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1
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Iluta S, Nistor M, Buruiana S, Dima D. Wnt Signaling Pathway in Tumor Biology. Genes (Basel) 2024; 15:1597. [PMID: 39766864 PMCID: PMC11675244 DOI: 10.3390/genes15121597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 12/02/2024] [Accepted: 12/10/2024] [Indexed: 01/11/2025] Open
Abstract
Relapse and metastasis are the major challenges that stand in the way of cancer healing and survival, mainly attributed to cancer stem cells (CSCs). Their capabilities of self-renewal and tumorigenic potential leads to treatment resistance development. CSCs function through signaling pathways such as the Wnt/β-catenin cascade. While commonly involved in embryogenesis and adult tissues homeostasis, the dysregulation of the Wnt pathway has direct correlations with tumorigenesis, metastasis, and drug resistance. The development of therapies that target CSCs and bulk tumors is both crucial and urgent. However, the extensive crosstalk present between Wnt and other signaling networks (Hedgehog and Notch) complicates the development of efficient long-term therapies with minimal side-effects on normal tissues. Despite the obstacles, the emergence of Wnt inhibitors and subsequent modulation of the signaling pathways would provide dynamic therapeutic approaches to impairing CSCs and reversing resistance mechanisms.
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Affiliation(s)
- Sabina Iluta
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, 400347 Cluj Napoca, Romania;
| | - Madalina Nistor
- Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400347 Cluj Napoca, Romania
| | - Sanda Buruiana
- Department of Hematology, Nicolae Testemitanu University of Medicine and Pharmacy, 2004 Chisinau, Moldova;
| | - Delia Dima
- Department of Hematology, Ion Chiricuta Oncology Institute, 400015 Cluj Napoca, Romania
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2
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Stauder MC. Radiation for inflammatory breast cancer: Updates. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2023; 384:25-46. [PMID: 38637098 DOI: 10.1016/bs.ircmb.2023.10.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/20/2024]
Abstract
Inflammatory breast cancer (IBC) is a diagnosis based on a constellation of clinical features of edema (peau d'orange) of a third or more of the skin of the breast with a palpable border and a rapid onset of breast erythema. Incidence of IBC has increased over time, although it still makes up only 1-4% of all breast cancer diagnoses. Despite recent encouraging data on clinical outcomes, the published local-regional control rates remain consistently lower than the rates for non-IBC. In this review, we focus on radiotherapy, provide a framework for multi-disciplinary care for IBC, describe local-regional treatment techniques for IBC; highlight new directions in the management of patients with metastatic IBC and offer an introduction to future directions regarding the optimal treatment and management of IBC.
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Affiliation(s)
- Michael C Stauder
- Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Department of Breast Radiation Oncology, Division of Radiation Oncology, University of Texas MD Anderson Cancer Center, Holcombe Blvd, Houston, TX, United States.
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Lacombe J, Zenhausern F. Effect of mechanical forces on cellular response to radiation. Radiother Oncol 2022; 176:187-198. [PMID: 36228760 DOI: 10.1016/j.radonc.2022.10.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 08/08/2022] [Accepted: 10/05/2022] [Indexed: 12/14/2022]
Abstract
While the cellular interactions and biochemical signaling has been investigated for long and showed to play a major role in the cell's fate, it is now also evident that mechanical forces continuously applied to the cells in their microenvironment are as important for tissue homeostasis. Mechanical cues are emerging as key regulators of cellular drug response and we aimed to demonstrate in this review that such effects should also be considered vital for the cellular response to radiation. In order to explore the mechanobiology of the radiation response, we reviewed the main mechanoreceptors and transducers, including integrin-mediated adhesion, YAP/TAZ pathways, Wnt/β-catenin signaling, ion channels and G protein-coupled receptors and showed their implication in the modulation of cellular radiosensitivity. We then discussed the current studies that investigated a direct effect of mechanical stress, including extracellular matrix stiffness, shear stress and mechanical strain, on radiation response of cancer and normal cells and showed through preliminary results that such stress effectively can alter cell response after irradiation. However, we also highlighted the limitations of these studies and emphasized some of the contradictory data, demonstrating that the effect of mechanical cues could involve complex interactions and potential crosstalk with numerous cellular processes also affected by irradiation. Overall, mechanical forces alter radiation response and although additional studies are required to deeply understand the underlying mechanisms, these effects should not be neglected in radiation research as they could reveal new fundamental knowledge for predicting radiosensitivity or understanding resistance to radiotherapy.
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Affiliation(s)
- Jerome Lacombe
- Center for Applied NanoBioscience and Medicine, College of Medicine Phoenix, University of Arizona, 475 North 5th Street, Phoenix, AZ 85004, USA; Department of Basic Medical Sciences, College of Medicine Phoenix, University of Arizona, 425 N 5th St, Phoenix, AZ 85004, USA.
| | - Frederic Zenhausern
- Center for Applied NanoBioscience and Medicine, College of Medicine Phoenix, University of Arizona, 475 North 5th Street, Phoenix, AZ 85004, USA; Department of Basic Medical Sciences, College of Medicine Phoenix, University of Arizona, 425 N 5th St, Phoenix, AZ 85004, USA; Department of Biomedical Engineering, College of Engineering, University of Arizona, 1127 E. James E. Rogers Way, Tucson, AZ 85721, USA.
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Vellichirammal NN, Sethi S, Pandey S, Singh J, Wise SY, Carpenter AD, Fatanmi OO, Guda C, Singh VK. Lung transcriptome of nonhuman primates exposed to total- and partial-body irradiation. MOLECULAR THERAPY. NUCLEIC ACIDS 2022; 29:584-598. [PMID: 36090752 PMCID: PMC9418744 DOI: 10.1016/j.omtn.2022.08.006] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Accepted: 08/01/2022] [Indexed: 12/25/2022]
Abstract
The focus of radiation biodosimetry has changed recently, and a paradigm shift for using molecular technologies of omic platforms in addition to cytogenetic techniques has been observed. In our study, we have used a nonhuman primate model to investigate the impact of a supralethal dose of 12 Gy radiation on alterations in the lung transcriptome. We used 6 healthy and 32 irradiated animal samples to delineate radiation-induced changes. We also used a medical countermeasure, γ-tocotrienol (GT3), to observe any changes. We demonstrate significant radiation-induced changes in the lung transcriptome for total-body irradiation (TBI) and partial-body irradiation (PBI). However, no major influence of GT3 on radiation was noted in either comparison. Several common signaling pathways, including PI3K/AKT, GADD45, and p53, were upregulated in both exposures. TBI activated DNA-damage-related pathways in the lungs, whereas PTEN signaling was activated after PBI. Our study highlights the various transcriptional profiles associated with γ- and X-ray exposures, and the associated pathways include LXR/RXR activation in TBI, whereas pulmonary wound-healing and pulmonary fibrosis signaling was repressed in PBI. Our study provides important insights into the molecular pathways associated with irradiation that can be further investigated for biomarker discovery.
