/STAT1 and eliminates the pro-inflammatory effects of IFN-γ, thus forming a feedback loop.
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Affiliation(s)
- Huiqiang Liu
- Department of Gynecology and Obstetrics, Chaoyang Hospital Affiliated to Capital Medical University, Chaoyang, Beijing 100020, P.R. China.,Department of Gynecology and Obstetrics, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
| | - Wenhao Wang
- Department of Gynecology and Obstetrics, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
| | - Chongdong Liu
- Department of Gynecology and Obstetrics, Chaoyang Hospital Affiliated to Capital Medical University, Chaoyang, Beijing 100020, P.R. China
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22
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Phosphorylated STAT3 expression linked to SOCS3 methylation is associated with proliferative ability of gastric mucosa in patients with early gastric cancer. Oncol Lett 2020; 19:3542-3550. [PMID: 32269628 PMCID: PMC7115067 DOI: 10.3892/ol.2020.11462] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Accepted: 02/07/2020] [Indexed: 12/19/2022] Open
Abstract
Gastric cancers (GCs) may develop in the gastric mucosa after elimination of Helicobacter pylori (H. pylori) using eradication therapy. Cytokine signaling is a key mechanism underlying GC development and progression, and STAT3 signaling may serve a central role in gastritis-associated tumorigenesis. In the present study, suppressor of cytokine signaling 3 (SOCS3) methylation was examined, as an activator of phosphorylated (p-)STAT3 expression in the non-neoplastic gastric mucosa (non-NGM) of patients with early GC. The methylation status of the SOCS3 gene promoter was analyzed using methylation-specific PCR in the non-NGM of patients with or without early GC. Expression levels of p-STAT3 and Ki67 were investigated immunohistochemically in non-NGM with early GC before and after H. pylori eradication. In non-NGM, SOCS3 promoter methylation was detected in 17/51 patients (33.3%) with early GC. In those patients, the non-NGM labeling indices of both Ki67 and p-STAT3 were significantly higher compared with that in patients with early GC without SOCS3 methylation. A significant correlation between Ki67 and p-STAT3 expression levels was demonstrated in the non-NGM of patients with early GC. In patients with early GC without SOCS3 methylation, the labeling indices of both Ki67 and p-STAT3 in non-NGM were significantly reduced after H. pylori eradication, whereas no such change was observed in patients with early GC with SOCS3 methylation. SOCS3 methylation is associated with continuous p-STAT3 overexpression and enhanced epithelial cell proliferation in non-NGM of patients with early GC.
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23
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Swiatek-Machado K, Kaminska B. STAT Signaling in Glioma Cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1202:203-222. [PMID: 32034715 DOI: 10.1007/978-3-030-30651-9_10] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
STAT (signal transducers and activators of transcription) are latent cytoplasmic transcription factors that function as downstream effectors of cytokine and growth factor receptor signaling. The canonical JAK/STAT signaling pathway involves the activation of Janus kinases (JAK) or growth factors receptor kinases, phosphorylation of STAT proteins, their dimerization and translocation into the nucleus where STATs act as transcription factors with pleiotropic downstream effects. STAT signaling is tightly controlled with restricted kinetics due to action of its negative regulators. While STAT1 is believed to play an important role in growth arrest and apoptosis, and to act as a tumor suppressor, STAT3 and 5 are involved in promoting cell cycle progression, cellular transformation, and preventing apoptosis. Aberrant activation of STATs, in particular STAT3 and STAT5, have been found in a large number of human tumors, including gliomas and may contribute to oncogenesis. In this chapter, we have (1) summarized the mechanisms of STAT activation in normal and malignant signaling; (2) discussed evidence for the critical role of constitutively activated STAT3 and STAT5 in glioma pathobiology; (3) disclosed molecular and pharmacological strategies to interfere with STAT signaling for potential therapeutic intervention in gliomas.
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Affiliation(s)
- Karolina Swiatek-Machado
- Laboratory of Transcription Regulation, Department of Cell Biology, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur St, PL 02-093, Warsaw, Poland.
| | - Bozena Kaminska
- Laboratory of Transcription Regulation, Department of Cell Biology, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur St, PL 02-093, Warsaw, Poland
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24
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Xu CH, Liu Y, Xiao LM, Chen LK, Zheng SY, Zeng EM, Li DH, Li YP. Silencing microRNA-221/222 cluster suppresses glioblastoma angiogenesis by suppressor of cytokine signaling-3-dependent JAK/STAT pathway. J Cell Physiol 2019; 234:22272-22284. [PMID: 31106423 DOI: 10.1002/jcp.28794] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Revised: 04/17/2019] [Accepted: 04/22/2019] [Indexed: 12/13/2022]
Abstract
Angiogenesis is a major pathologic characteristic of glioblastoma, which is one aggressive primary brain tumor. MicroRNA-221/222 (miR-221/222) cluster has been previously reported to function importantly in malignant glioma biological process. The current study aims at evaluating the effects of miR-221/222 cluster on angiogenesis of glioblastoma cells. Microarray data were analyzed to select glioblastoma-associated differentially expressed genes, and dual-luciferase reporter assay was performed to assess targeting correlation between miR-221/222 cluster and suppressor of cytokine signaling-3 (SOCS3). Subsequently, the expression patterns of miR-221 and miR-222 in glioblastoma cells were identified. miR-221 and miR-222 were overexpressed or silenced in glioblastoma cells to identify the effect of miR-221/222 cluster in cell invasion, migration, proliferation, and angiogenesis. To define downstream pathway of miR-221/222 cluster or SOCS3 in glioblastoma, levels of Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway-related proteins were assessed. Additionally, the functions of miR-221/222 on glioblastoma cell angiogenesis were measured in vivo with microvessel density assayed. miR-221 and miR-222 were expressed at a high level and SOCS3 was at a low level in glioblastoma. Downregulation of the miR-221/222 cluster diminished the invasion, migration, proliferation, and angiogenesis with reduced protein levels of matrix metalloproteinase-2 (MMP-2), MMP-9, and vascular endothelial growth factor in glioblastoma cells. Also, silencing miR-221/222 cluster reduced p-JAK2/JAK2 and p-STAT3/STAT3. Consistently, the inhibitory role of silencing miR-221/222 cluster on tumorigenesis of glioblastoma cells was confirmed in vivo. Collectively, the inhibition of miR-221/222 cluster could attenuate the glioblastoma angiogenesis through inactivation of the JAK/STAT pathway by upregulating SOCS3.
