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Repurposing Niclosamide for Targeting Pancreatic Cancer by Inhibiting Hh/Gli Non-Canonical Axis of Gsk3β. Cancers (Basel) 2021; 13:cancers13133105. [PMID: 34206370 PMCID: PMC8269055 DOI: 10.3390/cancers13133105] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Revised: 06/15/2021] [Accepted: 06/17/2021] [Indexed: 12/14/2022] Open
Abstract
Simple Summary The current obstacles for discovering new drugs for cancer therapy have necessitated the development of the alternative strategy of drug repurposing, the identification of new uses for approved or investigational drugs for new therapeutic purposes. Niclosamide (Nic) is a Food and Drug Administration (FDA)-approved anti-helminthic drug, reported to have anti-cancer effects, and is being assessed in various clinical trials. In the current study, we assessed the therapeutic efficacy of Nic on pancreatic cancer (PC) in vitro. Our results revealed mitochondrial stress and mTORC1-dependent autophagy as the predominant players of Nic-induced PC cell death. This study provided a novel mechanistic insight for anti-cancer efficacy of Nic by increasing p-Gsk3β that modulates molecular signaling(s), including inhibition of hedgehog (Hh) signaling-mediated cellular proliferation and increased apoptosis through mTORC1-dependent autophagy may prove helpful for the development of novel PC therapies. Abstract Niclosamide (Nic), an FDA-approved anthelmintic drug, is reported to have anti-cancer efficacy and is being assessed in clinical trials for various solid tumors. Based on its ability to target multiple signaling pathways, in the present study, we evaluated the therapeutic efficacy of Nic on pancreatic cancer (PC) in vitro. We observed an anti-cancerous effect of this drug as shown by the G0/G1 phase cell cycle arrest, inhibition of PC cell viability, colony formation, and migration. Our results revealed the involvement of mitochondrial stress and mTORC1-dependent autophagy as the predominant players of Nic-induced PC cell death. Significant reduction of Nic-induced reactive oxygen species (ROS) and cell death in the presence of a selective autophagy inhibitor spautin-1 demonstrated autophagy as a major contributor to Nic-mediated cell death. Mechanistically, Nic inhibited the interaction between BCL2 and Beclin-1 that supported the crosstalk of autophagy and apoptosis. Further, Nic treatment resulted in Gsk3β inactivation by phosphorylating its Ser-9 residue leading to upregulation of Sufu and Gli3, thereby negatively impacting hedgehog signaling and cell survival. Nic induced autophagic cell death, and p-Gsk3b mediated Sufu/Gli3 cascade was further confirmed by Gsk3β activator, LY-294002, by rescuing inactivation of Hh signaling upon Nic treatment. These results suggested the involvement of a non-canonical mechanism of Hh signaling, where p-Gsk3β acts as a negative regulator of Hh/Gli1 cascade and a positive regulator of autophagy-mediated cell death. Overall, this study established the therapeutic efficacy of Nic for PC by targeting p-Gsk3β mediated non-canonical Hh signaling and promoting mTORC1-dependent autophagy and cell death.