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Affiliation(s)
| | - Sahil Sethi
- Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Sanjit Pandey
- Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Jatinder Singh
- Division of Radioprotectants, Department of Pharmacology and Molecular Therapeutics, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
- Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
| | - Stephen Y. Wise
- Division of Radioprotectants, Department of Pharmacology and Molecular Therapeutics, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
- Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
| | - Alana D. Carpenter
- Division of Radioprotectants, Department of Pharmacology and Molecular Therapeutics, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
- Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
| | - Oluseyi O. Fatanmi
- Division of Radioprotectants, Department of Pharmacology and Molecular Therapeutics, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
- Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
| | - Chittibabu Guda
- Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Vijay K. Singh
- Division of Radioprotectants, Department of Pharmacology and Molecular Therapeutics, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
- Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
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Szczepaniak J, Sosnowska M, Wierzbicki M, Witkowska-Pilaszewicz O, Strojny-Cieslak B, Jagiello J, Fraczek W, Kusmierz M, Grodzik M. Reduced Graphene Oxide Modulates the FAK-Dependent Signaling Pathway in Glioblastoma Multiforme Cells In Vitro. MATERIALS (BASEL, SWITZERLAND) 2022; 15:ma15175843. [PMID: 36079225 PMCID: PMC9457042 DOI: 10.3390/ma15175843] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 06/28/2022] [Accepted: 08/19/2022] [Indexed: 05/27/2023]
Abstract
Aggressive invasiveness is a common feature of malignant gliomas, despite their high level of tumor heterogeneity and possible diverse cell origins. Therefore, it is important to explore new therapeutic methods. In this study, we evaluated and compared the effects of graphene (GN) and reduced graphene oxides (rGOs) on a highly invasive and neoplastic cell line, U87. The surface functional groups of the GN and rGO flakes were characterized by X-ray photoelectron spectroscopy. The antitumor activity of these flakes was obtained by using the neutral red assay and their anti-migratory activity was determined using the wound healing assay. Further, we investigated the mRNA and protein expression levels of important cell adhesion molecules involved in migration and invasiveness. The rGO flakes, particularly rGO/ATS and rGO/TUD, were found highly toxic. The migration potential of both U87 and Hs5 cells decreased, especially after rGO/TUD treatment. A post-treatment decrease in mobility and FAK expression was observed in U87 cells treated with rGO/ATS and rGO/TUD flakes. The rGO/TUD treatment also reduced β-catenin expression in U87 cells. Our results suggest that rGO flakes reduce the migration and invasiveness of U87 tumor cells and can, thus, be used as potential antitumor agents.
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Affiliation(s)
- Jaroslaw Szczepaniak
- Department of Nanobiotechnology, Institute of Biology, Warsaw University of Life Sciences (WULS-SGGW), 02-787 Warsaw, Poland
| | - Malwina Sosnowska
- Department of Nanobiotechnology, Institute of Biology, Warsaw University of Life Sciences (WULS-SGGW), 02-787 Warsaw, Poland
| | - Mateusz Wierzbicki
- Department of Nanobiotechnology, Institute of Biology, Warsaw University of Life Sciences (WULS-SGGW), 02-787 Warsaw, Poland
| | - Olga Witkowska-Pilaszewicz
- Department of Large Animal Diseases and Clinic, Institute of Veterinary Medicine, Warsaw University of Life Sciences, 02-787 Warsaw, Poland
| | - Barbara Strojny-Cieslak
- Department of Nanobiotechnology, Institute of Biology, Warsaw University of Life Sciences (WULS-SGGW), 02-787 Warsaw, Poland
| | - Joanna Jagiello
- Graphene and Composites Research Group, Łukasiewicz Research Network-Institute of Microelectronics and Photonics, 01-919 Warsaw, Poland
| | - Wiktoria Fraczek
- Department of Nanobiotechnology, Institute of Biology, Warsaw University of Life Sciences (WULS-SGGW), 02-787 Warsaw, Poland
| | - Marcin Kusmierz
- Analytical Laboratory, Institute of Chemical Sciences, Faculty of Chemistry, Maria Curie-Skłodowska University, 3 Maria Curie-Skłodowska Square, 20-031 Lublin, Poland
| | - Marta Grodzik
- Department of Nanobiotechnology, Institute of Biology, Warsaw University of Life Sciences (WULS-SGGW), 02-787 Warsaw, Poland
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Herbal Ingredients in the Prevention of Breast Cancer: Comprehensive Review of Potential Molecular Targets and Role of Natural Products. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:6044640. [PMID: 36017236 PMCID: PMC9398845 DOI: 10.1155/2022/6044640] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 07/06/2022] [Accepted: 07/26/2022] [Indexed: 11/17/2022]
Abstract
Among various cancers, breast cancer is the most prevalent type in women throughout the world. Breast cancer treatment is challenging due to complex nature of the etiology of disease. Cell division cycle alterations are often encountered in a variety of cancer types including breast cancer. Common treatments include chemotherapy, surgery, radiotherapy, and hormonal therapy; however, adverse effects and multidrug resistance lead to complications and noncompliance. Accordingly, there is an increasing demand for natural products from medicinal plants and foods. This review summarizes molecular mechanisms of signaling pathways in breast cancer and identifies mechanisms by which natural compounds may exert their efficacy in the treatment of breast cancer.
