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Zarezadeh SM, Sharafi AM, Erabi G, Tabashiri A, Teymouri N, Mehrabi H, Golzan SA, Faridzadeh A, Abdollahifar Z, Sami N, Arabpour J, Rahimi Z, Ansari A, Abbasi MR, Azizi N, Tamimi A, Poudineh M, Deravi N. Natural STAT3 Inhibitors for Cancer Treatment: A Comprehensive Literature Review. Recent Pat Anticancer Drug Discov 2024; 19:403-502. [PMID: 37534488 DOI: 10.2174/1574892818666230803100554] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 06/05/2023] [Accepted: 06/09/2023] [Indexed: 08/04/2023]
Abstract
Cancer is one of the leading causes of mortality and morbidity worldwide, affecting millions of people physically and financially every year. Over time, many anticancer treatments have been proposed and studied, including synthetic compound consumption, surgical procedures, or grueling chemotherapy. Although these treatments have improved the daily life quality of patients and increased their survival rate and life expectancy, they have also shown significant drawbacks, including staggering costs, multiple side effects, and difficulty in compliance and adherence to treatment. Therefore, natural compounds have been considered a possible key to overcoming these problems in recent years, and thorough research has been done to assess their effectiveness. In these studies, scientists have discovered a meaningful interaction between several natural materials and signal transducer and activator of transcription 3 molecules. STAT3 is a transcriptional protein that is vital for cell growth and survival. Mechanistic studies have established that activated STAT3 can increase cancer cell proliferation and invasion while reducing anticancer immunity. Thus, inhibiting STAT3 signaling by natural compounds has become one of the favorite research topics and an attractive target for developing novel cancer treatments. In the present article, we intend to comprehensively review the latest knowledge about the effects of various organic compounds on inhibiting the STAT3 signaling pathway to cure different cancer diseases.
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Affiliation(s)
- Seyed Mahdi Zarezadeh
- Students' Scientific Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir Mohammad Sharafi
- Students' Scientific Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Gisou Erabi
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran
| | - Arefeh Tabashiri
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Navid Teymouri
- Student Research Committee, Tabriz University of Medical Science, Tabriz, Iran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hoda Mehrabi
- Student Research Committee, School of Medicine, Arak University of Medical Sciences, Arak, Iran
| | - Seyyed Amirhossein Golzan
- Student Research Committee, Department of Food Science and Technology, National Nutrition and Food Technology Research Institute, Faculty of Nutrition Science and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Arezoo Faridzadeh
- Department of Immunology and Allergy, Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Zahra Abdollahifar
- Student Research Committee, School of Medicine, Arak University of Medical Sciences, Arak, Iran
| | - Nafiseh Sami
- Student Research Committee, Tehran Medical Sciences, Islamic Azad University Medical Branch of Tehran, Tehran, Iran
| | - Javad Arabpour
- Department of Microbiology, Faculty of New Sciences, Islamic Azad University Medical Branch of Tehran, Tehran, Iran
| | - Zahra Rahimi
- School of Medicine, Zanjan University of Medical Sciences Zanjan, Iran
| | - Arina Ansari
- Student Research Committee, School of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | | | - Nima Azizi
- Students' Scientific Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | | | | | - Niloofar Deravi
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Zong Y, Chen Y, Wang Y, Wang J, Yu Z, Ou Z, Chen J, Zhang H, Liu C. Induction of cardiotoxicity in zebrafish embryos by 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene through the JAK-STAT and NOTCH signaling pathways. Chem Biol Interact 2022; 368:110226. [DOI: 10.1016/j.cbi.2022.110226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 10/02/2022] [Accepted: 10/18/2022] [Indexed: 11/29/2022]
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Zeng Q, Che Y, Zhang Y, Chen M, Guo Q, Zhang W. Thymol Isolated from Thymus vulgaris L. Inhibits Colorectal Cancer Cell Growth and Metastasis by Suppressing the Wnt/β-Catenin Pathway. DRUG DESIGN DEVELOPMENT AND THERAPY 2020; 14:2535-2547. [PMID: 32669835 PMCID: PMC7335897 DOI: 10.2147/dddt.s254218] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Accepted: 05/26/2020] [Indexed: 12/31/2022]
Abstract
Purpose Colorectal cancer (CRC) is one of the most commonly occurring cancers and is associated with high morbidity and mortality. Nevertheless, there is currently no safe and effective treatment for this condition. Thymol is a phenolic compound that is recognized as safe for use in food as well as medical and cosmetic fields. Increasing evidence has indicated that thymol exerts prominent antitumor effects in a variety of cancers, including CRC. However, how thymol elicits these effects on CRC and the associated underlying mechanisms remains unclear. Methods HCT116 and Lovo cells were treated with different concentrations of thymol. Cell Counting Kit-8 (CCK-8) and transwell migration and invasion assays were used to evaluate cell proliferation, migration, and invasion, respectively. Cell apoptosis and cell cycle distribution were measured by flow cytometry. RT-qPCR, Western blot, and immunohistochemistry were used to detect the expression of related genes and their protein products. Results In this study, we tested the antitumor activity of thymol extracted from a Chinese medicinal herb, Thymus vulgaris L. We show that thymol treatment in vitro inhibited cell proliferation and induced apoptosis and cell cycle arrest in CRC. Furthermore, in vivo treatment with 75 and 150 mg/kg thymol led to a significant decrease in tumor volume. Thymol administration induced CRC cell apoptosis through activation of the BAX/Bcl-2 signaling pathway. In addition, thymol suppressed CRC cell epithelial–mesenchymal transition (EMT), invasion, and metastasis via inhibiting the activation of the Wnt/β-catenin pathway, both in vitro and in vivo. Conclusion Thymol may prevent CRC progression through inhibition of the Wnt/β-catenin signaling pathway, highlighting its potential as a novel therapeutic option for the treatment of CRC.