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Wang Y, Wang D, Dai Y, Kong X, Zhu X, Fan Y, Wang Y, Wu H, Jin J, Yao W, Gao J, Wang K, Xu H. Positive Crosstalk Between Hedgehog and NF-κB Pathways Is Dependent on KRAS Mutation in Pancreatic Ductal Adenocarcinoma. Front Oncol 2021; 11:652283. [PMID: 34046348 PMCID: PMC8144522 DOI: 10.3389/fonc.2021.652283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 04/23/2021] [Indexed: 11/13/2022] Open
Abstract
It has been shown that aberrant activation of the Hedgehog (Hh) and nuclear factor-kappa B (NF-κB) signaling pathways plays an important role in the pancreatic carcinogenesis, and KRAS mutation is a hallmark of pancreatic ductal adenocarcinoma (PDAC). Until now, the role of KRAS mutation in the context of crosstalk between Hh and NF-κB signaling pathways in PDAC has not been investigated. This study was to determine whether the crosstalk between the Hh and NF-κB pathways is dependent on KRAS mutation in PDAC. The correlation between Gli1, Shh, NF-κB p65 expression and KRAS mutation in PDAC tissues was firstly examined by immunohistochemistry. Next, Western blotting, qPCR, and immunofluorescence were conducted to examine the biological effects of interleukin-1β (IL-1β) and tumor necrosis factor-alpha (TNF-α) as NF-κB signaling agonists, Shh as an Hh ligand alone or in combination with KRAS small interfering RNA (si-KRAS) in KRAS-mutant PDAC cells (MT-KRAS; SW1990 and Panc-1), wild-type KRAS PDAC cells (WT-KRAS; BxPC-3) and mutant KRAS knock-in BxPC-3 cells in vitro as well as tumor growth in vivo. KRAS mutation-dependent crosstalk between Hh and NF-κB in PDAC cells was further assessed by Ras activity and luciferase reporter assays. The aberrant Hh and NF-κB pathway activation was found in PDAC tissues with KRAS mutation. The same findings were confirmed in MT-KRAS PDAC cells and MT-KRAS knock-in BxPC-3 cells, whereas this activation was not observed in WT-KRAS PDAC cells. However, the activation was significantly down-regulated by KRAS silencing in MT-KRAS PDAC cells. Furthermore, MT-KRAS cancer cell proliferation and survival in vitro and tumor growth after inoculation with MT-KRAS cells in vivo were promoted by NF-κB and Hh signaling activation. The pivotal factor for co-activation of NF-κB and Hh signaling is MT-KRAS protein upregulation, showing that positive crosstalk between Hh and NF-κB pathways is dependent upon KRAS mutation in PDAC.
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Affiliation(s)
- Yuqiong Wang
- Department of Gastroenterology, the Hospital of 92608 People's Liberation Army of China (PLA) Troops, Shanghai, China
| | - Dan Wang
- Institute of Oncology, Second Affiliated Hospital, Xi'an Medical University, Xi'an, China
| | - Yanmiao Dai
- Department of Gastroenterology, Kunshan Affiliated Hospital of Nanjing University of Chinese Medicine, Suzhou, China
| | - Xiangyu Kong
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Xian Zhu
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Yunxia Fan
- Institute of Oncology, Second Affiliated Hospital, Xi'an Medical University, Xi'an, China
| | - Yaodong Wang
- Department of Gastroenterology, Kunshan Affiliated Hospital of Nanjing University of Chinese Medicine, Suzhou, China
| | - Hongyu Wu
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Jing Jin
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Wenzhu Yao
- Bureau of headmaster, Xi'an Medical University, Xi'an, China
| | - Jun Gao
- Institute of Oncology, Second Affiliated Hospital, Xi'an Medical University, Xi'an, China
| | - Kaixuan Wang
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Hongwei Xu
- Department of Gastroenterology, Kunshan Affiliated Hospital of Nanjing University of Chinese Medicine, Suzhou, China
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Weighill D, Ben Guebila M, Glass K, Platig J, Yeh JJ, Quackenbush J. Gene Targeting in Disease Networks. Front Genet 2021; 12:649942. [PMID: 33968133 PMCID: PMC8103030 DOI: 10.3389/fgene.2021.649942] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 03/15/2021] [Indexed: 01/12/2023] Open
Abstract
Profiling of whole transcriptomes has become a cornerstone of molecular biology and an invaluable tool for the characterization of clinical phenotypes and the identification of disease subtypes. Analyses of these data are becoming ever more sophisticated as we move beyond simple comparisons to consider networks of higher-order interactions and associations. Gene regulatory networks (GRNs) model the regulatory relationships of transcription factors and genes and have allowed the identification of differentially regulated processes in disease systems. In this perspective, we discuss gene targeting scores, which measure changes in inferred regulatory network interactions, and their use in identifying disease-relevant processes. In addition, we present an example analysis for pancreatic ductal adenocarcinoma (PDAC), demonstrating the power of gene targeting scores to identify differential processes between complex phenotypes, processes that would have been missed by only performing differential expression analysis. This example demonstrates that gene targeting scores are an invaluable addition to gene expression analysis in the characterization of diseases and other complex phenotypes.
