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Xiu MX, Liu YM, Kuang BH. The Role of DLLs in Cancer: A Novel Therapeutic Target. Onco Targets Ther 2020; 13:3881-3901. [PMID: 32440154 PMCID: PMC7213894 DOI: 10.2147/ott.s244860] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2020] [Accepted: 04/06/2020] [Indexed: 12/18/2022] Open
Abstract
Delta-like ligands (DLLs) control Notch signaling. DLL1, DLL3 and DLL4 are frequently deregulated in cancer and influence tumor growth, the tumor vasculature and tumor immunity, which play different roles in cancer progression. DLLs have attracted intense research interest as anti-cancer therapeutics. In this review, we discuss the role of DLLs in cancer and summarize the emerging DLL-relevant targeting methods to aid future studies.
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Affiliation(s)
- Meng-Xi Xiu
- Medical School of Nanchang University, Nanchang, People's Republic of China
| | - Yuan-Meng Liu
- Medical School of Nanchang University, Nanchang, People's Republic of China
| | - Bo-Hai Kuang
- Medical School of Nanchang University, Nanchang, People's Republic of China
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Liu Z, Zhu Y, Li F, Xie Y. GATA1-regulated JAG1 promotes ovarian cancer progression by activating Notch signal pathway. PROTOPLASMA 2020; 257:901-910. [PMID: 31897811 DOI: 10.1007/s00709-019-01477-w] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Accepted: 12/16/2019] [Indexed: 06/10/2023]
Abstract
Ovarian cancer is the major cause of mortality due to late stage diagnoses and lower survival rates, and the mechanism of cancer progression is not completely understood. Thus, exploring the regulatory factors of ovarian cancer proliferation and metastasis is urgent. JAG1 expression in KOV3 and OVCA433 cells was detected by qPCR and western blot. MTT and Transwell assays were used to determine cell proliferation and metastasis. The tumor spheres formation assay, DOX, and Cisplatin administrations were performed to assess JAG1-induced stemness and chemoresistance. ChIP assay was used to verify the direct binding of GATA1 on JAG1 promoter. Ovarian cancer cells have higher JAG1 expression, which turns on Notch signaling and promotes cell proliferation, migration, invasion, stemness, and the resistance of chemotherapy. While knockdown JAG1 dramatically suppressed the ovarian cancer progression, GATA1 is the transcriptional factor of JAG1 in ovarian cells, knockdown JAG1 can inhibit GATA1-induced Notch activation and cell proliferation. This study demonstrates that JAG1, acting as an oncogenic gene, plays an important role in ovarian cancer progression and chemoresistance. Targeting GATA1/JAG1/Notch pathway may provide a novel strategy for ovarian cancer treatment.
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Affiliation(s)
- Zhenzhen Liu
- Shanxian Central Hospital of Shandong Province, No.1 Wenhua Road, Shancheng Town, Shanxian, Heze, 274300, Shandong, China
| | - Yongchun Zhu
- Shanxian Dongda Hospital of Shandong Province, No.1 Shunshi East Road, Shanxian, Heze, 274300, Shandong, China
| | - Fangfang Li
- Shanxian Dongda Hospital of Shandong Province, No.1 Shunshi East Road, Shanxian, Heze, 274300, Shandong, China
| | - Yuge Xie
- Shanxian Central Hospital of Shandong Province, No.1 Wenhua Road, Shancheng Town, Shanxian, Heze, 274300, Shandong, China.
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Kunanopparat A, Issara-Amphorn J, Leelahavanichkul A, Sanpavat A, Patumraj S, Tangkijvanich P, Palaga T, Hirankarn N. Delta-like ligand 4 in hepatocellular carcinoma intrinsically promotes tumour growth and suppresses hepatitis B virus replication. World J Gastroenterol 2018; 24:3861-3870. [PMID: 30228780 PMCID: PMC6141339 DOI: 10.3748/wjg.v24.i34.3861] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Revised: 07/05/2018] [Accepted: 07/16/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the role of Delta-like ligand 4 (DLL4) on tumour growth in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) in vivo.
METHODS We suppressed DLL4 expression in an HBV expressing HCC cell line, HepG2.2.15 and analysed the growth ability of cells as subcutaneous tumours in nude mice. The expression of tumour angiogenesis regulators, VEGF-A and VEGF-R2 in tumour xenografts were examined by western blotting. The tumour proliferation and neovasculature were examined by immunohistochemistry. The viral replication and viral protein expression were measured by quantitative PCR and western blotting, respectively.
RESULTS Eighteen days after implantation, tumour volume in mice implanted with shDLL4 HepG2.2.15 was significantly smaller than in mice implanted with control HepG2.2.15 (P < 0.0001). The levels of angiogenesis regulators, VEGF-A and VEGF-R2 were significantly decreased in implanted tumours with suppressed DLL4 compared with the control group (P < 0.001 and P < 0.05, respectively). Furthermore, the suppression of DLL4 expression in tumour cells reduced cell proliferation and the formation of new blood vessels in tumours. Unexpectedly, increased viral replication was observed after suppression of DLL4 in the tumours.