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Affiliation(s)
- Chun-Hua Xu
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, P.R. China
| | - Yue Liu
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, P.R. China
| | - Li-Min Xiao
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, P.R. China
| | - Li-Ke Chen
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, P.R. China
| | - Su-Yue Zheng
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, P.R. China
| | - Er-Ming Zeng
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, P.R. China
| | - Dong-Hai Li
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, P.R. China
| | - You-Ping Li
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, P.R. China
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25
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Tang XM, Dai J, Sun HL. Upregulation of suppressor of cytokine signaling 3 ameliorates spinal degenerative disease in adolescents by mediating leptin and tumor necrosis factor-α levels. Exp Ther Med 2019; 18:2231-2237. [PMID: 31410173 DOI: 10.3892/etm.2019.7786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2018] [Accepted: 01/25/2019] [Indexed: 11/06/2022] Open
Abstract
Spinal degenerative changes may occur following the rapid growth observed in adolescents, causing a reduced quality of life. The suppressor of cytokine signaling (SOCS) is involved in various degenerative diseases. The current study recruited adolescents with spinal degenerative disease (SDD) to identify the effect of SOCS-3 on leptin and tumor necrosis factor-α (TNF-α) levels in this disorder. From January 2010 to January 2016, 120 adolescents (aged 14 to 25) were enrolled in the current study, with 68 diagnosed with SDD and the remaining 52 treated as controls. Nucleus pulposus cells (NPCs) were extracted and cultured in vitro. TNF-α levels in NPCs were determined using flow cytometry. Degenerative NPCs were then transfected with pCR3.1-SOCS-3 and ELISA was performed to determined TNF-α and leptin levels. RT-qPCR was performed to measure the mRNA level of SOCS-3 and leptin in NPCs and western blotting was utilized to detect the protein level of leptin and the extent of leptin receptor phosphorylation. The results revealed that TNF-α levels in degenerative NPCs were higher than those in normal NPCs. The overexpression of SOCS-3 reduced levels of TNF-α and leptin in degenerative NPCs. In addition, the upregulation of leptin increased SOCS-3 levels in a concentration-dependent manner. Furthermore, the expression of the leptin receptor and phosphorylated leptin receptor gradually decreased with increasing leptin concentrations and the level of phosphorylated leptin receptor negatively correlated with SOCS-3 expression. The inductive effect of leptin on the level of SOCS-3 and the inhibitory effect of SOCS-3 on the activity of leptin were identified. The current study demonstrated that SOCS-3 reduces leptin and TNF-α levels in degenerative NPCs from adolescents, indicating its potential role in the development of novel SDD therapies.
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Affiliation(s)
- Xiao-Ming Tang
- Department of Orthopedics, The Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu 223300, P.R. China
| | - Jian Dai
- Department of Orthopedics, The Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu 223300, P.R. China
| | - Hai-Lang Sun
- Department of Orthopedics, The Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu 223300, P.R. China
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26
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Megalencephalic Leukoencephalopathy with Subcortical Cysts Protein-1 (MLC1) Counteracts Astrocyte Activation in Response to Inflammatory Signals. Mol Neurobiol 2019; 56:8237-8254. [DOI: 10.1007/s12035-019-01657-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Accepted: 05/20/2019] [Indexed: 01/08/2023]
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27
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Cai JY, Xu TT, Wang Y, Chang JJ, Li J, Chen XY, Chen X, Yin YF, Ni XJ. Histone deacetylase HDAC4 promotes the proliferation and invasion of glioma cells. Int J Oncol 2018; 53:2758-2768. [PMID: 30272277 DOI: 10.3892/ijo.2018.4564] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Accepted: 08/07/2018] [Indexed: 11/06/2022] Open
Abstract
Glioma is the most lethal type of primary brain tumor characterized by aggressiveness and a poor prognosis. Histone deacetylase 4 (HDAC4) is frequently dysregulated in human malignancies. However, its biological functions in the development of glioma are not fully understood. The present study aimed to evaluate HDAC4 expression in human glioma and to elucidate the mechanistic role of HDAC4 in glioma. The results suggested that HDAC4 was significantly upregulated in glioma tissues and a number of glioma cell lines compared with adjacent non-tumor tissues and the non-cancerous human glial cell line SVG p12, respectively (P<0.05). The proliferation, adenosine triphosphate (ATP) levels and invasion ability were substantially enhanced in U251 cells with HDAC4 overexpression, and suppressed in U251 cells with a knockdown of HDAC4 compared with that in U251 cells transfected with the negative control. Knockdown of HDAC4 resulted in cell cycle arrest at the G0/G1 phase and induced the increase of reactive oxygen species level in U251 cells. Furthermore, HDAC4 overexpression was revealed to substantially inhibit the expression of cyclin-dependent kinase (CDK) inhibitors p21 and p27, and the expression of E-cadherin and β‑catenin in glioma U251 cells. Knockdown of HDAC4 substantially promoted the expression of CDK1 and CDK2 and vimentin in glioma U251 cells. Mechanistically, the results of the present study demonstrated that HDAC4 displayed a significant upregulation in glioma, and promoted glioma cell proliferation and invasion mediated through the repression of p21, p27, E-cadherin and β‑catenin, and the potentiation of CDK1, CDK2 and vimentin. Altogether, the present study revealed that HDAC4 overexpression was central for the tumorigenesis of glioma, which may serve as a useful prognostic biomarker and potential therapeutic target for glioma.
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Affiliation(s)
- Jun-Yan Cai
- Department of Rehabilitation, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Tong-Tong Xu
- School of Medicine, Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Ye Wang
- School of Medicine, Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Jing-Jian Chang
- Department of Ultrasound, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Jian Li
- Department of Neurosurgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Xiao-Yang Chen
- Department of Ultrasound, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Xi Chen
- Department of Ultrasound, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Yi-Fei Yin
- Department of Ultrasound, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Xue-Jun Ni
- Department of Ultrasound, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
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28
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Wu S, Wang Y, Ning Y, Guo H, Wang X, Zhang L, Khan R, Cheng G, Wang H, Zan L. Genetic Variants in STAT3 Promoter Regions and Their Application in Molecular Breeding for Body Size Traits in Qinchuan Cattle. Int J Mol Sci 2018; 19:ijms19041035. [PMID: 29596388 PMCID: PMC5979584 DOI: 10.3390/ijms19041035] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Revised: 03/22/2018] [Accepted: 03/26/2018] [Indexed: 11/16/2022] Open
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 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.
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Affiliation(s)
- Sen Wu
- College of Animal Science and Technology, Northwest A & F University, Yangling 712100, China.
| | - Yaning Wang
- College of Animal Science and Technology, Northwest A & F University, Yangling 712100, China.
| | - Yue Ning
- College of Animal Science and Technology, Northwest A & F University, Yangling 712100, China.
| | - Hongfang Guo
- College of Animal Science and Technology, Northwest A & F University, Yangling 712100, China.
| | - Xiaoyu Wang
- College of Animal Science and Technology, Northwest A & F University, Yangling 712100, China.
| | - Le Zhang
- College of Animal Science and Technology, Northwest A & F University, Yangling 712100, China.
| | - Rajwali Khan
- College of Animal Science and Technology, Northwest A & F University, Yangling 712100, China.
| | - Gong Cheng
- College of Animal Science and Technology, Northwest A & F University, Yangling 712100, China.
- National Beef Cattle Improvement Center of Northwest A & F University, Yangling 712100, China.
| | - Hongbao Wang
- College of Animal Science and Technology, Northwest A & F University, Yangling 712100, China.
- National Beef Cattle Improvement Center of Northwest A & F University, Yangling 712100, China.
| | - Linsen Zan
- College of Animal Science and Technology, Northwest A & F University, Yangling 712100, China.
- National Beef Cattle Improvement Center of Northwest A & F University, Yangling 712100, China.
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29
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Naudin C, Chevalier C, Roche S. The role of small adaptor proteins in the control of oncogenic signalingr driven by tyrosine kinases in human cancer. Oncotarget 2017; 7:11033-55. [PMID: 26788993 PMCID: PMC4905456 DOI: 10.18632/oncotarget.6929] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2015] [Accepted: 01/01/2016] [Indexed: 12/15/2022] Open
Abstract
Protein phosphorylation on tyrosine (Tyr) residues has evolved as an important mechanism to coordinate cell communication in multicellular organisms. The importance of this process has been revealed by the discovery of the prominent oncogenic properties of tyrosine kinases (TK) upon deregulation of their physiological activities, often due to protein overexpression and/or somatic mutation. Recent reports suggest that TK oncogenic signaling is also under the control of small adaptor proteins. These cytosolic proteins lack intrinsic catalytic activity and signal by linking two functional members of a catalytic pathway. While most adaptors display positive regulatory functions, a small group of this family exerts negative regulatory functions by targeting several components of the TK signaling cascade. Here, we review how these less studied adaptor proteins negatively control TK activities and how their loss of function induces abnormal TK signaling, promoting tumor formation. We also discuss the therapeutic consequences of this novel regulatory mechanism in human oncology.