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Affiliation(s)
- Deborah Weighill
- Department of Biostatistics, Harvard T. H. Chan School of Public Health, Harvard University, Boston, MA, United States
| | - Marouen Ben Guebila
- Department of Biostatistics, Harvard T. H. Chan School of Public Health, Harvard University, Boston, MA, United States
| | - Kimberly Glass
- Department of Biostatistics, Harvard T. H. Chan School of Public Health, Harvard University, Boston, MA, United States
- Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, MA, United States
- Harvard Medical School, Harvard University, Boston, MA, United States
| | - John Platig
- Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, MA, United States
- Harvard Medical School, Harvard University, Boston, MA, United States
| | - Jen Jen Yeh
- Departments of Surgery and Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - John Quackenbush
- Department of Biostatistics, Harvard T. H. Chan School of Public Health, Harvard University, Boston, MA, United States
- Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, MA, United States
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Super-enhancers: novel target for pancreatic ductal adenocarcinoma. Oncotarget 2019; 10:1554-1571. [PMID: 30899425 PMCID: PMC6422180 DOI: 10.18632/oncotarget.26704] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Accepted: 02/01/2019] [Indexed: 01/02/2023] Open
Abstract
Super-enhancers (SEs) are unique areas of the genome which drive high-level of transcription and play a pivotal role in the cell physiology. Previous studies have established several important genes in cancer as SE-driven oncogenes. It is likely that oncogenes may hack the resident tissue regenerative program and interfere with SE-driven repair networks, leading to the specific pancreatic ductal adenocarcinoma (PDAC) phenotype. Here, we used ChIP-Seq to identify the presence of SE in PDAC cell lines. Differential H3K27AC marks were identified at enhancer regions of genes including c-MYC, MED1, OCT-4, NANOG, and SOX2 that can act as SE in non-cancerous, cancerous and metastatic PDAC cell lines. GZ17-6.02 affects acetylation of the genes, reduces transcription of major transcription factors, sonic hedgehog pathway proteins, and stem cell markers. In accordance with the decrease in Oct-4 expression, ChIP-Seq revealed a significant decrease in the occupancy of OCT-4 in the entire genome after GZ17-6.02 treatment suggesting the possible inhibitory effect of GZ17-6.02 on PDAC. Hence, SE genes are associated with PDAC and targeting their regulation with GZ17-6.02 offers a novel approach for treatment.
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Subramaniam D, Kaushik G, Dandawate P, Anant S. Targeting Cancer Stem Cells for Chemoprevention of Pancreatic Cancer. Curr Med Chem 2018; 25:2585-2594. [PMID: 28137215 DOI: 10.2174/0929867324666170127095832] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2016] [Revised: 12/17/2016] [Accepted: 12/17/2016] [Indexed: 02/06/2023]
Abstract
Pancreatic ductal adenocarcinoma is one of the deadliest cancers worldwide and the fourth leading cause of cancer-related deaths in United States. Regardless of the advances in molecular pathogenesis and consequential efforts to suppress the disease, this cancer remains a major health problem in United States. By 2030, the projection is that pancreatic cancer will be climb up to be the second leading cause of cancer-related deaths in the United States. Pancreatic cancer is a rapidly invasive and highly metastatic cancer, and does not respond to standard therapies. Emerging evidence supports that the presence of a unique population of cells called cancer stem cells (CSCs) as potential cancer inducing cells and efforts are underway to develop therapeutic strategies targeting these cells. CSCs are rare quiescent cells, and with the capacity to self-renew through asymmetric/symmetric cell division, as well as differentiate into various lineages of cells in the cancer. Studies have been shown that CSCs are highly resistant to standard therapy and also responsible for drug resistance, cancer recurrence and metastasis. To overcome this problem, we need novel preventive agents that target these CSCs. Natural compounds or phytochemicals have ability to target these CSCs and their signaling pathways. Therefore, in the present review article, we summarize our current understanding of pancreatic CSCs and their signaling pathways, and the phytochemicals that target these cells including curcumin, resveratrol, tea polyphenol EGCG (epigallocatechin- 3-gallate), crocetinic acid, sulforaphane, genistein, indole-3-carbinol, vitamin E δ- tocotrienol, Plumbagin, quercetin, triptolide, Licofelene and Quinomycin. These natural compounds or phytochemicals, which inhibit cancer stem cells may prove to be promising agents for the prevention and treatment of pancreatic cancers.