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Affiliation(s)
- Qiongyao Zeng
- Faculty of Life Science and Biotechnology, Kunming University of Science and Technology, Kunming 650500, People's Republic of China.,Medical School, Kunming University of Science and Technology, Kunming 650500, People's Republic of China
| | - Yuncheng Che
- Medical School, Kunming University of Science and Technology, Kunming 650500, People's Republic of China
| | - Yu Zhang
- Department of Gastroenterology, The First People's Hospital of Yunnan Province, Yunnan Provincial Institute of Digestive Medicine, Kunming 650032, People's Republic of China
| | - Mei Chen
- Medical School, Kunming University of Science and Technology, Kunming 650500, People's Republic of China
| | - Qiang Guo
- Faculty of Life Science and Biotechnology, Kunming University of Science and Technology, Kunming 650500, People's Republic of China.,Medical School, Kunming University of Science and Technology, Kunming 650500, People's Republic of China.,Department of Gastroenterology, The First People's Hospital of Yunnan Province, Yunnan Provincial Institute of Digestive Medicine, Kunming 650032, People's Republic of China
| | - Wenjing Zhang
- Medical School, Kunming University of Science and Technology, Kunming 650500, People's Republic of China.,Department of Medical Oncology, The First People's Hospital of Yunnan Province, Kunming 650032, People's Republic of China
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Jiang L, Zhao XH, Mao YL, Wang JF, Zheng HJ, You QS. Long non-coding RNA RP11-468E2.5 curtails colorectal cancer cell proliferation and stimulates apoptosis via the JAK/STAT signaling pathway by targeting STAT5 and STAT6. J Exp Clin Cancer Res 2019; 38:465. [PMID: 31718693 PMCID: PMC6852742 DOI: 10.1186/s13046-019-1428-0] [Citation(s) in RCA: 101] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Accepted: 09/23/2019] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND Long non-coding RNAs (lncRNAs) are tumor-associated biological molecules and have been found to be implicated in the progression of colorectal cancer (CRC). This study aims to examine the effects of lncRNA RP11-468E2.5 and its target genes (STAT5 and STAT6) on the biological activities of CRC cells via the Janus kinase-signal transducer and activator of transcription (JAK/STAT) signaling pathway. METHODS We initially screened the GEO database for differentially expressed lncRNAs related to CRC and then made a prediction of the implicated target genes. Then we collected CRC tissues and adjacent normal tissues from 169 CRC patients. Human CRC HCT116 and SW480 cells were treated with small interference RNA (siRNA) against RP11-468E2.5, AG490 (an inhibitor of the JAK/STAT signaling pathway), or both in combination. Next, we measured the effects of RP11-468E2.5 treatment on cellular activities such as cell viability, cycle distribution and cell apoptosis, and studied interactions among RP11-468E2.5, STAT5/STAT6, and the JAK/STAT signaling pathway. Finally, an in vivo tumor formation assay was performed to observe the effect of RP11-468E2.5 on tumor growth. RESULTS The CRC-related gene microarray data showed low expression of RP11-468E2.5 in CRC surgical specimens. However, RP11-468E2.5 was confirmed to target STAT5 and STAT6, which participate in the JAK/STAT signaling pathway. CRC tissues showed lower expression of RP11-468E2.5, higher expression of STAT5, STAT6 and of the cell cycle marker Cyclin D1 (CCND1), compared to the findings in adjacent normal tissues. The treatment of siRNA against RP11-468E2.5 increased expression of JAK2, STAT3, STAT5, STAT6, CCND1 and Bcl-2 along with the extent of STAT3, STAT5 and STAT6 phosphorylation, while lowering expression of P21 and P27. Treatment with AG490 exhibited approximately opposite effects, whereas siRNA against RP11-468E2.5 treatment stimulated CRC cell proliferation and reduced cell apoptosis, while promoting cell cycle entry; AG490 treatment reversed these results. CONCLUSIONS Altogether, we conclude that up-regulation of RP11-468E2.5 inhibits the JAK/STAT signaling pathway by targeting STAT5 and STAT6, thereby suppressing cell proliferation and promoting cell apoptosis in CRC.