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7
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Kumar S, Fathima E, Khanum F, Malini SS. Significance of the Wnt canonical pathway in radiotoxicity via oxidative stress of electron beam radiation and its molecular control in mice. Int J Radiat Biol 2022; 99:459-473. [PMID: 35758974 DOI: 10.1080/09553002.2022.2094018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
PURPOSE Radiation triggers cell death events through signaling proteins, but the combined mechanism of these events is unexplored The Wnt canonical pathway, on the other hand, is essential for cell regeneration and cell fate determination. AIM The relationship between the Wnt pathway's response to radiation and its role in radiotoxicity is overlooked, even though it is a critical molecular control of the cell. The Wnt pathway has been predicted to have radioprotective properties in some reports, but the overall mechanism is unknown. We intend to investigate how this combined cascade works throughout the radiation process and its significance over radiotoxicity. MATERIALS AND METHODS Thirty adult mice were irradiated with electron beam radiation, and 5 served as controls. Mice were sacrificed after 24 h and 30 days of irradiation. We assessed DNA damage studies, oxidative stress parameters, mRNA profiles, protein level (liver, kidney, spleen, and germ cells), sperm viability, and motility. OBSERVATION The mRNA profile helps to understand how the combined cascade of the Wnt pathway and NHEJ work together during radiation to combat oxidative response and cell survival. The quantitative examination of mRNA uncovers unique critical changes in all mRNA levels in all cases, particularly in germ cells. Recuperation was likewise seen in post-30 day's radiation in the liver, spleen, and kidney followed by oxidative stress parameters, however not in germ cells. It proposes that reproductive physiology is exceptionally sensitive to radiation, even at the molecular level. It also suggests the suppression of Lef1/Axin2 could be the main reason for the permanent failure of the sperm function process. Post-irradiation likewise influences the morphology of sperm. The decrease in mRNA levels of Lef1, Axin2, Survivin, Ku70, and XRCC6 levels suggests radiation inhibits the Wnt canonical pathway and failure in DNA repair mechanisms in a coupled manner. An increase in Bax, Bcl2, and caspase3 suggests apoptosis activation followed by the decreased expression of enzymatic antioxidants. CONCLUSION Controlled several interlinked such as the Wnt canonical pathway, NHEJ pathway, and intrinsic apoptotic pathway execute when the whole body is exposed to radiation. These pathways decide the cell fate whether it will survive or will go to apoptosis which may further be used in a study to counterpart and better comprehend medication focus on radiation treatment.
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Affiliation(s)
- Shashank Kumar
- Molecular Reproductive and Human Genetics Laboratory, Department of Zoology, University of Mysore, Mysuru, India
| | - Eram Fathima
- Defense Food Research Laboratory, Defense Research Development Organisation, Mysuru, India
| | - Farhath Khanum
- Defense Food Research Laboratory, Defense Research Development Organisation, Mysuru, India
| | - Suttur S Malini
- Molecular Reproductive and Human Genetics Laboratory, Department of Zoology, University of Mysore, Mysuru, India
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Werner RL, Nekritz EA, Yan KK, Ju B, Shaner B, Easton J, Yu PJ, Silva J. Single-cell analysis reveals Comma-1D as a unique cell model for mammary gland development and breast cancer. J Cell Sci 2022; 135:275228. [PMID: 35502723 DOI: 10.1242/jcs.259329] [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: 09/02/2021] [Accepted: 04/11/2022] [Indexed: 11/20/2022] Open
Abstract
The mammary epithelial tree contains two distinct populations, luminal and basal. The investigation of how this heterogeneity is developed and how it influences tumorigenesis has been hampered by the need to perform these studies using animal models. Comma-1D is an immortalized mouse mammary epithelial cell line that has unique morphogenetic properties. By performing single-cell RNA-seq studies we found that Comma-1D cultures consist of two main populations with luminal and basal features and a smaller population with mixed lineage and bipotent characteristics. We demonstrated that multiple transcription factors associated with the differentiation of the mammary epithelium in vivo also modulate this process in Comma-1D cultures. Additionally, we found that only cells with luminal features were able to acquire transformed characteristics after an oncogenic HER2 mutant was introduced in their genomes. Overall, our studies characterize at a single-cell level the heterogeneity of the Comma-1D cell line and illustrate how Comma-1D cells can be used as an experimental model to study both the differentiation and the transformation processes in vitro.
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Affiliation(s)
- Rachel L Werner
- Graduate School, Department of Pathology, Icahn School of Medicine at Mount Sinai Hospital, New York, NY, USA
| | - Erin A Nekritz
- Graduate School, Department of Pathology, Icahn School of Medicine at Mount Sinai Hospital, New York, NY, USA
| | - Koon-Kiu Yan
- Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Bensheng Ju
- Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Bridget Shaner
- Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - John Easton
- Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Partha Jiyang Yu
- Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Jose Silva
- Graduate School, Department of Pathology, Icahn School of Medicine at Mount Sinai Hospital, New York, NY, USA
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Chen Y, Gong S, Liu Y, Cao X, Zhao M, Xiao J, Feng C. Geraniin inhibits cell growth and promoted autophagy-mediated cell death in the nasopharyngeal cancer C666-1 cells. Saudi J Biol Sci 2022; 29:168-174. [PMID: 35002405 PMCID: PMC8716868 DOI: 10.1016/j.sjbs.2021.08.076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 08/09/2021] [Accepted: 08/22/2021] [Indexed: 12/08/2022] Open
Abstract
Background Nasopharyngeal carcinoma (NPC) is a rare malignant tumor developing from epithelial linings of nasopharynx, and 10–50 out of 100,000 NPC cases were recorded globally particularly in the Asian countries. Methodology The cytotoxicity of geraniin against the NPC C666-1 cells were analyzed using MTT assay. The influences of geraniin on the C666-1 cell viability with the presence of ROS and apoptosis inhibitors were also studied. The expressions of PI3K, Akt, mTOR, and autophagic markers LC3, ATG7, P62/SQSTM1 expressions in the C666-1 cells were studied by western blotting analysis. The ROS production was assayed using DCFH-DA staining. The immunofluorescence assay was performed to detect the NF-κB and β-catenin expressions in the C666-1 cells. Results The cell viability of C666-1 cells were appreciably prevented by the geraniin. The geraniin treatment also inhibited the C666-1 cell growth with the presence of apoptotic inhibitor Z-VAD-FMK. The geraniin-treatment effectively improved the ROS production and inhibited the NF-κB and β-catenin expressions in the C666-1 cells. Geraniin appreciably modulated the PI3K/Akt/mTOR signaling axis and improved the autophagy-mediated cell death via improving the autophagic markers LC3 and ATG7 expressions in the C666-1 cells. Conclusion In conclusion, our results proved that geraniin inhibits C666-1 cell growth and initiated autophagy-mediated cell death via modulating PI3K/Akt/mTOR cascade and improving LC3 and ATG7 expressions in the C666-1. Geraniin and it could be a hopeful and efficient candidate to treat the human NPC in the future.