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Affiliation(s)
- Dharmalingam Subramaniam
- Department of Surgery, the University of Kansas Medical Center, Kansas City, KS 66160, United States.,The University of Kansas Cancer Center, The University of Kansas Medical Center, Kansas City, KS 66160, United States
| | - Gaurav Kaushik
- Department of Surgery, the University of Kansas Medical Center, Kansas City, KS 66160, United States
| | - Prasad Dandawate
- Department of Surgery, the University of Kansas Medical Center, Kansas City, KS 66160, United States
| | - Shrikant Anant
- Department of Surgery, the University of Kansas Medical Center, Kansas City, KS 66160, United States.,The University of Kansas Cancer Center, The University of Kansas Medical Center, Kansas City, KS 66160, United States
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Klieser E, Swierczynski S, Mayr C, Jäger T, Schmidt J, Neureiter D, Kiesslich T, Illig R. Differential role of Hedgehog signaling in human pancreatic (patho-) physiology: An up to date review. World J Gastrointest Pathophysiol 2016; 7:199-210. [PMID: 27190692 PMCID: PMC4867399 DOI: 10.4291/wjgp.v7.i2.199] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2015] [Revised: 10/21/2015] [Accepted: 03/09/2016] [Indexed: 02/06/2023] Open
Abstract
Since the discovery of the Hedgehog (Hh) pathway in drosophila melanogaster, our knowledge of the role of Hh in embryonic development, inflammation, and cancerogenesis in humans has dramatically increased over the last decades. This is the case especially concerning the pancreas, however, real therapeutic breakthroughs are missing until now. In general, Hh signaling is essential for pancreatic organogenesis, development, and tissue maturation. In the case of acute pancreatitis, Hh has a protective role, whereas in chronic pancreatitis, Hh interacts with pancreatic stellate cells, leading to destructive parenchym fibrosis and atrophy, as well as to irregular tissue remodeling with potency of initiating cancerogenesis. In vitro and in situ analysis of Hh in pancreatic cancer revealed that the Hh pathway participates in the development of pancreatic precursor lesions and ductal adenocarcinoma including critical interactions with the tumor microenvironment. The application of specific inhibitors of components of the Hh pathway is currently subject of ongoing clinical trials (phases 1 and 2). Furthermore, a combination of Hh pathway inhibitors and established chemotherapeutic drugs could also represent a promising therapeutic approach. In this review, we give a structured survey of the role of the Hh pathway in pancreatic development, pancreatitis, pancreatic carcinogenesis and pancreatic cancer as well as an overview of current clinical trials concerning Hh pathway inhibitors and pancreas cancer.