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Affiliation(s)
- Cécile Naudin
- CNRS UMR5237, University Montpellier, CRBM, Montpellier, France.,Present address: INSERM U1016, CNRS UMR8104, Institut Cochin, Paris, France
| | - Clément Chevalier
- CNRS UMR5237, University Montpellier, CRBM, Montpellier, France.,Present address: SFR Biosit (UMS CNRS 3480/US INSERM 018), MRic Photonics Platform, University Rennes, Rennes, France
| | - Serge Roche
- CNRS UMR5237, University Montpellier, CRBM, Montpellier, France.,Equipe Labellisée LIGUE 2014, Ligue Contre le Cancer, Paris, France
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30
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Detection of promoter methylation status of suppressor of cytokine signaling 3 (SOCS3) in tissue and plasma from Chinese patients with different hepatic diseases. Clin Exp Med 2017; 18:79-87. [DOI: 10.1007/s10238-017-0473-2] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Accepted: 09/07/2017] [Indexed: 12/19/2022]
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31
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Chu Q, Shen D, He L, Wang H, Liu C, Zhang W. Prognostic significance of SOCS3 and its biological function in colorectal cancer. Gene 2017; 627:114-122. [DOI: 10.1016/j.gene.2017.06.013] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2016] [Revised: 06/05/2017] [Accepted: 06/07/2017] [Indexed: 01/22/2023]
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32
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Chang N, Ahn SH, Kong DS, Lee HW, Nam DH. The role of STAT3 in glioblastoma progression through dual influences on tumor cells and the immune microenvironment. Mol Cell Endocrinol 2017; 451:53-65. [PMID: 28089821 DOI: 10.1016/j.mce.2017.01.004] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Accepted: 01/05/2017] [Indexed: 01/07/2023]
Abstract
Glioblastoma multiforme (GBM) is the most aggressive form of cancer that begins within the brain; generally, the patient has a dismal prognosis and limited therapeutic options. Signal transducer and activator of transcription 3 (STAT3) is a critical mediator of tumorigenesis, tumor progression, and suppression of anti-tumor immunity in GBM. In a high percentage of GBM cells and tumor microenvironments, persistent activation of STAT3 induces cell proliferation, anti-apoptosis, glioma stem cell maintenance, tumor invasion, angiogenesis, and immune evasion. This makes STAT3 an attractive therapeutic target and a prognostic indicator in GBM. Targeting STAT3 affords an opportunity to disrupt multiple pro-oncogenic pathways at a single molecular hub. Unfortunately, there are no successful STAT3 inhibitors currently in clinical trials. However, strong clinical evidence implicating STAT3 as a major factor in GBM justifies the identification of safe and effective strategies for inhibiting STAT3.
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Affiliation(s)
- Nakho Chang
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul 06351, South Korea; Institute for Refractory Cancer Research, Samsung Medical Center, Seoul 06351, South Korea
| | - Sun Hee Ahn
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul 06351, South Korea; Institute for Refractory Cancer Research, Samsung Medical Center, Seoul 06351, South Korea
| | - Doo-Sik Kong
- Departments of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea
| | - Hye Won Lee
- Institute for Refractory Cancer Research, Samsung Medical Center, Seoul 06351, South Korea; Institute for Future Medicine, Samsung Medical Center, Seoul 06351, South Korea.
| | - Do-Hyun Nam
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul 06351, South Korea; Institute for Refractory Cancer Research, Samsung Medical Center, Seoul 06351, South Korea; Departments of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea.
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33
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Jaraíz-Rodríguez M, Tabernero MD, González-Tablas M, Otero A, Orfao A, Medina JM, Tabernero A. A Short Region of Connexin43 Reduces Human Glioma Stem Cell Migration, Invasion, and Survival through Src, PTEN, and FAK. Stem Cell Reports 2017; 9:451-463. [PMID: 28712848 PMCID: PMC5549880 DOI: 10.1016/j.stemcr.2017.06.007] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Revised: 06/13/2017] [Accepted: 06/14/2017] [Indexed: 12/22/2022] Open
Abstract
Connexin43 (CX43), a protein that forms gap junction channels and hemichannels in astrocytes, is downregulated in high-grade gliomas. Its relevance for glioma therapy has been thoroughly explored; however, its positive effects on proliferation are counterbalanced by its effects on migration and invasion. Here, we show that a cell-penetrating peptide based on CX43 (TAT-Cx43266-283) inhibited c-Src and focal adhesion kinase (FAK) and upregulated phosphatase and tensin homolog in glioma stem cells (GSCs) derived from patients. Consequently, TAT-Cx43266-283 reduced GSC motility, as analyzed by time-lapse microscopy, and strongly reduced their invasive ability. Interestingly, we investigated the effects of TAT-Cx43266-283 on freshly removed surgical specimens as undissociated glioblastoma blocks, which revealed a dramatic reduction in the growth, migration, and survival of these cells. In conclusion, a region of CX43 (amino acids 266–283) exerts an important anti-tumor effect in patient-derived glioblastoma models that includes impairment of GSC migration and invasion.
TAT-Cx43266-283 exerts anti-tumor effects in patient-derived glioblastoma models TAT-Cx43266-283 targets Src, PTEN, and FAK TAT-Cx43266-283 inhibits glioma stem cell migration and invasion
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Affiliation(s)
- Myriam Jaraíz-Rodríguez
- Instituto de Neurociencias de Castilla y León (INCYL), Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, C/ Pintor Fernando Gallego 1, 37007 Salamanca, Spain
| | - Ma Dolores Tabernero
- Instituto de Estudios de Ciencias de la Salud de Castilla y León (IECSCYL), Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain; Centre for Cancer Research (CIC-IBMCC; CSIC/USAL; IBSAL), Departamento de Medicina Universidad de Salamanca, 37007 Salamanca, Spain
| | - María González-Tablas
- Instituto de Estudios de Ciencias de la Salud de Castilla y León (IECSCYL), Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain; Centre for Cancer Research (CIC-IBMCC; CSIC/USAL; IBSAL), Departamento de Medicina Universidad de Salamanca, 37007 Salamanca, Spain
| | - Alvaro Otero
- Neurosurgery Service, Hospital Universitario de Salamanca and IBSAL, 37007 Salamanca, Spain
| | - Alberto Orfao
- Centre for Cancer Research (CIC-IBMCC; CSIC/USAL; IBSAL), Departamento de Medicina Universidad de Salamanca, 37007 Salamanca, Spain
| | - Jose M Medina
- Instituto de Neurociencias de Castilla y León (INCYL), Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, C/ Pintor Fernando Gallego 1, 37007 Salamanca, Spain
| | - Arantxa Tabernero
- Instituto de Neurociencias de Castilla y León (INCYL), Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, C/ Pintor Fernando Gallego 1, 37007 Salamanca, Spain.