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Affiliation(s)
- Li Jiang
- Department of Hematology and Lymphatic Diseases, Harbin Medical University Tumour Hospital, Harbin, 150081, People's Republic of China
| | - Xu-Hai Zhao
- Department of Breast Surgery, Harbin Medical University Tumour Hospital, Harbin, 150081, People's Republic of China
| | - Yin-Ling Mao
- Department of Abdominal Radiotherapy, Harbin Medical University Tumour Hospital, No. 150, Haping Road, Nangang District, Harbin, 150081, People's Republic of China.
| | - Jun-Feng Wang
- Department of Thoracic Surgery, Harbin Medical University Tumour Hospital, Harbin, 150081, People's Republic of China
| | - Hui-Jun Zheng
- Department of General Surgery, Kangying Hospital of Mingshui County, Suihua, 151700, People's Republic of China
| | - Qing-Shan You
- Department of Abdominal Radiotherapy, Harbin Medical University Tumour Hospital, No. 150, Haping Road, Nangang District, Harbin, 150081, People's Republic of China
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Search for novel STAT3-dependent genes reveals SERPINA3 as a new STAT3 target that regulates invasion of human melanoma cells. J Transl Med 2019; 99:1607-1621. [PMID: 31278347 DOI: 10.1038/s41374-019-0288-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Revised: 04/19/2019] [Accepted: 06/05/2019] [Indexed: 02/04/2023] Open
Abstract
Transcription factor signal transducer and activator of transcription 3 (STAT3) is constitutively activated in many cancers and promotes uncontrolled tumor growth and progression through multiple mechanisms. Compelling evidence shows tissue and cell-specific sets of STAT3 targets. Transcriptional targets of STAT3 in melanoma cells are largely unknown. Malignant melanoma is a deadly disease with highly aggressive and drug-resistant behavior. Less than 10% of patients with advanced melanomas reach the 5-year survival, partly due to the aggressive character of the tumor and ineffectiveness of current therapeutics for treating metastatic melanoma. STAT3 is constitutively activated in melanoma cells and plays important roles in its growth and angiogenesis in tumor xenograft studies. Moreover, highly metastatic melanoma cells have higher levels of active STAT3 than poorly metastatic ones. To identify genes that are driven by STAT3 in human melanoma cells, we performed JAK/STAT signaling specific and global gene expression profiling of human melanoma cells with silenced STAT3 expression. For selected genes, we performed computational identification of putative STAT3-binding sites and validated direct interactions STAT3 with defined promoters by using chromatin immunoprecipitation followed by qPCR. We found that STAT3 knockdown does not affect human melanoma cell viability, proliferation, or response to chemotherapeutics. We show that STAT3 regulates a discrete set of genes in melanoma cells, including SERPINA3, a novel STAT3 target gene, which is functionally involved in regulation of melanoma migration and invasion. Knockdown of STAT3 impaired cell migration and invasion, in part via regulation of its transcriptional target SERPINA3. Our results present novel targets and functions of STAT3 in melanoma cells.