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Affiliation(s)
- Yulian Chen
- Department of Otolaryngology Head and Neck Surgery, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan 650032, China
| | - Shunmin Gong
- Department of Otolaryngology Head and Neck Surgery, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan 650032, China
| | - Yongjun Liu
- Department of Otolaryngology Head and Neck Surgery, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan 650032, China
| | - Xianbao Cao
- Department of Otolaryngology Head and Neck Surgery, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan 650032, China
| | - Ming Zhao
- Department of Otolaryngology Head and Neck Surgery, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan 650032, China
| | - Jing Xiao
- Department of Otolaryngology Head and Neck Surgery, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan 650032, China
| | - Chun Feng
- Department of Otolaryngology Head and Neck Surgery, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan 650032, China
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Effects of MicroRNA-195-5p on Biological Behaviors and Radiosensitivity of Lung Adenocarcinoma Cells via Targeting HOXA10. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:4522210. [PMID: 34925694 PMCID: PMC8672108 DOI: 10.1155/2021/4522210] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Revised: 10/19/2021] [Accepted: 11/08/2021] [Indexed: 12/15/2022]
Abstract
Objective To explore the effects of miR-195-5p and its target gene HOXA10 on the biological behaviors and radiosensitivity of lung adenocarcinoma (LUAD) cells. Methods The effects of miR-195-5p on LUAD cell proliferation, migration, invasion, cycle arrest, apoptosis, and radiosensitivity were investigated by in vitro experiments. The bioinformatics analysis was used to assess its clinical value and predict target genes. Double-luciferase experiments were used to verify whether the miR-195-5p directly targeted HOXA10. A xenograft tumor-bearing mouse model was used to examine its effects on the radiosensitivity of LUAD in vivo. Results Both gain- and loss-of-function assays demonstrated that miR-195-5p inhibited LUAD cell proliferation, invasion, and migration, induced G1 phase arrest and apoptosis, and enhanced radiosensitivity. Double-luciferase experiments confirmed that miR-195-5p directly targeted HOXA10. Downregulation of HOXA10 also inhibited LUAD cell proliferation, migration, and invasion, induced G1 phase arrest and apoptosis, and enhanced radiosensitivity. The protein levels of β-catenin, c-myc, and Wnt1 were decreased by miR-195-5p and increased by its inhibitor. Moreover, the effects of the miR-195-5p inhibitor could be eliminated by HOXA10-siRNA. Furthermore, miR-195-5p improved radiosensitivity of LUAD cells in vivo. Conclusion miR-195-5p has excellent antitumor effects via inhibiting cancer cell growth, invasion, and migration, arresting the cell cycle, promoting apoptosis, and sensitizing LUAD cells to X-ray irradiation by targeting HOXA10. Thus, miR-195-5p may serve as a potential candidate for the treatment of LUAD.
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11
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Wu T, Wang Y, Xiao T, Ai Y, Li J, Zeng YA, Yu QC. Lentiviral CRISPR-guided RNA library screening identified Adam17 as an upstream negative regulator of Procr in mammary epithelium. BMC Biotechnol 2021; 21:42. [PMID: 34281556 PMCID: PMC8290623 DOI: 10.1186/s12896-021-00703-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 05/24/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Protein C receptor (Procr) has recently been shown to mark resident adult stem cells in the mammary gland, vascular system, and pancreatic islets. More so, high Procr expression was also detected and used as indicator for subsets of triple-negative breast cancers (TNBCs). Previous study has revealed Procr as a target of Wnt/β-catenin signaling; however, direct upstream regulatory mechanism of Procr remains unknown. To comprehend the molecular role of Procr during physiology and pathology, elucidating the upstream effectors of Procr is necessary. Here, we provide a system for screening negative regulators of Procr, which could be adapted for broad molecular analysis on membrane proteins. RESULTS We established a screening system which combines CRISPR-Cas9 guided gene disruption with fluorescence activated cell sorting technique (FACS). CommaDβ (murine epithelial cells line) was used for the initial Procr upstream effector screening using lentiviral CRISPR-gRNA library. Shortlisted genes were further validated through individual lentiviral gRNA infection followed by Procr expression evaluation. Adam17 was identified as a specific negative inhibitor of Procr expression. In addition, MDA-MB-231 cells and Hs578T cells (human breast cancer cell lines) were used to verify the conserved regulation of ADAM17 over PROCR expression. CONCLUSION We established an efficient CRISPR-Cas9/FACS screening system, which identifies the regulators of membrane proteins. Through this system, we identified Adam17 as the negative regulator of Procr membrane expression both in mammary epithelial cells and breast cancer cells.
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Affiliation(s)
- Ting Wu
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China
| | - Yinghua Wang
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China
| | - Tianxiong Xiao
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China
| | - Yirui Ai
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China
| | - Jinsong Li
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China.
- School of life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
| | - Yi Arial Zeng
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China.
- School of life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
| | - Qing Cissy Yu
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China.
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12
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Jariyal H, Gupta C, Andhale S, Gadge S, Srivastava A. Comparative stemness and differentiation of luminal and basal breast cancer stem cell type under glutamine-deprivation. J Cell Commun Signal 2021; 15:207-222. [PMID: 33511560 PMCID: PMC7991029 DOI: 10.1007/s12079-020-00603-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Accepted: 12/20/2020] [Indexed: 12/12/2022] Open
Abstract
Glutamine (gln) metabolism has emerged as a cancer therapeutic target in past few years, however, the effect of gln-deprivation of bCSCs remains elusive in breast cancer. In this study, effect of glutamine on stemness and differentiation potential of bCSCs isolated from MCF-7 and MDAMB-231 were studied. We have shown that bCSCs differentiate into CD24+ epithelial population under gln-deprivation and demonstrated increased expression of epithelial markers such as e-cadherin, claudin-1 and decreased expression of mesenchymal protein n-cadherin. MCF-7-bCSCs showed a decrease in EpCAMhigh population whereas MDAMB-231-bCSCs increased CD44high population in response to gln-deprivation. The expression of intracellular stem cell markers such sox-2, oct-4 and nanog showed a drastic decrease in gene expression under gln-deprived MDAMB-231-bCSCs. Finally, localization of β-catenin in MCF-7 and MDAMB-231 cells showed its accumulation in cytosol or perinuclear space reducing its efficiency to transcribe downstream genes. Conclusively, our study demonstrated that gln-deprivation induces differentiation of bCSCs into epithelial subtypes and also reduces stemness of bCSCs mediated by reduced nuclear localization of β-catenin. It also suggests that basal and luminal bCSCs respond differentially towards changes in extracellular and intracellular gln. This study could significantly affect the gln targeting regimen of breast cancer therapeutics.