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MiR-181b modulates EGFR-dependent VCAM-1 expression and monocyte adhesion in glioblastoma. Oncogene 2017; 36:5006-5022. [PMID: 28459461 DOI: 10.1038/onc.2017.129] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2016] [Revised: 03/06/2017] [Accepted: 03/27/2017] [Indexed: 12/25/2022]
Abstract
Tumor-associated macrophages (TAMs) originate as circulating monocytes, and are recruited to gliomas, where they facilitate tumor growth and migration. Understanding the interaction between TAM and cancer cells may identify therapeutic targets for glioblastoma multiforme (GBM). Vascular cell adhesion molecule-1 (VCAM-1) is a cytokine-induced adhesion molecule expressed on the surface of cancer cells, which is involved in interactions with immune cells. Analysis of the glioma patient database and tissue immunohistochemistry showed that VCAM-1 expression correlated with the clinico-pathological grade of gliomas. Here, we found that VCAM-1 expression correlated positively with monocyte adhesion to GBM, and knockdown of VCAM-1 abolished the enhancement of monocyte adhesion. Importantly, upregulation of VCAM-1 is dependent on epidermal-growth-factor-receptor (EGFR) expression, and inhibition of EGFR effectively reduced VCAM-1 expression and monocyte adhesion activity. Moreover, GBM possessing higher EGFR levels (U251 cells) had higher VCAM-1 levels compared to GBMs with lower levels of EGFR (GL261 cells). Using two- and three-dimensional cultures, we found that monocyte adhesion to GBM occurs via integrin α4β1, which promotes tumor growth and invasion activity. Increased proliferation and tumor necrosis factor-α and IFN-γ levels were also observed in the adherent monocytes. Using a genetic modification approach, we demonstrated that VCAM-1 expression and monocyte adhesion were regulated by the miR-181 family, and lower levels of miR-181b correlated with high-grade glioma patients. Our results also demonstrated that miR-181b/protein phosphatase 2A-modulated SP-1 de-phosphorylation, which mediated the EGFR-dependent VCAM-1 expression and monocyte adhesion to GBM. We also found that the EGFR-dependent VCAM-1 expression is mediated by the p38/STAT3 signaling pathway. Our study suggested that VCAM-1 is a critical modulator of EGFR-dependent interaction of monocytes with GBM, which raises the possibility of developing effective and improved therapies for GBM.
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Liu LH, Li H, Cheng XX, Kong QY, Chen XY, Wu ML, Li Y, Liu J, Li C. Correlative analyses of the expression levels of PIAS3, p-SHP2, SOCS1 and SOCS3 with STAT3 activation in human astrocytomas. Mol Med Rep 2016; 15:847-852. [PMID: 28035384 DOI: 10.3892/mmr.2016.6079] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2015] [Accepted: 11/10/2016] [Indexed: 11/06/2022] Open
Abstract
The importance of signal transducer and activator of transcription 3 (STAT3) signaling in the growth and survival of glioblastoma cells has been well documented, while the reasons leading to STAT3 activation remains to be elucidated. Suppressors of cytokine signaling (SOCS) 1 and SOCS3, SH2 domain‑containing phosphatase (SHP2) and protein inhibitors of activated STAT3 (PIAS3) are known to inhibit STAT3 signal transduction, while their expression statuses in the four grades of astrocytomas and relevance with STAT3 activation remain to be described. The present study aimed to address these issues by tissue microarray‑based immunohistochemical profiling the expression levels of phosphorylated (p)‑STAT3, SOCS1, SOCS3, PIAS3 and p‑SHP2. The results revealed that p‑STAT3 nuclear translocation was rarely observed in non‑cancerous brain tissues and its frequencies were increased in a tumor grade‑associated manner (65.2, 77.1, 81.8 and 85.7% for grade I‑IV, respectively). PIAS3, p‑SHP2, SOCS1 and SOCS3 were expressed in higher levels (++ and +++) in 63.6, 90, 87.5 and 81.8% of tumor surrounding brain tissues, which reduced to 13.1, 47.8, 33.3 and 50% in grade I, 11.4, 65.7, 58.3 and 77.1% in grade II, 9.1, 63.6, 38.1 and 31.8% in grade III and 7.1, 66.7, 30.8 and 7.1% in grade IV astrocytomas. The above results revealed that although the expression levels of SOCS1, SOCS3 and, in particular, p‑SHP2, tend to decrease in the four types of astrocytomas, PIAS3 downregulation is more negatively correlated with STAT3 activation in the stepwise progress of astrocytomas and would indicate an unfavorable outcome.
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Affiliation(s)
- Li-Hong Liu
- Liaoning Laboratory of Cancer Genetics and Epigenetics, Department of Cell Biology, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| | - Hong Li
- Liaoning Laboratory of Cancer Genetics and Epigenetics, Department of Cell Biology, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| | - Xiao-Xin Cheng
- Liaoning Laboratory of Cancer Genetics and Epigenetics, Department of Cell Biology, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| | - Qing-You Kong
- Liaoning Laboratory of Cancer Genetics and Epigenetics, Department of Cell Biology, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| | - Xiao-Yan Chen
- Liaoning Laboratory of Cancer Genetics and Epigenetics, Department of Cell Biology, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| | - Mo-Li Wu
- Liaoning Laboratory of Cancer Genetics and Epigenetics, Department of Cell Biology, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| | - Yan Li
- Liaoning Laboratory of Cancer Genetics and Epigenetics, Department of Cell Biology, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| | - Jia Liu
- Liaoning Laboratory of Cancer Genetics and Epigenetics, Department of Cell Biology, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| | - Cong Li
- Liaoning Laboratory of Cancer Genetics and Epigenetics, Department of Cell Biology, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
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Katakowski M, Charteris N, Chopp M, Khain E. Density-Dependent Regulation of Glioma Cell Proliferation and Invasion Mediated by miR-9. CANCER MICROENVIRONMENT 2016; 9:149-159. [PMID: 27975329 DOI: 10.1007/s12307-016-0190-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Accepted: 12/05/2016] [Indexed: 01/11/2023]
Abstract
The phenotypic axis of invasion and proliferation in malignant glioma cells is a well-documented phenomenon. Invasive glioma cells exhibit a decreased proliferation rate and a resistance to apoptosis, and invasive tumor cells dispersed in brain subsequently revert to proliferation and contribute to secondary tumor formation. One miRNA can affect dozens of mRNAs, and some miRNAs are potent oncogenes. Multiple miRNAs are implicated in glioma malignancy, and several of which have been identified to regulate tumor cell motility and division. Using rat 9 L gliosarcoma and human U87 glioblastoma cell lines, we investigated miRNAs associated with the switch between glioma cell invasion and proliferation. Using micro-dissection of 9 L glioma tumor xenografts in rat brain, we identified disparate expression of miR-9 between cells within the periphery of the primary tumor, and those comprising tumor islets within the invasive zone. Modifying miR-9 expression in in vitro assays, we report that miR-9 controls the axis of glioma cell invasion/proliferation, and that its contribution to invasion or proliferation is biphasic and dependent upon local tumor cell density. In addition, immunohistochemistry revealed elevated hypoxia inducible factor 1 alpha (HIF-1α) in the invasive zone as compared to the primary tumor periphery. We also found that hypoxia promotes miR-9 expression in glioma cells. Based upon these findings, we propose a hypothesis for the contribution of miR-9 to the dynamics glioma invasion and satellite tumor formation in brain adjacent to tumor.