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Wan R, Luan Y, Wu Z, Deng S, Peng M, Xu L, Wu Y, Qin X, Fan G. The target therapeutic effect of functionalized graphene oxide nanoparticles graphene oxide–polyethylene glycol–folic acid-1–pyrenemethylamine hydrochloride-mediated RNA interference of HIF-1α gene in human pancreatic cancer cells. J Biomater Appl 2019; 34:155-177. [PMID: 31079557 DOI: 10.1177/0885328219847019] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Affiliation(s)
- Renming Wan
- Department of Clinical Laboratory, Changzhou Second People’s Hospital, Nanjing Medical University, Changzhou, China
| | - Yufen Luan
- Department of Nuclear Medicine, Changzhou Second People’s Hospital, Nanjing Medical University, Changzhou, China
| | - Zhouquan Wu
- Department of Anesthesia, Changzhou Second People’s Hospital Affiliated to Nanjing Medical University, Changzhou, China
| | - Shengming Deng
- Department of Nuclear Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Mingya Peng
- Department of Nuclear Medicine, Changzhou Second People’s Hospital, Nanjing Medical University, Changzhou, China
| | - Longbao Xu
- Department of Nuclear Medicine, Changzhou Second People’s Hospital, Nanjing Medical University, Changzhou, China
| | - Yiwei Wu
- Department of Nuclear Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xihu Qin
- Department of General Surgery, Changzhou Second People’s Hospital, Nanjing Medical University, Changzhou, China
| | - Guanglei Fan
- Department of Nuclear Medicine, Changzhou Second People’s Hospital, Nanjing Medical University, Changzhou, China
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Yang Y, Zheng B, Han Q, Zhang C, Tian Z, Zhang J. Targeting blockage of STAT3 inhibits hepatitis B virus-related hepatocellular carcinoma. Cancer Biol Ther 2017; 17:449-56. [PMID: 26934469 DOI: 10.1080/15384047.2016.1156257] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Hepatitis B virus (HBV) infection is a significant cause of liver disease pathogenesis, which results in the development of hepatic dysfunction, cirrhosis and hepatocellular carcinoma (HCC). Our previous studies showed that oncogene STAT3 might be an ideal target for HCC therapy. Here, we investigated whether targeting blockage of STAT3 signaling is efficient for HBV-related HCC. Based on the refractory of HCC and the persistence of HBV, in this study, we designed shRNAs targeting STAT3. The results showed that blocking STAT3 signaling by shRNAs could promote HBV positive HCC cell apoptosis and induce cell cycle arrest, resulting in HCC cell growth inhibition in vitro. Importantly, STAT3-shRNAs efficiently suppressed HBV replication, which would reduce HBV-derived stimulation to STAT3 signaling and augment STAT3-shRNAs-mediated anti-HCC effect. Finally, STAT3-shRNAs-mediated anti-HBV positive HCC effect was confirmed in xenograft nude mice. This study suggested that targeting STAT3 therapies such as STAT3-shRNAs may be an efficacious strategy for HBV-related HCC.
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Affiliation(s)
- Yinli Yang
- a Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University , China
| | - Bingqing Zheng
- a Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University , China
| | - Qiuju Han
- a Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University , China
| | - Cai Zhang
- a Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University , China
| | - Zhigang Tian
- a Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University , China.,b School of Life Sciences, University of Science and Technology of China , China
| | - Jian Zhang
- a Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University , China
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Roeser JC, Leach SD, McAllister F. Emerging strategies for cancer immunoprevention. Oncogene 2015; 34:6029-39. [PMID: 26364615 PMCID: PMC11073473 DOI: 10.1038/onc.2015.98] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2015] [Revised: 02/25/2015] [Accepted: 02/27/2015] [Indexed: 12/13/2022]
Abstract
The crucial role of the immune system in the formation and progression of tumors has been widely accepted. On one hand, the surveillance role of the immune system plays an important role in endogenous tumor prevention, but on the other hand, in some special circumstances such as in chronic inflammation, the immune system can actually contribute to the formation and progression of tumors. In recent years, there has been an explosion of novel targeted immunotherapies for advanced cancers. In the present manuscript, we explore known and potential various types of cancer prevention strategies and focus on nonvaccine-based cancer preventive strategies targeting the immune system at the early stages of tumorigenesis.
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Affiliation(s)
| | - Steven D. Leach
- The David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Florencia McAllister
- Department of Clinical Cancer Prevention. The University of Texas MD Anderson Cancer Center. Houston, TX
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Fan G, Bo J, Wan R, Peng M, Luan Y, Deng M, Xu L. The effect of lentiviral vector-mediated RNA interference targeting hypoxia-inducible factor 1α on the uptake of fluorodeoxyglucose ((18)f) in the human pancreatic cancer cell line, patu8988. Cancer Biother Radiopharm 2015; 30:160-8. [PMID: 25853522 DOI: 10.1089/cbr.2014.1700] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Hypoxia can stimulate (18)F-fluorodeoxyglucose ((18)F-FDG) uptake in cultured tumor cells. This study has investigated the effect of lentiviral vector-mediated RNA interference (RNAi) targeting hypoxia-inducible factor 1α (HIF-1α) on the changes in HIF-1 and glucose transporter 1 (Glut-1) expression, the cell growth, and the uptake of (18)F-FDG in the human pancreatic cancer cell line, Patu8988. Lentiviral RNAi vector targeting the HIF-1α gene (LV-HIF-1αRNAi) was constructed and used to treat cells at various concentrations (25-200 nM). The expression changes of HIF-1α and Glut-1 in hypoxic Patu8988 cells after RNAi treatment were determined using real time reverse transcription-polymerase chain reaction (real-time PCR). The inhibition rate of cell proliferation 48 hours after the addition of 10 μL of different concentrations of LV-HIF-1αRNAi (25-200 nM) was assayed using the MTT method. Meanwhile, the cell uptake of (18)F-FDG was also assessed. After RNAi transfection, the relative expression levels of HIF-1α mRNA and Glut-1 under hypoxia were reduced and the relative expression levels of HIF-1α protein also decreased. Compared with the control group, the inhibition rates of cell proliferation under different viral dosages were 5.98%, 15.65%, 26.42%, and 40.81%, respectively, positively correlated with the viral doses (r=0.558, p<0.05). Under hypoxia, Glut-1 mRNA expression in Patu8988 cells treated with 200 nM of LV-HIF-1αRNAi for 24, 48, and 72 hours, respectively, was positively correlated with the inhibition rate of cell proliferation (r=0.618, p<0.05) as well as the inhibition rate of (18)F-FDG uptake (r=0.664, p<0.05), while the latter two displayed a positive correlation with each other too (r=0.582, p<0.05). Under hypoxia, RNAi targeting HIF-1α significantly inhibited the expression of Glut-1 mRNA in Patu8988 pancreatic cancer cells and their uptake of (18)F-FDG. These results suggest that LV-HIF-1αRNAi may form a new treatment for pancreatic cancer, and the effectiveness of the treatment can be readily assessed with (18)F-FDG imaging.