CONCLUSION This study demonstrates that DLL4 is important in regulating the tumour growth of HBV-associated HCC as well as the neovascularization and suppression of HBV replication.
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Affiliation(s)
- Areerat Kunanopparat
- Center of Excellence in Immunology and Immune Mediated Diseases, Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
| | - Jiraphorn Issara-Amphorn
- Center of Excellence in Immunology and Immune Mediated Diseases, Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
| | - Asada Leelahavanichkul
- Center of Excellence in Immunology and Immune Mediated Diseases, Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
| | - Anapat Sanpavat
- Department of Pathology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
| | - Suthiluk Patumraj
- Center of Excellence for Microcirculation, Department of Physiology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
| | - Pisit Tangkijvanich
- Research Unit of Hepatitis and Liver Cancer, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
| | - Tanapat Palaga
- Department of Microbiology, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand
| | - Nattiya Hirankarn
- Center of Excellence in Immunology and Immune Mediated Diseases, Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
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Huo L, Wei W, Wu S, Zhao X, Zhao C, Zhao H, Sun L. Effect of dihydroarteminin combined with siRNA targeting Notch1 on Notch1/c-Myc signaling in T-cell lymphoma cells. Exp Ther Med 2018; 15:3059-3065. [PMID: 29599840 DOI: 10.3892/etm.2018.5784] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2017] [Accepted: 01/16/2018] [Indexed: 02/07/2023] Open
Abstract
The effectiveness of therapy combining dihydroartemisinin (DHA) and small interfering RNA targeting Notch1 (siNotch1) in T-cell lymphoma remains unknown. The present study explored the potential and possible mechanisms of combined dihydroarteminin, and siNotch1 therapy for T-cell lymphoma. It was demonstrated that the viability rates of siRNA-DHA-treated cells was significantly suppressed in comparison with those in control cells, control siRNA cells, siRNA-treated cells and DHA-treated cells (P<0.01). Additionally, there was a significant increase in cell apoptosis of siRNA-DHA-treated cells in comparison with those of control cells, control siRNA cells, siRNA-treated cells, DHA-treated cells (P<0.05). Furthermore, Notch1 and c-Myc mRNA and protein expression were decreased in siRNA-DHA-treated cells (P<0.05). The present study demonstrated that DHA combined with siNotch1 is able to suppress proliferation and promote apoptosis, and downregulate the expression of Notch1 and c-Myc mRNA and protein in T-cell lymphoma cells. Targeting Notch1/c-Myc signaling with siRNA and DHA may represent a novel strategy for treating human T-cell lymphoma.
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Affiliation(s)
- Lanfen Huo
- Department of Hematology, Affiliated Hospital, Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Wenwen Wei
- Department of Hematology, Affiliated Hospital, Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Shaoling Wu
- Department of Hematology, Affiliated Hospital, Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Xindong Zhao
- Department of Hematology, School of Medicine, Qingdao University, Qingdao, Shandong 266021, P.R. China
| | - Chunting Zhao
- Department of Hematology, Affiliated Hospital, Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Hongguo Zhao
- Department of Hematology, Affiliated Hospital, Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Lingjie Sun
- Department of Hematology, Affiliated Hospital, Qingdao University, Qingdao, Shandong 266003, P.R. China
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Li D, Masiero M, Banham AH, Harris AL. The notch ligand JAGGED1 as a target for anti-tumor therapy. Front Oncol 2014; 4:254. [PMID: 25309874 PMCID: PMC4174884 DOI: 10.3389/fonc.2014.00254] [Citation(s) in RCA: 136] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2014] [Accepted: 09/04/2014] [Indexed: 12/26/2022] Open
Abstract
The Notch pathway is increasingly attracting attention as a source of therapeutic targets for cancer. Ligand-induced Notch signaling has been implicated in various aspects of cancer biology; as a consequence, pan-Notch inhibitors and therapeutic antibodies targeting one or more of the Notch receptors have been investigated for cancer therapy. Alternatively, Notch ligands provide attractive options for therapy in cancer treatment due to their more restricted expression and better-defined functions, as well as their low rate of mutations in cancer. One of the Notch ligands, Jagged1 (JAG1), is overexpressed in many cancer types, and plays an important role in several aspects of tumor biology. In fact, JAG1-stimulated Notch activation is directly implicated in tumor growth through maintaining cancer stem cell populations, promoting cell survival, inhibiting apoptosis, and driving cell proliferation and metastasis. In addition, JAG1 can indirectly affect cancer by influencing tumor microenvironment components such as tumor vasculature and immune cell infiltration. This article gives an overview of JAG1 and its role in tumor biology, and its potential as a therapeutic target.