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Ertao Z, Jianhui C, Chuangqi C, Changjiang Q, Sile C, Yulong H, Hui W, Shirong C. Autocrine Sonic hedgehog signaling promotes gastric cancer proliferation through induction of phospholipase Cγ1 and the ERK1/2 pathway. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2016; 35:63. [PMID: 27039174 PMCID: PMC4818860 DOI: 10.1186/s13046-016-0336-9] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/22/2015] [Accepted: 03/28/2016] [Indexed: 12/21/2022]
Abstract
Background Sonic hedgehog (SHH) plays critical roles in cell growth and development. Tumor cells express SHH, which can promote cell proliferation and epithelial-to-mesenchymal transition. However, the autocrine SHH pathway has not been described in gastric cancer. The aim of this study was to explore molecular mechanisms underlying autocrine SHH signaling in gastric cancer cells. Methods SHH expression was assessed using immunohistochemistry and the results were compared with clinicopathologic parameters, including survival. Using gastric cancer cell lines, we measured SHH mRNA and protein expression, and studied the effects of SHH signaling on cell proliferation and SHH secretion. We also studied the effects of an inhibitor of PLC-γ1 on phosphorylation of phospholipase Cγ1 and extracellular signal-regulated kinases (ERK)1/2. Results SHH protein expression in gastric cancer tissue was significantly higher compared with that in normal gastric tissue (P < 0.001), and the increased expression was significantly associated with pT staging (P = 0.004), pN staging (P = 0.018), pM staging (P = 0.006), and pTNM staging (P < 0.001). In multivariate analyses, overall survival in gastric cancer was significantly shorter in cases with high SHH expression (HR = 1.734, 95 % CI: 1.109–2.713, P = 0.016). The AGS and SGC-7901 gastric cancer cell lines expressed SHH mRNA and protein. In these cell lines, SHH promoted carcinogenesis through activation of the PLCγ1-ERK1/2 pathway, resulting in increased cell proliferation and survival. Conclusions Increased SHH expression is associated with shorter survival in gastric cancer patients, and SHH could represent a useful biomarker or therapeutic target for this disease.
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Affiliation(s)
- Zhai Ertao
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan 2nd Road, Guangzhou, Guangdong, 510080, China
| | - Chen Jianhui
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan 2nd Road, Guangzhou, Guangdong, 510080, China
| | - Chen Chuangqi
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan 2nd Road, Guangzhou, Guangdong, 510080, China
| | - Qin Changjiang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan 2nd Road, Guangzhou, Guangdong, 510080, China
| | - Chen Sile
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan 2nd Road, Guangzhou, Guangdong, 510080, China
| | - He Yulong
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan 2nd Road, Guangzhou, Guangdong, 510080, China
| | - Wu Hui
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan 2nd Road, Guangzhou, Guangdong, 510080, China
| | - Cai Shirong
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan 2nd Road, Guangzhou, Guangdong, 510080, China.
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Wu X, Wu G, Wu Z, Yao X, Li G. MiR-200a Suppresses the Proliferation and Metastasis in Pancreatic Ductal Adenocarcinoma through Downregulation of DEK Gene. Transl Oncol 2016; 9:25-31. [PMID: 26947878 PMCID: PMC4800058 DOI: 10.1016/j.tranon.2015.11.005] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2015] [Revised: 11/10/2015] [Accepted: 11/10/2015] [Indexed: 12/24/2022] Open
Abstract
MiR-200a has been reported to be able to suppress the epithelial-mesenchymal transition process in pancreatic cancer stem cells, suggesting that miR-200a could suppress the metastasis of pancreatic ductal adenocarcinoma (PDAC). However, its role in proliferation and metastasis of PDAC and the underlying mechanism by which miR-200a works in PDAC have not been elucidated. In our study, we for the first time identified that DEK gene is a direct downstream target of miR-200a. It was found that overexpression of miR-200a decreased DEK expression, suppressing the proliferation, migration, and invasion of PDAC cells. Meanwhile, knockdown of miR-200a can increase DEK level, promoting the proliferation, migration, and invasion of PDAC cells. Our study demonstrated that miR-200a suppresses the metastasis in pancreatic PDAC through downregulation of DEK, suggesting that miR-200a may be used as a novel potential marker in prediction of metastasis of PDAC.