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Affiliation(s)
- Guanglei Fan
- Department of Nuclear Medicine, Changzhou Second People's Hospital, Nanjing Medical University , Changzhou, P.R. China
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Xuan X, Li S, Lou X, Zheng X, Li Y, Wang F, Gao Y, Zhang H, He H, Zeng Q. Stat3 promotes invasion of esophageal squamous cell carcinoma through up-regulation of MMP2. Mol Biol Rep 2014; 42:907-15. [DOI: 10.1007/s11033-014-3828-8] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2013] [Accepted: 11/10/2014] [Indexed: 01/06/2023]
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Li H, Xiao W, Ma J, Zhang Y, Li R, Ye J, Wang X, Zhong X, Wang S. Dual high expression of STAT3 and cyclinD1 is associated with poor prognosis after curative resection of esophageal squamous cell carcinoma. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2014; 7:7989-7998. [PMID: 25550842 PMCID: PMC4270557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 09/11/2014] [Accepted: 10/31/2014] [Indexed: 06/04/2023]
Abstract
BACKGROUND Signal transducer of activator of transcription 3 (STAT3) and cyclinD1 are overexpressed in various human cancers, and their overexpression positively correlates to tumor progression and poor prognosis. However, the clinical significance of dual high expression of these two proteins in esophageal squamous cell carcinoma (ESCC) has yet to be determined. METHODS The expression of STAT3 and cyclinD1 was analyzed in tissue microarrays containing tumor and adjacent tissue samples from 82 patients who had undergone curative resection for histologically proven ESCC. Kaplan-Meier plots and Cox proportional hazards regression model were used to analyze the prognostic value of STAT3 and cyclinD1 expression. RESULTS We discovered that expressions of STAT3 and cyclinD1 in cancer tissues were significantly higher than that in adjacent tissues. High expression of STAT3 and cyclinD1 was associated with malignant behaviors. Moreover, the expression of STAT3 was positively associated with the expression of cyclinD1. High STAT3 or cyclinD1 expression alone was associated with lower overall survival (OS) rates. Furthermore, dual high expression of STAT3 and cyclinD1 expression predict even worse survival outcome in both univariate and multivariate analysis. CONCLUSION STAT3 and cyclinD1 correlate with more aggressive tumor behavior in ESCC. When STAT3 and cyclinD1 are considered together, they serve as effective prognostic markers in patients with surgically resected ESCC.