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Affiliation(s)
- Mark Katakowski
- Department of Neurology, Henry Ford Hospital, Detroit, MI, USA.
| | | | - Michael Chopp
- Department of Neurology, Henry Ford Hospital, Detroit, MI, USA
- Department of Physics, Oakland University, Rochester, MI, USA
| | - Evgeniy Khain
- Department of Physics, Oakland University, Rochester, MI, USA
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Liu C, Liu H, Chen J. [The Role of SOCS in the Development of Tumors]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2016; 19:620-5. [PMID: 27666555 PMCID: PMC5972954 DOI: 10.3779/j.issn.1009-3419.2016.09.11] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Suppressor of cytokine signaling (SOCS) family proteins are a group of negative regulatory factors that plays important roles in the negative regulation of cytokine responses by terminating the activation of the JAK-STAT and other signaling pathways. The family is composed of eight structurally related proteins. mainly through the inhibition of the activation of JAK-STAT signaling pathway and regulates cell proliferation, differentiation and apoptosis. In the process of tumor progression, the promoter CG island hypermethylation, gene mutation, gene deletion and inactivation lead to the abnormal expression of SOCS protein make JAK-STAT continuous activation, resulting in the development and metastasis of tumor. Here, we review the SOCS family members found, composition and molecular structure, the domain of the function, and the latest progress of development in tumor. Based on the important role of SOCS in tumor development, SOCS as a negative regulator factor represent a kind of tumor suppressor genes, has become a new target for tumor therapy.
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Affiliation(s)
- Chunlai Liu
- Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Hongyu Liu
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General
Hospital, Tianjin 300052, China
| | - Jun Chen
- Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China;Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General
Hospital, Tianjin 300052, China
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Ferreira WAS, Pinheiro DDR, Costa Junior CAD, Rodrigues-Antunes S, Araújo MD, Leão Barros MB, Teixeira ACDS, Faro TAS, Burbano RR, Oliveira EHCD, Harada ML, Borges BDN. An update on the epigenetics of glioblastomas. Epigenomics 2016; 8:1289-305. [PMID: 27585647 DOI: 10.2217/epi-2016-0040] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Glioblastomas, also known as glioblastoma multiforme (GBM), are the most aggressive and malignant type of primary brain tumor in adults, exhibiting notable variability at the histopathological, genetic and epigenetic levels. Recently, epigenetic alterations have emerged as a common hallmark of many tumors, including GBM. Considering that a deeper understanding of the epigenetic modifications that occur in GBM may increase the knowledge regarding the tumorigenesis, progression and recurrence of this disease, in this review we discuss the recent major advances in GBM epigenetics research involving histone modification, glioblastoma stem cells, DNA methylation, noncoding RNAs expression, including their main alterations and the use of epigenetic therapy as a valid option for GBM treatment.
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Affiliation(s)
- Wallax Augusto Silva Ferreira
- Molecular Biology Laboratory, Institute of Biological Sciences, Federal University of Pará (Universidade Federal do Pará-UFPA)-Belém, Pará, Brazil
| | - Danilo do Rosário Pinheiro
- Molecular Biology Laboratory, Institute of Biological Sciences, Federal University of Pará (Universidade Federal do Pará-UFPA)-Belém, Pará, Brazil
| | - Carlos Antonio da Costa Junior
- Molecular Biology Laboratory, Institute of Biological Sciences, Federal University of Pará (Universidade Federal do Pará-UFPA)-Belém, Pará, Brazil
| | - Symara Rodrigues-Antunes
- Molecular Biology Laboratory, Institute of Biological Sciences, Federal University of Pará (Universidade Federal do Pará-UFPA)-Belém, Pará, Brazil
| | - Mariana Diniz Araújo
- Molecular Biology Laboratory, Institute of Biological Sciences, Federal University of Pará (Universidade Federal do Pará-UFPA)-Belém, Pará, Brazil
| | - Mariceli Baia Leão Barros
- Molecular Biology Laboratory, Institute of Biological Sciences, Federal University of Pará (Universidade Federal do Pará-UFPA)-Belém, Pará, Brazil
| | - Adriana Corrêa de Souza Teixeira
- Molecular Biology Laboratory, Institute of Biological Sciences, Federal University of Pará (Universidade Federal do Pará-UFPA)-Belém, Pará, Brazil
| | - Thamirys Aline Silva Faro
- Molecular Biology Laboratory, Institute of Biological Sciences, Federal University of Pará (Universidade Federal do Pará-UFPA)-Belém, Pará, Brazil
| | | | | | - Maria Lúcia Harada
- Molecular Biology Laboratory, Institute of Biological Sciences, Federal University of Pará (Universidade Federal do Pará-UFPA)-Belém, Pará, Brazil
| | - Bárbara do Nascimento Borges
- Molecular Biology Laboratory, Institute of Biological Sciences, Federal University of Pará (Universidade Federal do Pará-UFPA)-Belém, Pará, Brazil
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Mahony R, Ahmed S, Diskin C, Stevenson NJ. SOCS3 revisited: a broad regulator of disease, now ready for therapeutic use? Cell Mol Life Sci 2016; 73:3323-36. [PMID: 27137184 PMCID: PMC11108554 DOI: 10.1007/s00018-016-2234-x] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2015] [Revised: 03/24/2016] [Accepted: 04/19/2016] [Indexed: 12/17/2022]
Abstract
Since their discovery, SOCS have been characterised as regulatory cornerstones of intracellular signalling. While classically controlling the JAK/STAT pathway, their inhibitory effects are documented across several cascades, underpinning their essential role in homeostatic maintenance and disease. After 20 years of extensive research, SOCS3 has emerged as arguably the most important family member, through its regulation of both cytokine- and pathogen-induced cascades. In fact, low expression of SOCS3 is associated with autoimmunity and oncogenesis, while high expression is linked to diabetes and pathogenic immune evasion. The induction of SOCS3 by both viruses and bacteria and its impact upon inflammatory disorders, underscores this protein's increasing clinical potential. Therefore, with the aim of highlighting SOCS3 as a therapeutic target for future development, this review revisits its multi-faceted immune regulatory functions and summarises its role in a broad ranges of diseases.
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Affiliation(s)
- R Mahony
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute (TBSI), Trinity College Dublin, Dublin, Ireland
| | - S Ahmed
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute (TBSI), Trinity College Dublin, Dublin, Ireland
| | - C Diskin
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute (TBSI), Trinity College Dublin, Dublin, Ireland
| | - N J Stevenson
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute (TBSI), Trinity College Dublin, Dublin, Ireland.