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Affiliation(s)
- Xiaoyu Wu
- Department of Surgical Oncology, Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, No. 155 Hanzhong Road, Nanjing 210029, PR China
| | - Guannan Wu
- Department of Surgical Oncology, Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, No. 155 Hanzhong Road, Nanjing 210029, PR China
| | - Zhenfeng Wu
- Department of Surgical Oncology, Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, No. 155 Hanzhong Road, Nanjing 210029, PR China
| | - Xuequan Yao
- Department of Surgical Oncology, Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, No. 155 Hanzhong Road, Nanjing 210029, PR China
| | - Gang Li
- Department of General Surgery, Jiangsu Cancer Hospital, Affiliated Cancer Hospital of Nanjing Medical University, No. 42 Baiziting Road, Nanjing 210009, PR China
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Tang C, Tang L, Wu X, Xiong W, Ruan H, Hussain M, Wu J, Zou C, Wu X. Glioma-associated Oncogene 2 Is Essential for Trophoblastic Fusion by Forming a Transcriptional Complex with Glial Cell Missing-a. J Biol Chem 2016; 291:5611-5622. [PMID: 26769961 DOI: 10.1074/jbc.m115.700336] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2015] [Indexed: 01/20/2023] Open
Abstract
Cell-cell fusion of human villous trophoblasts, referred to as a process of syncytialization, acts as a prerequisite for the proper development and functional maintenance of the human placenta. Given the fact that the main components of the Hedgehog signaling pathway are expressed predominantly in the syncytial layer of human placental villi, in this study, we investigated the potential roles and underlying mechanisms of Hedgehog signaling in trophoblastic fusion. Activation of Hedgehog signaling by a variety of approaches robustly induced cell fusion and the expression of syncytial markers, whereas suppression of Hedgehog signaling significantly attenuated cell fusion and the expression of syncytial markers in both human primary cytotrophoblasts and trophoblast-like BeWo cells. Moreover, among glioma-associated oncogene (GLI) family transcriptional factors in Hedgehog signaling, knockdown of GLI2 but not GLI1 and GLI3 significantly attenuated Hedgehog-induced cell fusion, whereas overexpression of the GLI2 activator alone was sufficient to induce cell fusion. Finally, GLI2 not only stabilized glial cell missing-a, a pivotal transcriptional factor for trophoblastic syncytialization, but also formed a transcriptional heterodimer with glial cell missing-a to transactivate syncytin-1, a trophoblastic fusogen, and promote trophoblastic syncytialization. Taken together, this study uncovered a so far uncharacterized role of Hedgehog/GLI2 signaling in trophoblastic fusion, implicating that Hedgehog signaling, through GLI2, could be required for human placental development and pregnancy maintenance.
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Affiliation(s)
- Chao Tang
- From the Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, China,; the Department of Microbiology, School of Medicine, University of Tokyo, Tokyo 1130033, Japan, and
| | | | - Xiaokai Wu
- From the Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, China
| | | | - Hongfeng Ruan
- From the Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, China
| | - Musaddique Hussain
- From the Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, China
| | - Junsong Wu
- First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China
| | | | - Ximei Wu
- From the Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, China,.
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Luo HS, Zhan T, Huang XD. Relationship between Hedgehog signaling pathway and pancreatic cancer. Shijie Huaren Xiaohua Zazhi 2016; 24:75-80. [DOI: 10.11569/wcjd.v24.i1.75] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hedgehog (Hh) signaling pathway consists of ligands such as Hh, receptor (patched), transmembrane protein Smo, nuclear transcription factor Gli, and downstream target genes. This pathway plays an important role in cell differentiation, tissue development and organ formation in the embryonic stage. In recent years, the Hh signaling pathway has been reported to play an important role in the development of pancreatic cancer. It can induce differentiation, proliferation and invasion of pancreatic cancer cells. Blocking the Hh signaling pathway in pancreatic cancer cells will provide a new and effective method for the treatment of pancreatic cancer. In this review, we will summarize the composition of the Hh signaling pathway and its relationship with the development of pancreatic cancer.
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