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Affiliation(s)
- Heena Jariyal
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research-Ahmedabad, Gandhinagar, Gujarat, India
| | - Chanchal Gupta
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research-Ahmedabad, Gandhinagar, Gujarat, India
| | - Shambhavi Andhale
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research-Ahmedabad, Gandhinagar, Gujarat, India
| | - Sonali Gadge
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research-Ahmedabad, Gandhinagar, Gujarat, India
| | - Akshay Srivastava
- Department of Medical Devices, National Institute of Pharmaceutical Education and Research-Ahmedabad, Opposite Air force Station, Palaj, Gandhinagar, Gujarat, 382355, India.
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13
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Mamun MA, Mannoor K, Cao J, Qadri F, Song X. SOX2 in cancer stemness: tumor malignancy and therapeutic potentials. J Mol Cell Biol 2021; 12:85-98. [PMID: 30517668 PMCID: PMC7109607 DOI: 10.1093/jmcb/mjy080] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2018] [Revised: 11/18/2018] [Accepted: 12/04/2018] [Indexed: 12/12/2022] Open
Abstract
Cancer stem cells (CSCs), a minor subpopulation of tumor bulks with self-renewal and seeding capacity to generate new tumors, posit a significant challenge to develop effective and long-lasting anti-cancer therapies. The emergence of drug resistance appears upon failure of chemo-/radiation therapy to eradicate the CSCs, thereby leading to CSC-mediated clinical relapse. Accumulating evidence suggests that transcription factor SOX2, a master regulator of embryonic and induced pluripotent stem cells, drives cancer stemness, fuels tumor initiation, and contributes to tumor aggressiveness through major drug resistance mechanisms like epithelial-to-mesenchymal transition, ATP-binding cassette drug transporters, anti-apoptotic and/or pro-survival signaling, lineage plasticity, and evasion of immune surveillance. Gaining a better insight and comprehensive interrogation into the mechanistic basis of SOX2-mediated generation of CSCs and treatment failure might therefore lead to new therapeutic targets involving CSC-specific anti-cancer strategies.
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Affiliation(s)
- Mahfuz Al Mamun
- Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, China
| | - Kaiissar Mannoor
- Oncology Laboratory, Institute for Developing Science & Health Initiatives (ideSHi), Dhaka, Bangladesh
| | - Jun Cao
- Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, China
| | - Firdausi Qadri
- Oncology Laboratory, Institute for Developing Science & Health Initiatives (ideSHi), Dhaka, Bangladesh
| | - Xiaoyuan Song
- Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, China.,CAS Key Laboratory of Brain Function and Disease, CAS Center for Excellence in Molecular Cell Science, School of Life Sciences, University of Science and Technology of China, Hefei, China
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14
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Tomkinson AE, Naila T, Khattri Bhandari S. Altered DNA ligase activity in human disease. Mutagenesis 2021; 35:51-60. [PMID: 31630206 DOI: 10.1093/mutage/gez026] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Accepted: 09/09/2019] [Indexed: 12/18/2022] Open
Abstract
The joining of interruptions in the phosphodiester backbone of DNA is critical to maintain genome stability. These breaks, which are generated as part of normal DNA transactions, such as DNA replication, V(D)J recombination and meiotic recombination as well as directly by DNA damage or due to DNA damage removal, are ultimately sealed by one of three human DNA ligases. DNA ligases I, III and IV each function in the nucleus whereas DNA ligase III is the sole enzyme in mitochondria. While the identification of specific protein partners and the phenotypes caused either by genetic or chemical inactivation have provided insights into the cellular functions of the DNA ligases and evidence for significant functional overlap in nuclear DNA replication and repair, different results have been obtained with mouse and human cells, indicating species-specific differences in the relative contributions of the DNA ligases. Inherited mutations in the human LIG1 and LIG4 genes that result in the generation of polypeptides with partial activity have been identified as the causative factors in rare DNA ligase deficiency syndromes that share a common clinical symptom, immunodeficiency. In the case of DNA ligase IV, the immunodeficiency is due to a defect in V(D)J recombination whereas the cause of the immunodeficiency due to DNA ligase I deficiency is not known. Overexpression of each of the DNA ligases has been observed in cancers. For DNA ligase I, this reflects increased proliferation. Elevated levels of DNA ligase III indicate an increased dependence on an alternative non-homologous end-joining pathway for the repair of DNA double-strand breaks whereas elevated level of DNA ligase IV confer radioresistance due to increased repair of DNA double-strand breaks by the major non-homologous end-joining pathway. Efforts to determine the potential of DNA ligase inhibitors as cancer therapeutics are on-going in preclinical cancer models.
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Affiliation(s)
- Alan E Tomkinson
- Departments of Internal Medicine and Molecular Genetics and Microbiology, and the University of New Mexico Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM, USA
| | - Tasmin Naila
- Departments of Internal Medicine and Molecular Genetics and Microbiology, and the University of New Mexico Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM, USA
| | - Seema Khattri Bhandari
- Departments of Internal Medicine and Molecular Genetics and Microbiology, and the University of New Mexico Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM, USA
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15
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Kang Y, He W, Ren C, Qiao J, Guo Q, Hu J, Xu H, Jiang X, Wang L. Advances in targeted therapy mainly based on signal pathways for nasopharyngeal carcinoma. Signal Transduct Target Ther 2020; 5:245. [PMID: 33093441 PMCID: PMC7582884 DOI: 10.1038/s41392-020-00340-2] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 09/12/2020] [Accepted: 09/16/2020] [Indexed: 02/07/2023] Open
Abstract
Nasopharyngeal carcinoma (NPC) is a malignant epithelial carcinoma of the head and neck region which mainly distributes in southern China and Southeast Asia and has a crucial association with the Epstein-Barr virus. Based on epidemiological data, both incidence and mortality of NPC have significantly declined in recent decades grounded on the improvement of living standard and medical level in an endemic region, in particular, with the clinical use of individualized chemotherapy and intensity-modulated radiotherapy (IMRT) which profoundly contributes to the cure rate of NPC patients. To tackle the challenges including local recurrence and distant metastasis in the current NPC treatment, we discussed the implication of using targeted therapy against critical molecules in various signal pathways, and how they synergize with chemoradiotherapy in the NPC treatment. Combination treatment including targeted therapy and IMRT or concurrent chemoradiotherapy is presumably to be future options, which may reduce radiation or chemotherapy toxicities and open new avenues for the improvement of the expected functional outcome for patients with advanced NPC.