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Jiao W, Xun X, Liu J, Yang J, Wang Q, Wang L, Chen C, Wang H, Dai P. Diagnostic significance of suppressor of cytokine signalling 3 (SOCS3) methylation and its correlation with IDH1 mutation in Chinese glioma patients. Biomarkers 2016; 21:686-691. [DOI: 10.3109/1354750x.2016.1139001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Affiliation(s)
- Weili Jiao
- The National Engineering Research Center for Miniaturized Detection Systems, School of Life Sciences, Northwest University, Xi’an, PR China
| | - Xiaojie Xun
- The National Engineering Research Center for Miniaturized Detection Systems, School of Life Sciences, Northwest University, Xi’an, PR China
| | - Jinhui Liu
- The National Engineering Research Center for Miniaturized Detection Systems, School of Life Sciences, Northwest University, Xi’an, PR China
| | - Jianhui Yang
- The National Engineering Research Center for Miniaturized Detection Systems, School of Life Sciences, Northwest University, Xi’an, PR China
| | - Qi Wang
- The National Engineering Research Center for Miniaturized Detection Systems, School of Life Sciences, Northwest University, Xi’an, PR China
| | - Lin Wang
- The National Engineering Research Center for Miniaturized Detection Systems, School of Life Sciences, Northwest University, Xi’an, PR China
| | - Chao Chen
- The National Engineering Research Center for Miniaturized Detection Systems, School of Life Sciences, Northwest University, Xi’an, PR China
| | - Huijuan Wang
- The National Engineering Research Center for Miniaturized Detection Systems, School of Life Sciences, Northwest University, Xi’an, PR China
| | - Penggao Dai
- The National Engineering Research Center for Miniaturized Detection Systems, School of Life Sciences, Northwest University, Xi’an, PR China
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Cacalano NA. Regulation of Natural Killer Cell Function by STAT3. Front Immunol 2016; 7:128. [PMID: 27148255 PMCID: PMC4827001 DOI: 10.3389/fimmu.2016.00128] [Citation(s) in RCA: 68] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2015] [Accepted: 03/21/2016] [Indexed: 01/05/2023] Open
Abstract
Natural killer (NK) cells, key members of a distinct hematopoietic lineage, innate lymphoid cells, are not only critical effectors that mediate cytotoxicity toward tumor and virally infected cells but also regulate inflammation, antigen presentation, and the adaptive immune response. It has been shown that NK cells can regulate the development and activation of many other components of the immune response, such as dendritic cells, which in turn, modulate the function of NK cells in multiple synergistic feed back loops driven by cell–cell contact, and the secretion of cytokines and chemokines that control effector function and migration of cells to sites of immune activation. The signal transducer and activator of transcription (STAT)-3 is involved in driving almost all of the pathways that control NK cytolytic activity as well as the reciprocal regulatory interactions between NK cells and other components of the immune system. In the context of tumor immunology, NK cells are a first line of defense that eliminates pre-cancerous and transformed cells early in the process of carcinogenesis, through a mechanism of “immune surveillance.” Even after tumors become established, NK cells are critical components of anticancer immunity: dysfunctional NK cells are often found in the peripheral blood of cancer patients, and the lack of NK cells in the tumor microenvironment often correlates to poor prognosis. The pathways and soluble factors activated in tumor-associated NK cells, cancer cells, and regulatory myeloid cells, which determine the outcome of cancer immunity, are all critically regulated by STAT3. Using the tumor microenvironment as a paradigm, we present here an overview of the research that has revealed fundamental mechanisms through which STAT3 regulates all aspects of NK cell biology, including NK development, activation, target cell killing, and fine tuning of the innate and adaptive immune responses.
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Affiliation(s)
- Nicholas A Cacalano
- Department of Radiation Oncology, David Geffen School of Medicine at UCLA , Los Angeles, CA , USA
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Handle F, Erb HHH, Luef B, Hoefer J, Dietrich D, Parson W, Kristiansen G, Santer FR, Culig Z. SOCS3 Modulates the Response to Enzalutamide and Is Regulated by Androgen Receptor Signaling and CpG Methylation in Prostate Cancer Cells. Mol Cancer Res 2016; 14:574-85. [PMID: 27053681 DOI: 10.1158/1541-7786.mcr-15-0495] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2015] [Accepted: 03/23/2016] [Indexed: 11/16/2022]
Abstract
UNLABELLED The proinflammatory cytokine IL6 is associated with bad prognosis in prostate cancer and implicated in progression to castration resistance. Suppressor of cytokine signaling 3 (SOCS3) is an IL6-induced negative feedback regulator of the IL6/Janus kinase (JAK)/STAT3 pathway. This study reveals that the SOCS3 promoter is hypermethylated in cancerous regions compared with adjacent benign tissue in prostate cancer using methylation-specific qPCR. A series of in vitro experiments was performed to assess the functional impact of low SOCS3 expression during anti-androgen treatment. Using lentivirus-mediated knockdown, it was demonstrated for the first time that SOCS3 regulates IL6/JAK/STAT3 signaling in androgen receptor-positive LNCaP cells. In addition, SOCS3 mRNA is upregulated by the anti-androgens bicalutamide and enzalutamide. This effect is caused by androgen receptor-mediated suppression of IL6ST and JAK1 expression, which leads to altered STAT3 signaling. Functionally, knockdown of SOCS3 led to enhanced androgen receptor activity after 3 weeks of enzalutamide treatment in an inflammatory setting. Furthermore, the stemness/self-renewal associated genes SOX2 and NANOG were strongly upregulated by the long-term treatment, and modulation of SOCS3 expression was sufficient to counteract this effect. These findings prove that SOCS3 plays an important role during anti-androgen treatment in an inflammatory environment. IMPLICATIONS SOCS3 is frequently inactivated by promoter hypermethylation in prostate cancer, which disrupts the feedback regulation of IL6 signaling and leads to reduced efficacy of enzalutamide in the presence of inflammatory cytokines. Mol Cancer Res; 14(6); 574-85. ©2016 AACR.
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Affiliation(s)
- Florian Handle
- Division of Experimental Urology, Department of Urology, Medical University of Innsbruck, Innsbruck, Austria
| | - Holger H H Erb
- Division of Experimental Urology, Department of Urology, Medical University of Innsbruck, Innsbruck, Austria. Yorkshire Cancer Research Unit, University of York, York, United Kingdom
| | - Birgit Luef
- Division of Experimental Urology, Department of Urology, Medical University of Innsbruck, Innsbruck, Austria
| | - Julia Hoefer
- Division of Experimental Urology, Department of Urology, Medical University of Innsbruck, Innsbruck, Austria
| | - Dimo Dietrich
- Institute of Pathology, University Hospital Bonn, Bonn, Germany
| | - Walther Parson
- Institute of Legal Medicine, Medical University of Innsbruck, Innsbruck, Austria. Forensic Science Program, The Pennsylvania State University, University Park, Pennsylvania
| | | | - Frédéric R Santer
- Division of Experimental Urology, Department of Urology, Medical University of Innsbruck, Innsbruck, Austria.
| | - Zoran Culig
- Division of Experimental Urology, Department of Urology, Medical University of Innsbruck, Innsbruck, Austria.
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IL-6 promotes an increase in human mast cell numbers and reactivity through suppression of suppressor of cytokine signaling 3. J Allergy Clin Immunol 2016; 137:1863-1871.e6. [PMID: 26774658 DOI: 10.1016/j.jaci.2015.09.059] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2015] [Revised: 09/16/2015] [Accepted: 09/30/2015] [Indexed: 12/21/2022]
Abstract
BACKGROUND IL-6, levels of which are reported to be increased in association with mastocytosis, asthma, and urticaria, is used in conjunction with stem cell factor to generate CD34(+) cell-derived primary human mast cell (HuMC) cultures. Despite these associations, the effects on and mechanisms by which prolonged exposure to IL-6 alters HuMC numbers and function are not well understood. OBJECTIVES We sought to study the effect of IL-6 on HuMC function, the mechanisms by which IL-6 exerts its effects, and the relationship of these findings to mastocytosis. METHODS HuMCs were cultured in stem cell factor with or without IL-6. Responses to FcεRI aggregation and expression of proteases and receptors, including the soluble IL-6 receptor (sIL-6R), were then quantitated. Epigenetic changes in suppressor of cytokine signaling 3 (SOCS3) were determined by using methylation-specific PCR. Serum samples from healthy control subjects and patients with mastocytosis were assayed for IL-6, tryptase, and sIL-6R. RESULTS IL-6 enhanced mast cell (MC) proliferation, maturation, and reactivity after FcεRI aggregation. IL-6 reduced expression of SOCS3, which correlated with methylation of the SOCS3 promoter and increased expression and activation of signal transducer and activator of transcription 3. IL-6 also suppressed constitutive production of sIL-6R, and serum levels of sIL-6R were similarly reduced in patients with mastocytosis. CONCLUSION IL-6 increases MC proliferation and formation of a more reactive phenotype enabled by suppressing proteolytic cleavage of sIL-6R from IL-6R and downregulation of the SOCS3 autoinhibitory pathway. We suggest IL-6 blockade might ameliorate MC-related symptoms and pathology in patients with MC-related diseases associated with increased IL-6 levels, including mastocytosis.