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Affiliation(s)
- Demin Li
- Radcliffe Department of Medicine, Nuffield Division of Clinical Laboratory Sciences, Weatherall Institute of Molecular Medicine, University of Oxford , Oxford , UK
| | - Massimo Masiero
- Radcliffe Department of Medicine, Nuffield Division of Clinical Laboratory Sciences, Weatherall Institute of Molecular Medicine, University of Oxford , Oxford , UK
| | - Alison H Banham
- Radcliffe Department of Medicine, Nuffield Division of Clinical Laboratory Sciences, Weatherall Institute of Molecular Medicine, University of Oxford , Oxford , UK
| | - Adrian L Harris
- Cancer Research UK Molecular Oncology Laboratories, Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford , Oxford , UK
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Kobayashi E, Iyer AK, Hornicek FJ, Amiji MM, Duan Z. Lipid-functionalized dextran nanosystems to overcome multidrug resistance in cancer: a pilot study. Clin Orthop Relat Res 2013; 471:915-25. [PMID: 23011844 PMCID: PMC3563790 DOI: 10.1007/s11999-012-2610-2] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND The toxicity of anticancer agents and the difficulty in delivering drugs selectively to tumor cells pose a challenge in overcoming multidrug resistance (MDR). Recently, nanotechnology has emerged as a powerful tool in addressing some of the barriers to drug delivery, including MDR in cancer, by utilizing alternate routes of cellular entry and targeted delivery of drugs and genes. However, it is unclear whether doxorubicin (Dox) can be delivered by nanotechnologic approaches. QUESTIONS/PURPOSES We asked whether (1) Dox-loaded lipid-functionalized dextran-based biocompatible nanoparticles (Dox/NP) can reverse MDR, (2) Dox/NP has more potent cytotoxic effect on MDR tumors than poly(ethylene glycol)-modified liposomal Dox (PLD), and (3) multidrug resistance protein 1 (MDR1) small interfering RNA loaded in these nanoparticles (siMDR1/NP) can modulate MDR. METHODS To create stable Dox/NP and siMDR1/NP, we used two different lipid-modified dextran derivatives. The effect of Dox or Dox/NP was tested on drug-sensitive osteosarcoma (KHOS) and ovarian cancer (SKOV-3) cell cultures in triplicate and their respective MDR counterparts KHOS(R2) and SKOV-3(TR) in triplicate. We determined the effects on drug retention, transfection efficacy of siMDR1/NP, and P-glycoprotein expression and the antiproliferative effect between Dox/NP and PLD in MDR tumor cells. RESULTS Fluorescence microscopy revealed efficient uptake of the Dox/NP and fluorescently tagged siMDR1/NP. Dox/NP showed five- to 10-fold higher antiproliferative activity at the 50% inhibitory concentration than free Dox in tumor cells. Dox/NP showed twofold higher activity than PLD in MDR tumor cells. siMDR1/NP (100 nM) suppressed P-glycoprotein expression in KHOS(R2). CONCLUSIONS Dextran-lipid nanoparticles are a promising platform for delivering Dox and siRNAs. CLINICAL RELEVANCE Biocompatible dextran-based nanoparticles that are directly translatable to clinical medicine may lead to new potential therapeutics for reversing MDR in patients with cancer.
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MESH Headings
- ATP Binding Cassette Transporter, Subfamily B
- ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics
- ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism
- Antibiotics, Antineoplastic/chemistry
- Antibiotics, Antineoplastic/metabolism
- Antibiotics, Antineoplastic/pharmacology
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Chemistry, Pharmaceutical
- Dextrans/chemistry
- Dose-Response Relationship, Drug
- Doxorubicin/chemistry
- Doxorubicin/metabolism
- Doxorubicin/pharmacology
- Drug Carriers
- Drug Resistance, Multiple/genetics
- Drug Resistance, Neoplasm/genetics
- Humans
- Lipids/chemistry
- Microscopy, Fluorescence
- Nanotechnology
- Neoplasms/genetics
- Neoplasms/metabolism
- Neoplasms/pathology
- Pilot Projects
- Polyethylene Glycols/chemistry
- RNA Interference
- RNA, Small Interfering/chemistry
- RNA, Small Interfering/metabolism
- Time Factors
- Transfection
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Affiliation(s)
- Eisuke Kobayashi
- />Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, 100 Blossom St, Jackson 1115, Boston, MA 02114 USA
- />Department of Orthopaedic Surgery, Massachusetts General Hospital, Boston, MA USA
- />Harvard Medical School, Massachusetts General Hospital, Boston, MA USA
| | - Arun K. Iyer
- />Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, Boston, MA USA
| | - Francis J. Hornicek
- />Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, 100 Blossom St, Jackson 1115, Boston, MA 02114 USA
- />Department of Orthopaedic Surgery, Massachusetts General Hospital, Boston, MA USA
- />Harvard Medical School, Massachusetts General Hospital, Boston, MA USA
| | - Mansoor M. Amiji
- />Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, Boston, MA USA
| | - Zhenfeng Duan
- />Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, 100 Blossom St, Jackson 1115, Boston, MA 02114 USA
- />Department of Orthopaedic Surgery, Massachusetts General Hospital, Boston, MA USA
- />Harvard Medical School, Massachusetts General Hospital, Boston, MA USA
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