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Affiliation(s)
- Yuanbo Kang
- Department of Neurosurgery, Cancer Research Institute, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China
- Cancer Research Institute, Collaborative Innovation Center for Cancer Medicine, School of Basic Medical Science, Central South University, 410008, Changsha, Hunan, China
- The NHC Key Laboratory of Carcinogenesis and The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China
| | - Weihan He
- Department of Neurosurgery, Cancer Research Institute, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China
- Cancer Research Institute, Collaborative Innovation Center for Cancer Medicine, School of Basic Medical Science, Central South University, 410008, Changsha, Hunan, China
- The NHC Key Laboratory of Carcinogenesis and The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China
| | - Caiping Ren
- Department of Neurosurgery, Cancer Research Institute, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China.
- Cancer Research Institute, Collaborative Innovation Center for Cancer Medicine, School of Basic Medical Science, Central South University, 410008, Changsha, Hunan, China.
- The NHC Key Laboratory of Carcinogenesis and The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China.
| | - Jincheng Qiao
- Department of Neurosurgery, Cancer Research Institute, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China
- Cancer Research Institute, Collaborative Innovation Center for Cancer Medicine, School of Basic Medical Science, Central South University, 410008, Changsha, Hunan, China
- The NHC Key Laboratory of Carcinogenesis and The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China
| | - Qiuyong Guo
- Department of Neurosurgery, Cancer Research Institute, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China
- Cancer Research Institute, Collaborative Innovation Center for Cancer Medicine, School of Basic Medical Science, Central South University, 410008, Changsha, Hunan, China
- The NHC Key Laboratory of Carcinogenesis and The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China
| | - Jingyu Hu
- Department of Neurosurgery, Cancer Research Institute, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China
- Cancer Research Institute, Collaborative Innovation Center for Cancer Medicine, School of Basic Medical Science, Central South University, 410008, Changsha, Hunan, China
- The NHC Key Laboratory of Carcinogenesis and The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China
| | - Hongjuan Xu
- Department of Neurosurgery, Cancer Research Institute, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China
- Cancer Research Institute, Collaborative Innovation Center for Cancer Medicine, School of Basic Medical Science, Central South University, 410008, Changsha, Hunan, China
- The NHC Key Laboratory of Carcinogenesis and The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China
| | - Xingjun Jiang
- Department of Neurosurgery, Cancer Research Institute, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China
| | - Lei Wang
- Department of Neurosurgery, Cancer Research Institute, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China.
- Cancer Research Institute, Collaborative Innovation Center for Cancer Medicine, School of Basic Medical Science, Central South University, 410008, Changsha, Hunan, China.
- The NHC Key Laboratory of Carcinogenesis and The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China.
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16
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Mao A, Tang J, Tang D, Wang F, Liao S, Yuan H, Tian C, Sun C, Si J, Zhang H, Xia X. MicroRNA-29b-3p enhances radiosensitivity through modulating WISP1-mediated mitochondrial apoptosis in prostate cancer cells. J Cancer 2020; 11:6356-6364. [PMID: 33033519 PMCID: PMC7532503 DOI: 10.7150/jca.48216] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 08/26/2020] [Indexed: 12/18/2022] Open
Abstract
Radiotherapy is frequently applied for clinically localized prostate cancer while its efficacy could be significantly hindered by radioresistance. MicroRNAs (miRNAs) are important regulators in mediating cellular responses to ionizing radiation (IR), and strongly associate with radiosensitivity in many cancers. In this study, enhancement of radiosensitivity by miR-29b-3p was demonstrated in prostate cancer cell line LNCaP in vitro. Results showed that miR-29b-3p expression was significantly upregulated in response to IR from both X-rays and carbon ion irradiations. Knockdown of miR-29b-3p resulted in radioresistance while overexpression of miR-29b-3p led to increased radiosensitivity (showing reduced cell viability, suppressed cell proliferation and decreased colony formation). In addition, miR-29b-3p was found to directly target Wnt1-inducible-signaling protein 1 (WISP1). Inhibition of WISP1 facilitated the mitochondrial apoptosis pathway through suppressing Bcl-XL expression while activating caspase-3 and poly (ADP-ribose) polymerase (PARP). The results indicated that miR-29b-3p was a radiosensitizing miRNAs and could enhance radiosensitivity of LNCaP cells by targeting WISP1. These findings suggested a novel treatment to overcome radioresistance in prostate cancer patients, especially those with higher levels of the WISP1 expression.
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Affiliation(s)
- Aihong Mao
- Gansu Provincial Academic Institute for Medical Research, Lanzhou, China.,Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
| | - Jinzhou Tang
- Gansu Provincial Academic Institute for Medical Research, Lanzhou, China
| | - Deping Tang
- School of Chemical & Biological Engineering, Lanzhou Jiaotong University, Lanzhou 730070, PR China
| | - Fang Wang
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
| | - Shiqi Liao
- Gansu Provincial Academic Institute for Medical Research, Lanzhou, China
| | - Hongxia Yuan
- Gansu Provincial Academic Institute for Medical Research, Lanzhou, China
| | - Caiping Tian
- Gansu Provincial Academic Institute for Medical Research, Lanzhou, China
| | - Chao Sun
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
| | - Jing Si
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
| | - Hong Zhang
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
| | - Xiaojun Xia
- Gansu Provincial Academic Institute for Medical Research, Lanzhou, China.,Gansu Provincial Cancer Hospital, Lanzhou, China
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17
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Ghandadi M, Valadan R, Mohammadi H, Akhtari J, Khodashenas S, Ashari S. Wnt-β-catenin Signaling Pathway, the Achilles' Heels of Cancer Multidrug Resistance. Curr Pharm Des 2020; 25:4192-4207. [PMID: 31721699 DOI: 10.2174/1381612825666191112142943] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2019] [Accepted: 11/08/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND Most of the anticancer chemotherapies are hampered via the development of multidrug resistance (MDR), which is the resistance of tumor cells against cytotoxic effects of multiple chemotherapeutic agents. Overexpression and/or over-activation of ATP-dependent drug efflux transporters is a key mechanism underlying MDR development. Moreover, enhancement of drug metabolism, changes in drug targets and aberrant activation of the main signaling pathways, including Wnt, Akt and NF-κB are also responsible for MDR. METHODS In this study, we have reviewed the roles of Wnt signaling in MDR as well as its potential therapeutic significance. Pubmed and Scopus have been searched using Wnt, β-catenin, cancer, MDR and multidrug resistance as keywords. The last search was done in March 2019. Manuscripts investigating the roles of Wnt signaling in MDR or studying the modulation of MDR through the inhibition of Wnt signaling have been involved in the study. The main focus of the manuscript is regulation of MDR related transporters by canonical Wnt signaling pathway. RESULT AND CONCLUSION Wnt signaling has been involved in several pathophysiological states, including carcinogenesis and embryonic development. Wnt signaling is linked to various aspects of MDR including P-glycoprotein and multidrug resistance protein 1 regulation through its canonical pathways. Aberrant activation of Wnt/β- catenin signaling leads to the induction of cancer MDR mainly through the overexpression and/or over-activation of MDR related transporters. Accordingly, Wnt/β-catenin signaling can be a potential target for modulating cancer MDR.