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Boosani CS, Agrawal DK. Methylation and microRNA-mediated epigenetic regulation of SOCS3. Mol Biol Rep 2015; 42:853-72. [PMID: 25682267 DOI: 10.1007/s11033-015-3860-3] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Epigenetic gene silencing of several genes causes different pathological conditions in humans, and DNA methylation has been identified as one of the key mechanisms that underlie this evolutionarily conserved phenomenon associated with developmental and pathological gene regulation. Recent advances in the miRNA technology with high throughput analysis of gene regulation further increased our understanding on the role of miRNAs regulating multiple gene expression. There is increasing evidence supporting that the miRNAs not only regulate gene expression but they also are involved in the hypermethylation of promoter sequences, which cumulatively contributes to the epigenetic gene silencing. Here, we critically evaluated the recent progress on the transcriptional regulation of an important suppressor protein that inhibits cytokine-mediated signaling, SOCS3, whose expression is directly regulated both by promoter methylation and also by microRNAs, affecting its vital cell regulating functions. SOCS3 was identified as a potent inhibitor of Jak/Stat signaling pathway which is frequently upregulated in several pathologies, including cardiovascular disease, cancer, diabetes, viral infections, and the expression of SOCS3 was inhibited or greatly reduced due to hypermethylation of the CpG islands in its promoter region or suppression of its expression by different microRNAs. Additionally, we discuss key intracellular signaling pathways regulated by SOCS3 involving cellular events, including cell proliferation, cell growth, cell migration and apoptosis. Identification of the pathway intermediates as specific targets would not only aid in the development of novel therapeutic drugs, but, would also assist in developing new treatment strategies that could successfully be employed in combination therapy to target multiple signaling pathways.
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Affiliation(s)
- Chandra S Boosani
- Center for Clinical and Translational Science, Creighton University School of Medicine, Omaha, NE, 68178, USA
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Rolón-Reyes K, Kucheryavykh YV, Cubano LA, Inyushin M, Skatchkov SN, Eaton MJ, Harrison JK, Kucheryavykh LY. Microglia Activate Migration of Glioma Cells through a Pyk2 Intracellular Pathway. PLoS One 2015; 10:e0131059. [PMID: 26098895 PMCID: PMC4476590 DOI: 10.1371/journal.pone.0131059] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Accepted: 05/27/2015] [Indexed: 01/03/2023] Open
Abstract
Glioblastoma is one of the most aggressive and fatal brain cancers due to the highly invasive nature of glioma cells. Microglia infiltrate most glioma tumors and, therefore, make up an important component of the glioma microenvironment. In the tumor environment, microglia release factors that lead to the degradation of the extracellular matrix and stimulate signaling pathways to promote glioma cell invasion. In the present study, we demonstrated that microglia can promote glioma migration through a mechanism independent of extracellular matrix degradation. Using western blot analysis, we found upregulation of proline rich tyrosine kinase 2 (Pyk2) protein phosphorylated at Tyr579/580 in glioma cells treated with microglia conditioned medium. This upregulation occurred in rodent C6 and GL261 as well as in human glioma cell lines with varying levels of invasiveness (U-87MG, A172, and HS683). siRNA knock-down of Pyk2 protein and pharmacological blockade by the Pyk2/focal-adhesion kinase (FAK) inhibitor PF-562,271 reversed the stimulatory effect of microglia on glioma migration in all cell lines. A lower concentration of PF-562,271 that selectively inhibits FAK, but not Pyk2, did not have any effect on glioma cell migration. Moreover, with the use of the CD11b-HSVTK microglia ablation mouse model we demonstrated that elimination of microglia in the implanted tumors (GL261 glioma cells were used for brain implantation) by the local in-tumor administration of Ganciclovir, significantly reduced the phosphorylation of Pyk2 at Tyr579/580 in implanted tumor cells. Taken together, these data indicate that microglial cells activate glioma cell migration/dispersal through the pro-migratory Pyk2 signaling pathway in glioma cells.
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Affiliation(s)
- Kimberleve Rolón-Reyes
- Department of Biochemistry, Universidad Central del Caribe, School of Medicine, Bayamón, Puerto Rico, United States of America
| | - Yuriy V. Kucheryavykh
- Department of Biochemistry, Universidad Central del Caribe, School of Medicine, Bayamón, Puerto Rico, United States of America
| | - Luis A. Cubano
- Department of Anatomy and Cell Biology, Universidad Central del Caribe, School of Medicine, Bayamón, Puerto Rico, United States of America
| | - Mikhail Inyushin
- Department of Physiology, Universidad Central del Caribe, School of Medicine, Bayamón, Puerto Rico, United States of America
| | - Serguei N. Skatchkov
- Department of Biochemistry, Universidad Central del Caribe, School of Medicine, Bayamón, Puerto Rico, United States of America
- Department of Physiology, Universidad Central del Caribe, School of Medicine, Bayamón, Puerto Rico, United States of America
| | - Misty J. Eaton
- Department of Biochemistry, Universidad Central del Caribe, School of Medicine, Bayamón, Puerto Rico, United States of America
| | - Jeffrey K. Harrison
- Department of Pharmacology and Therapeutics, College of Medicine, University of Florida, Gainesville, Florida
| | - Lilia Y. Kucheryavykh
- Department of Biochemistry, Universidad Central del Caribe, School of Medicine, Bayamón, Puerto Rico, United States of America
- * E-mail:
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Targeting JAK kinase in solid tumors: emerging opportunities and challenges. Oncogene 2015; 35:939-51. [DOI: 10.1038/onc.2015.150] [Citation(s) in RCA: 153] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2014] [Revised: 03/24/2015] [Accepted: 03/24/2015] [Indexed: 02/07/2023]
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Wang GP, Han XF. CD9 modulates proliferation of human glioblastoma cells via epidermal growth factor receptor signaling. Mol Med Rep 2015; 12:1381-6. [PMID: 25760022 DOI: 10.3892/mmr.2015.3466] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2014] [Accepted: 01/02/2015] [Indexed: 12/14/2022] Open
Abstract
The tetraspanin CD9 has previously been shown to be involved in various cellular activities, including proliferation and migration. In addition, CD9 has been shown to be associated with epidermal growth factor receptor (EGFR). A common characteristic of glioblastoma multiforme histology is EGFR amplification, which affects signal transduction processes. The anti-proliferative effects of CD9 have been linked to EGFR signaling pathways, including phosphorylation of phosphoinositide-3-kinase (PI3K)/Akt and activation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated protein kinase (Erk). The present study demonstrated that CD9 decreased the phosphorylation of EGFR at specific sites. In addition, CD9 attenuated EGFR signaling of PI3K/Akt and MAPK/Erk, which was associated with cell growth and proliferation. Conversely, small hairpin RNA-mediated knockdown of CD9 expression enhanced the activation of EGFR signal transduction pathways, including PI3K/Akt and MAPK/Erk. These results suggested that the mechanism underlying CD9-induced suppression of cell proliferation may involve the inhibition of phosphorylation of EGFR and the activity of PI3K/Akt and MAPK/Erk signaling pathways.