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Affiliation(s)
- Haiying Li
- Department of Pathology, School of Medicine, Jinan UniversityGuangzhou 510632, Guangdong Province, China
- Guangdong Province Key Laboratory of Molecular Immunology and Antibody Engineering, School of Medicine, Jinan UniversityGuangzhou 510632, Guangdong Province, China
| | - Weiwei Xiao
- Department of Radiation Oncology, Sun Yat-Sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer MedicineGuangzhou, Guangdong, China
| | - Jiwei Ma
- Department of Pathology, School of Medicine, Jinan UniversityGuangzhou 510632, Guangdong Province, China
- Guangdong Province Key Laboratory of Molecular Immunology and Antibody Engineering, School of Medicine, Jinan UniversityGuangzhou 510632, Guangdong Province, China
| | - Yong Zhang
- Department of Pathology, School of Medicine, Jinan UniversityGuangzhou 510632, Guangdong Province, China
- Guangdong Province Key Laboratory of Molecular Immunology and Antibody Engineering, School of Medicine, Jinan UniversityGuangzhou 510632, Guangdong Province, China
| | - Ru Li
- Department of Pathology, School of Medicine, Jinan UniversityGuangzhou 510632, Guangdong Province, China
- Guangdong Province Key Laboratory of Molecular Immunology and Antibody Engineering, School of Medicine, Jinan UniversityGuangzhou 510632, Guangdong Province, China
| | - Jiecheng Ye
- Department of Pathology, School of Medicine, Jinan UniversityGuangzhou 510632, Guangdong Province, China
- Guangdong Province Key Laboratory of Molecular Immunology and Antibody Engineering, School of Medicine, Jinan UniversityGuangzhou 510632, Guangdong Province, China
| | - Xiao Wang
- Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan UniversityGuangzhou 510632, Guangdong Province, China
| | - Xueyun Zhong
- Department of Pathology, School of Medicine, Jinan UniversityGuangzhou 510632, Guangdong Province, China
- Guangdong Province Key Laboratory of Molecular Immunology and Antibody Engineering, School of Medicine, Jinan UniversityGuangzhou 510632, Guangdong Province, China
| | - Shaoxiang Wang
- Institute of Molecular Medicine, Shenzhen UniversityShenzhen 518060, China
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Abstract
Silencing of abnormally activated genes can be accomplished in a highly specific manner using nucleic acid based approaches. The focus of this review includes the different nucleic acid based inhibition strategies such as antisense oligodeoxynucleotides, small interfering RNA (siRNA), dominant-negative constructs, G-quartet oligonucleotides and decoy oligonucleotides, their mechanism of action and the effectiveness of these approaches to targeting the STAT (signal transducer and activator of transcription) proteins in cancer. Among the STAT proteins, especially STAT3, followed by STAT5, are the most frequently activated oncogenic STATs, which have emerged as plausible therapeutic cancer targets. Both STAT3 and STAT5 have been shown to regulate numerous oncogenic signaling pathways including proliferation, survival, angiogenesis and migration/invasion.
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Affiliation(s)
- Malabika Sen
- Department of Otolaryngology; University of Pittsburgh School of Medicine; Pittsburgh, PA USA
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Huang C, Du J, Xie K. FOXM1 and its oncogenic signaling in pancreatic cancer pathogenesis. Biochim Biophys Acta Rev Cancer 2014; 1845:104-16. [PMID: 24418574 DOI: 10.1016/j.bbcan.2014.01.002] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2013] [Revised: 12/30/2013] [Accepted: 01/03/2014] [Indexed: 02/08/2023]
Abstract
Pancreatic cancer is a devastating disease with an overall 5-year survival rate less than 5%. Multiple signaling pathways are implicated in the pathogenesis of pancreatic cancer, such as Wnt/β-catenin, Notch, Hedgehog, hypoxia-inducible factor, signal transducer and activator of transcription, specificity proteins/Krüppel-like factors, and Forkhead box (FOX). Recently, increasing evidence has demonstrated that the transcription factor FOXM1 plays important roles in the initiation, progression, and metastasis of a variety of human tumors, including pancreatic cancer. In this review, we focus on the current understanding of the molecular pathogenesis of pancreatic cancer with a special focus on the function and regulation of FOXM1 and rationale for FOXM1 as a novel molecular target for pancreatic cancer prevention and treatment.
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Affiliation(s)
- Chen Huang
- Department of General Surgery, Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai, People's Republic of China; Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
| | - Jiawei Du
- Department of Laboratory Medicine, Zhenjiang Second People's Hospital, Jiangsu University College of Medicine, Zhenjiang, People's Republic of China
| | - Keping Xie
- Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
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Ramji K, Kulesza DW, Chouaib S, Kaminska B. Off-target effects of plasmid-transcribed shRNAs on NFκB signaling pathway and cell survival of human melanoma cells. Mol Biol Rep 2013; 40:6977-86. [PMID: 24170218 PMCID: PMC3835955 DOI: 10.1007/s11033-013-2817-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2012] [Accepted: 10/16/2013] [Indexed: 11/29/2022]
Abstract
Signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) are transcription factors involved in cell survival, inflammation and metastasis. Constitutively activated STAT3 is found in many cancers, including melanoma. To study the crosstalk between STAT3 and NFκB signaling and its role in regulation of cancer cell survival, we used RNA interference (RNAi) to down-regulate STAT3 expression in human melanoma cells. RNAi strategies including double-stranded RNA, small interfering RNA (siRNA), short hairpin RNA (shRNA) and microRNA are widely used to knock down disease-causing genes in a targeted fashion. We found that shRNAs up-regulate non-specific NFκB activity, while siRNA directed against STAT3 specifically increase NFκB activity. The basal survival of melanoma cells is unaffected by STAT3 knockdown—likely due to activation of pro-survival NFκB signaling. Whereas, owing to off-target effects, plasmid-transcribed shRNA affects melanoma survival. Our data show that shRNA-mediated gene silencing induces non-specific or off-target effects that may influence cell functions.