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Affiliation(s)
- Morteza Ghandadi
- Pharmaceutical Sciences Research Center, Mazandaran University of Medical Sciences, Sari, Iran.,Department of Pharmacognosy and Pharmaceutical Biotechnology, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
| | - Reza Valadan
- Molecular and Cell Biology Research Center (MCBRC), Faculty of Medicine, Mazandaran University of Medical Sciences, Sari 48157-33971, Iran.,Department of Immunology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari 48157-33971, Iran
| | - Hamidreza Mohammadi
- Pharmaceutical Sciences Research Center, Mazandaran University of Medical Sciences, Sari, Iran.,Department of toxicology and pharmacology, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
| | - Javad Akhtari
- Molecular and Cell Biology Research Center (MCBRC), Faculty of Medicine, Mazandaran University of Medical Sciences, Sari 48157-33971, Iran.,Department of Medical Nanotechnology, School of Advanced Technologies in Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Shabanali Khodashenas
- Department of Medical Biotechnology, Faculty of Medical Sciences, Immunogenetics Research Center, Mazandaran University of Medical Sciences, Sari, Iran
| | - Sorour Ashari
- Pharmaceutical Sciences Research Center, Mazandaran University of Medical Sciences, Sari, Iran.,Department of toxicology and pharmacology, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
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18
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Goldsmith JR, Spitofsky N, Zamani A, Hood R, Boggs A, Li X, Li M, Reiner E, Ayyaz A, Etwebi Z, Lu L, Rivera Guzman J, Bou-Dargham MJ, Cathoupolis T, Hakonarson H, Sun H, Wrana JL, Gonzalez MV, Chen YH. TNFAIP8 controls murine intestinal stem cell homeostasis and regeneration by regulating microbiome-induced Akt signaling. Nat Commun 2020; 11:2591. [PMID: 32444641 PMCID: PMC7244529 DOI: 10.1038/s41467-020-16379-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Accepted: 04/29/2020] [Indexed: 01/22/2023] Open
Abstract
The intestine is a highly dynamic environment that requires tight control of the various inputs to maintain homeostasis and allow for proper responses to injury. It was recently found that the stem cell niche and epithelium is regenerated after injury by de-differentiated adult cells, through a process that gives rise to Sca1+ fetal-like cells and is driven by a transient population of Clu+ revival stem cells (revSCs). However, the molecular mechanisms that regulate this dynamic process have not been fully defined. Here we show that TNFAIP8 (also known as TIPE0) is a regulator of intestinal homeostasis that is vital for proper regeneration. TIPE0 functions through inhibiting basal Akt activation by the commensal microbiota via modulating membrane phospholipid abundance. Loss of TIPE0 in mice results in injury-resistant enterocytes, that are hyperproliferative, yet have regenerative deficits and are shifted towards a de-differentiated state. Tipe0-/- enterocytes show basal induction of the Clu+ regenerative program and a fetal gene expression signature marked by Sca1, but upon injury are unable to generate Sca-1+/Clu+ revSCs and could not regenerate the epithelium. This work demonstrates the role of TIPE0 in regulating the dynamic signaling that determines the injury response and enables intestinal epithelial cell regenerative plasticity.
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Affiliation(s)
- Jason R Goldsmith
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
| | - Nina Spitofsky
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Ali Zamani
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Ryan Hood
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Amanda Boggs
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Xinyuan Li
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Mingyue Li
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Elizabeth Reiner
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- University of Pikeville-Kentucky School of Osteopathic Medicine, Pikeville, KY, 41501, USA
| | - Arshad Ayyaz
- Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
| | - Zienab Etwebi
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Ling Lu
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Javier Rivera Guzman
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Department of Biology, University of Maryland Baltimore College, Baltimore, MD, 21250, USA
| | - Mayassa J Bou-Dargham
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Terry Cathoupolis
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Hakon Hakonarson
- Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA
- Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Honghong Sun
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Jeffrey L Wrana
- Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
| | - Michael V Gonzalez
- Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA
- Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Youhai H Chen
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
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19
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Zhao X, Jiang C, Xu R, Liu Q, Liu G, Zhang Y. TRIP6 enhances stemness property of breast cancer cells through activation of Wnt/β-catenin. Cancer Cell Int 2020; 20:51. [PMID: 32082081 PMCID: PMC7023708 DOI: 10.1186/s12935-020-1136-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Accepted: 02/04/2020] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND The urgent problem in the treatment of breast cancer is the recurrence induced by breast cancer stem cells (CSCs). Understanding the role and molecular mechanism of specific molecules in breast cancer stem cells can provide a theoretical basis for better treatment. TRIP6 is an adapter protein which belongs to the zyxin family of LIM proteins and is important in regulating the functions of CSCs. The present study aims to investigate the effects and mechanism of TRIP6 in breast cancer. METHODS TRIP6 expression in breast cancer cells and tissues were detected by Real-Time PCR, western blot and immunohistochemistry (IHC). MTT assays, colony formation assays, Xenografted tumor model and mammosphere formation assays were performed to investigate the oncogenic functions of TRIP6 in the tumorigenic capability and the tumor-initiating cell-like phenotype of breast cancer cells in vitro and in vivo. Luciferase reporter, subcellular fractionation and immunofluorescence staining assays were performed to determine the underlying mechanism of TRIP6-mediated stemness of breast cancer cells. RESULTS TRIP6 expression was significantly upregulated in breast cancer, and was closely related to the clinicopathologic characteristics, poor overall survival (OS), relapse-free survival (RFS) and poor prognosis of breast cancer patients. Functional studies revealed that overexpression of TRIP6 significantly enhanced proliferative, tumorigenicity capability and the cancer stem cell-like properties of breast cancer in vitro and in vivo. On the contrary, silencing TRIP6 achieved the opposite results. Notably, we found that TRIP6 promoted Wnt/β-catenin signaling pathway in breast cancer to strengthen the tumor-initiating cell-like phenotype of breast cancer cells. CONCLUSIONS This study indicates that TRIP6 plays an important role in maintaining the stem cell-like characteristics of breast cancer cells, supporting the significance of TRIP6 as a novel potential prognostic biomarker and therapeutic target for diagnosis and treatment of breast cancer.