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Affiliation(s)
- Gong-Ping Wang
- First Department of Neurosurgery, Xianyang Hospital of Yanan University, Central Hospital of 20th Bureau of China Railway Group, Xianyang, Shaanxi 712000, P.R. China
| | - Xiao-Fang Han
- Department of Medical Teaching, Xianyang Hospital of Yanan University, Central Hospital of 20th Bureau of China Railway Group, Xianyang, Shaanxi 712000, P.R. China
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Sexton-Oates A, MacGregor D, Dodgshun A, Saffery R. The potential for epigenetic analysis of paediatric CNS tumours to improve diagnosis, treatment and prognosis. Ann Oncol 2015; 26:1314-24. [PMID: 25605740 DOI: 10.1093/annonc/mdv024] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2014] [Accepted: 12/17/2014] [Indexed: 12/31/2022] Open
Abstract
Tumours of central nervous system (CNS) origin are the second most prevalent group of cancers in children, yet account for the majority of childhood cancer-related deaths. Such tumours show diverse location, cell type of origin, disease course and long-term outcome, both across and within tumour types, making treatment problematic and contributing to the relatively modest progress in reducing mortality over recent decades. As technological advances begin to reveal the genetic landscape of all cancers, it is becoming increasingly clear that genetic disruption represents only one 'layer' of molecular disruption associated with disease aetiology. Obtaining a full understanding of tumour behaviour requires an understanding of the cellular and molecular pathways disrupted during tumourigenesis, particularly in relation to gene expression. The utility of such an approach has allowed stratification of cancers such as medulloblastoma into subgroups based on molecular features, with potential to refine risk prediction. Given that epigenetic disruption is a universal feature of all human cancers, it is logical to speculate that interrogating epigenetic marks may help to further define the molecular profile, and therefore the clinical trajectory, of tumours. An integrated approach to build a molecular 'signature' of individual tumours that incorporates traditional morphological and demographic information, genetic and transcriptome analysis, in addition to epigenomics (DNA methylation and non-coding RNA analysis), offers tremendous promise to (i) inform treatment approach, (ii) facilitate accurate early identification (preferably at diagnosis) of variable risk groups (both good and poor prognosis groups), and (iii) track disease progression in childhood CNS tumours.
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Affiliation(s)
- A Sexton-Oates
- Department of Paediatrics, The University of Melbourne, Melbourne Murdoch Childrens Research Institute, Melbourne
| | - D MacGregor
- Department of Anatomical Pathology, The Royal Children's Hospital, Melbourne Department of Pathology, The University of Melbourne, Melbourne
| | - A Dodgshun
- Children's Cancer Centre, The Royal Children's Hospital, Melbourne, Australia
| | - R Saffery
- Department of Paediatrics, The University of Melbourne, Melbourne Murdoch Childrens Research Institute, Melbourne
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Tarassishin L, Casper D, Lee SC. Aberrant expression of interleukin-1β and inflammasome activation in human malignant gliomas. PLoS One 2014; 9:e103432. [PMID: 25054228 PMCID: PMC4108401 DOI: 10.1371/journal.pone.0103432] [Citation(s) in RCA: 82] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2014] [Accepted: 07/02/2014] [Indexed: 11/18/2022] Open
Abstract
Objective Glioblastoma is the most frequent and malignant form of primary brain tumor with grave prognosis. Mounting evidence supports that chronic inflammation (such as chronic overactivation of IL-1 system) is a crucial event in carcinogenesis and tumor progression. IL-1 also is an important cytokine with species-dependent regulations and roles in CNS cell activation. While much attention is paid to specific anti-tumor immunity, little is known about the role of chronic inflammation/innate immunity in glioma pathogenesis. In this study, we examined whether human astrocytic cells (including malignant gliomas) can produce IL-1 and its role in glioma progression. Methods We used a combination of cell culture, real-time PCR, ELISA, western blot, immunocytochemistry, siRNA and plasmid transfection, micro-RNA analysis, angiogenesis (tube formation) assay, and neurotoxicity assay. Results Glioblastoma cells produced large quantities of IL-1 when activated, resembling macrophages/microglia. The activation signal was provided by IL-1 but not the pathogenic components LPS or poly IC. Glioblastoma cells were highly sensitive to IL-1 stimulation, suggesting its relevance in vivo. In human astrocytes, IL-1β mRNA was not translated to protein. Plasmid transfection also failed to produce IL-1 protein, suggesting active repression. Suppression of microRNAs that can target IL-1α/β did not induce IL-1 protein. Glioblastoma IL-1β processing occurred by the NLRP3 inflammasome, and ATP and nigericin increased IL-1β processing by upregulating NLRP3 expression, similar to macrophages. RNAi of annexin A2, a protein strongly implicated in glioma progression, prevented IL-1 induction, demonstrating its new role in innate immune activation. IL-1 also activated Stat3, a transcription factor crucial in glioma progression. IL-1 activated glioblastoma-conditioned media enhanced angiogenesis and neurotoxicity. Conclusions Our results demonstrate unique, species-dependent immune activation mechanisms involving human astrocytes and astrogliomas. Specifically, the ability to produce IL-1 by glioblastoma cells may confer them a mesenchymal phenotype including increased migratory capacity, unique gene signature and proinflammatory signaling.
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Affiliation(s)
- Leonid Tarassishin
- Department of Pathology (Neuropathology), Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, United States of America
| | - Diana Casper
- Department of Neurosurgery, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, United States of America
| | - Sunhee C Lee
- Department of Pathology (Neuropathology), Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, United States of America
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SOCS3 methylation in synergy with Reg3A overexpression promotes cell growth in pancreatic cancer. J Mol Med (Berl) 2014; 92:1257-69. [PMID: 24996521 DOI: 10.1007/s00109-014-1184-8] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2014] [Revised: 06/03/2014] [Accepted: 06/16/2014] [Indexed: 01/05/2023]
Abstract
UNLABELLED Pancreatic cancer (PaC) is the fifth leading cause of cancer death in the world, but the molecular mechanisms for its development remain unclear. Regenerating islet-derived protein 3-alpha (Reg3A) has been reported overexpressed in pancreatic inflammation and associated with PaC malignancies, thus believed as a potential target in inflammation-linked pancreatic carcinogenesis. Silencing of suppressor of cytokine signaling SOCS3, a well-known feedback inhibitor of cell proliferation, has been found in many human cancers. Here, we identified that SOCS3 was aberrantly methylated in its CpG island in 3/5 human PaC cell lines and 11/36 cancer tissue samples. SOCS3 restoration by a demethylating agent, 5-aza-2'-deoxycytidine, remarkably suppressed cell proliferation and induced apoptosis of methylated PaC cells. Moreover, we also have shown that Reg3A was highly expressed in PaC cells and tissue samples. Assessment of potential relationship between SOCS3 and Reg3A aberrations in vitro revealed that SOCS3 worked downstream of Reg3A and modulated Reg3A-linked pro-tumor functions. siRNA-mediated SOCS3 knock-down in normal pancreatic epithelial cells and plasmid-transfected SOCS3 overexpression in PaC cells, respectively, resulted in the obvious promotion and inhibition of Reg3A-induced cell proliferation, thereby suggesting SOCS3 negatively regulating Reg3A-mediated PaC progression. In addition, our findings also revealed that JAK/STAT3/NF-κB appear involved in the effect of SOCS3-Reg3A interaction on pancreatic cell growth. In summary, SOCS3 inactivation by methylation was demonstrated to act in synergy with Reg3A overexpression to promote PaC cell growth and maybe the progress of inflammation-linked pancreatic carcinogenesis. KEY MESSAGES Reg3A overexpression promoted cell growth in pancreatic cancer. SOCS3 is a key target in cancer by inhibiting cell growth and inducing apoptosis. SOCS3 negatively regulated Reg3A-mediated cell growth in pancreatic cancer. SOCS3 methylation act in synergy with Reg3A overexpression to promote pancreatic cancer cell growth.
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