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Affiliation(s)
- Kavita Ramji
- Laboratory of Transcription Regulation, Department of Cell Biology, The Nencki Institute of Experimental Biology, 3 Pasteur Str., 02-093, Warsaw, Poland
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15
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Koperek O, Aumayr K, Schindl M, Werba G, Soleiman A, Schoppmann S, Sahora K, Birner P. Phosphorylation of STAT3 correlates with HER2 status, but not with survival in pancreatic ductal adenocarcinoma. APMIS 2013; 122:476-81. [PMID: 24164699 DOI: 10.1111/apm.12194] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2013] [Accepted: 07/30/2013] [Indexed: 12/16/2022]
Abstract
Activation of signal-transcriptional factor signal transducer and activator of transcription 3 (STAT3) is associated with more aggressive behaviour in a variety of human malignancies. As selective STAT3 inhibitors exist, this protein might represent a novel therapeutic target. Although STAT3 seems to play an important role in progression of pancreatic ductal carcinoma (PDAC), only few data on this subject exist. The aim of our study was the investigation of STAT3 activation and its correlation with its possible regulator HER2. Expression of tyrosine-705 phosphorylated STAT3 (pSTAT3) was determined immunohistochemically in 79 PDACs. HER2 status assessed by immunohistochemistry and double colour silver in situ hybridization was available from a previous study. PSTAT3 expression was seen in 33 (41.8%) patients. Six patients were scored as HER2 positive having strong correlation with pSTAT3 expression (p = 0.004, Fisher's exact test). No association of pSTAT3 expression with patients' age, tumour staging and grading, perineural invasion of tumour cells or survival time was seen. pSTAT3 is frequently expressed in PDAC. Nevertheless, its immediate clinical relevance seems to be low. However, further research needs to determine whether STAT3 status in PDAC is predictive for the response to novel targeting therapies.
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Affiliation(s)
- Oskar Koperek
- Department of Pathology, Medical University of Vienna, Vienna
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16
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Zhu L, Cheng X, Ding Y, Shi J, Jin H, Wang H, Wu Y, Ye J, Lu Y, Wang TC, Yang CS, Tu SP. Bone marrow-derived myofibroblasts promote colon tumorigenesis through the IL-6/JAK2/STAT3 pathway. Cancer Lett 2013; 343:80-9. [PMID: 24145153 DOI: 10.1016/j.canlet.2013.09.017] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2013] [Revised: 09/09/2013] [Accepted: 09/14/2013] [Indexed: 12/14/2022]
Abstract
Bone marrow-derived myofibroblasts (BMFs) have been shown to promote tumor growth. Here, we found that BMFs or BMF conditioned medium (BMF-CM) induced cancer stem cell-like sphere formation of colon cancer cells. The co-cultured BMFs, but not co-cultured cancer cells, expressed higher levels of IL-6 than BMFs or cancer cells cultured alone. Anti-mouse IL-6 neutralizing antibody, JAK2 inhibitors and STAT3 knockdown in mouse cancer cells reduced BMF- and BMF-CM-induced sphere formation of colon cancer cells. When co-injected, BMFs significantly enhanced tumorigenesis of colon cancer cells in mice. Our results demonstrate that BMFs promote tumorigenesis via the activation of the IL-6/JAK2/STAT3 pathway.
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Affiliation(s)
- Liming Zhu
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China; Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
| | - Xiaojiao Cheng
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
| | - Yanfei Ding
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
| | - Jindong Shi
- Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
| | - Huanyu Jin
- Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
| | - Hong Wang
- Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
| | - Yunlin Wu
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
| | - Jing Ye
- Emergency Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
| | - Yiming Lu
- Emergency Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
| | - Timothy C Wang
- Department of Medicine, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA
| | - Chung S Yang
- Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
| | - Shui Ping Tu
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China; Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
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17
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Kulesza DW, Carré T, Chouaib S, Kaminska B. Silencing of the transcription factor STAT3 sensitizes lung cancer cells to DNA damaging drugs, but not to TNFα- and NK cytotoxicity. Exp Cell Res 2012; 319:506-16. [PMID: 23149124 DOI: 10.1016/j.yexcr.2012.11.005] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2012] [Revised: 10/19/2012] [Accepted: 11/05/2012] [Indexed: 11/29/2022]
Abstract
Transcription factor STAT3 (Signal Transducers and Activators of Transcription 3) is persistently active in human tumors and may contribute to tumor progression. Inhibition of STAT3 expression/activity could be a good strategy to modulate tumor cell survival and responses to cancer chemotherapeutics or immune cytotoxicity. We silenced STAT3 expression in human A549 lung cancer cells to elucidate its role in cell survival and resistance to chemotherapeutics, TNFα and natural killer (NK)-mediated cytotoxicity. We demonstrate that STAT3 is not essential for basal survival and proliferation of A549 cancer cells. Stable silencing of STAT3 expression sensitized A549 cells to DNA damaging chemotherapeutics doxorubicin and cisplatin in a p53-independent manner. Sensitization to DNA damage-inducing chemotherapeutics could be due to down-regulation of the Bcl-xL expression in STAT3 depleted cells. In contrast, knockdown of STAT3 in cancer cells did not modulate responses to TNFα and NK-mediated cytotoxicity. We found that STAT3 depletion increased the NFκB activity likely providing the compensatory, pro-survival signal. The treatment with TNFα, but not doxorubicin, enhanced this effect. We conclude that STAT3 is not crucial for the control of basal cell proliferation and survival of lung carcinoma cells but modulates susceptibility to DNA damaging chemotherapeutics by regulation of intrinsic pro-survival pathways.
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Affiliation(s)
- Dorota W Kulesza
- Laboratory of Transcription Regulation, Department of Cell Biology, The Nencki Institute of Experimental Biology, Warsaw, Poland
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18
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Sen M, Thomas SM, Kim S, Yeh JI, Ferris RL, Johnson JT, Duvvuri U, Lee J, Sahu N, Joyce S, Freilino ML, Shi H, Li C, Ly D, Rapireddy S, Etter JP, Li PK, Wang L, Chiosea S, Seethala RR, Gooding WE, Chen X, Kaminski N, Pandit K, Johnson DE, Grandis JR. First-in-human trial of a STAT3 decoy oligonucleotide in head and neck tumors: implications for cancer therapy. Cancer Discov 2012; 2:694-705. [PMID: 22719020 DOI: 10.1158/2159-8290.cd-12-0191] [Citation(s) in RCA: 268] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
UNLABELLED Despite evidence implicating transcription factors, including STAT3, in oncogenesis, these proteins have been regarded as "undruggable." We developed a decoy targeting STAT3 and conducted a phase 0 trial. Expression levels of STAT3 target genes were decreased in head and neck cancers following injection with the STAT3 decoy compared with tumors receiving saline control. Decoys have not been amenable to systemic administration due to instability. To overcome this barrier, we linked the oligonucleotide strands using hexaethylene glycol spacers. This cyclic STAT3 decoy bound with high affinity to STAT3 protein, reduced cellular viability, and suppressed STAT3 target gene expression in cancer cells. Intravenous injection of the cyclic STAT3 decoy inhibited xenograft growth and downregulated STAT3 target genes in the tumors. These results provide the first demonstration of a successful strategy to inhibit tumor STAT3 signaling via systemic administration of a selective STAT3 inhibitor, thereby paving the way for broad clinical development. SIGNIFICANCE This is the fi rst study of a STAT3-selective inhibitor in humans and the fi rst evidence that a transcription factor decoy can be modifi ed to enable systemic delivery. These findings have therapeutic implications beyond STAT3 to other “undruggable” targets in human cancers.
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Affiliation(s)
- Malabika Sen
- Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
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Crosstalk of Sp1 and Stat3 signaling in pancreatic cancer pathogenesis. Cytokine Growth Factor Rev 2012; 23:25-35. [PMID: 22342309 DOI: 10.1016/j.cytogfr.2012.01.003] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2012] [Accepted: 01/23/2012] [Indexed: 12/17/2022]
Abstract
Pancreatic cancer progression is attributed to genetic and epigenetic alterations and a chaotic tumor microenvironment. Those diverse "upstream signal" factors appear to converge on specific sets of central nuclear regulators, namely, transcription factors. Specificity Protein 1 (Sp1) and signal transducer and activator of transcription 3 (Stat3) are central transcription factors that regulate a number of pathways important to tumorigenesis, including tumor cell-cycle progression, apoptosis, angiogenesis, metastasis, and evasion of the immune system. Recently, researchers demonstrated many types of crosstalk of Sp1 and Stat3 in tumor signal transduction and that these factors function cooperatively to activate targeted genes and promote tumorigenesis in pancreatic cancer. Therefore, targeting both Sp1 and Stat3 is a potential preventive and therapeutic strategy for pancreatic cancer.
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