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Affiliation(s)
- Xiaohui Zhao
- GMU-Joint School of Life Sciences, Guangzhou Medical University, Guangzhou, 511436 China
| | - Chao Jiang
- Department of Cancer Center, People’s Hospital of Baoan District, Shenzhen, 518101 China
| | - Rui Xu
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, 510095 China
| | - Qingnan Liu
- GMU-Joint School of Life Sciences, Guangzhou Medical University, Guangzhou, 511436 China
| | - Guanglin Liu
- Novartis Oncology (China) AG, Guangzhou, 510630 China
- The First Affiliation Hospital of Guangzhou Medical University, Guangzhou, 510120 China
| | - Yan Zhang
- Department of Medicine Oncology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655 Guangdong China
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20
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Su M, Xiao Y, Ma J, Cao D, Zhou Y, Wang H, Liao Q, Wang W. Long non-coding RNAs in esophageal cancer: molecular mechanisms, functions, and potential applications. J Hematol Oncol 2018; 11:118. [PMID: 30223861 PMCID: PMC6142629 DOI: 10.1186/s13045-018-0663-8] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2018] [Accepted: 09/06/2018] [Indexed: 12/20/2022] Open
Abstract
Esophageal cancer (EC) is the sixth leading cause of cancer-related death worldwide. The lack of early diagnostic biomarkers and effective prognostic indicators for metastasis and recurrence has resulted in the poor prognosis of EC. In addition, the underlying molecular mechanisms of EC development have yet to be elucidated. Accumulating evidence has demonstrated that lncRNAs play a vital role in the pathological progression of EC. LncRNAs may regulate gene expression through the recruitment of histone-modifying complexes to the chromatin and through interactions with RNAs or proteins. Recent evidence has demonstrated that the dysregulation of lncRNAs plays important roles in the proliferation, metastasis, invasion, angiogenesis, apoptosis, chemoradiotherapy resistance, and stemness of EC, which suggests potential clinical implications. In this review, we highlight the emerging roles and regulatory mechanisms of lncRNAs in the context of EC and discuss their potential clinical applications as diagnostic and prognostic biomarkers.
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Affiliation(s)
- Min Su
- Department of the 2nd Department of Thoracic Surgery, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, People's Republic of China. .,Department of the Central Laboratory, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, People's Republic of China.
| | - Yuhang Xiao
- Department of Pharmacy, Xiangya Hospital of Xiangya School of Medicine, Central South University, Changsha, 410001, Hunan, People's Republic of China
| | - Junliang Ma
- Department of the 2nd Department of Thoracic Surgery, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, People's Republic of China
| | - Deliang Cao
- Department of the 2nd Department of Thoracic Surgery, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, People's Republic of China
| | - Yong Zhou
- Department of the 2nd Department of Thoracic Surgery, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, People's Republic of China
| | - Hui Wang
- Department of Thoracic Radiotherapy, Key laboratory of Translational Radiation Oncology, Department of Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, People's Republic of China
| | - Qianjin Liao
- Department of the Central Laboratory, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, People's Republic of China.
| | - Wenxiang Wang
- Department of the 2nd Department of Thoracic Surgery, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, People's Republic of China.
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21
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Feng Y, Spezia M, Huang S, Yuan C, Zeng Z, Zhang L, Ji X, Liu W, Huang B, Luo W, Liu B, Lei Y, Du S, Vuppalapati A, Luu HH, Haydon RC, He TC, Ren G. Breast cancer development and progression: Risk factors, cancer stem cells, signaling pathways, genomics, and molecular pathogenesis. Genes Dis 2018; 5:77-106. [PMID: 30258937 PMCID: PMC6147049 DOI: 10.1016/j.gendis.2018.05.001] [Citation(s) in RCA: 731] [Impact Index Per Article: 104.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Accepted: 05/08/2018] [Indexed: 12/14/2022] Open
Abstract
As the most commonly occurring cancer in women worldwide, breast cancer poses a formidable public health challenge on a global scale. Breast cancer consists of a group of biologically and molecularly heterogeneous diseases originated from the breast. While the risk factors associated with this cancer varies with respect to other cancers, genetic predisposition, most notably mutations in BRCA1 or BRCA2 gene, is an important causative factor for this malignancy. Breast cancers can begin in different areas of the breast, such as the ducts, the lobules, or the tissue in between. Within the large group of diverse breast carcinomas, there are various denoted types of breast cancer based on their invasiveness relative to the primary tumor sites. It is important to distinguish between the various subtypes because they have different prognoses and treatment implications. As there are remarkable parallels between normal development and breast cancer progression at the molecular level, it has been postulated that breast cancer may be derived from mammary cancer stem cells. Normal breast development and mammary stem cells are regulated by several signaling pathways, such as estrogen receptors (ERs), HER2, and Wnt/β-catenin signaling pathways, which control stem cell proliferation, cell death, cell differentiation, and cell motility. Furthermore, emerging evidence indicates that epigenetic regulations and noncoding RNAs may play important roles in breast cancer development and may contribute to the heterogeneity and metastatic aspects of breast cancer, especially for triple-negative breast cancer. This review provides a comprehensive survey of the molecular, cellular and genetic aspects of breast cancer.
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Affiliation(s)
- Yixiao Feng
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, Departments of General Surgery, Clinical Laboratory Medicine, Orthopaedic Surgery, Plastic Surgery and Burn, and Otolaryngology, Head and Neck Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Mia Spezia
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Shifeng Huang
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, Departments of General Surgery, Clinical Laboratory Medicine, Orthopaedic Surgery, Plastic Surgery and Burn, and Otolaryngology, Head and Neck Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Chengfu Yuan
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Department of Biochemistry and Molecular Biology, China Three Gorges University School of Medicine, Yichang 443002, China
| | - Zongyue Zeng
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Ministry of Education Key Laboratory of Diagnostic Medicine and School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Linghuan Zhang
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Stem Cell Biology and Therapy Laboratory, Ministry of Education Key Laboratory of Child Development and Disorders, The Children's Hospital of Chongqing Medical University, Chongqing 400014, China
| | - Xiaojuan Ji
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Stem Cell Biology and Therapy Laboratory, Ministry of Education Key Laboratory of Child Development and Disorders, The Children's Hospital of Chongqing Medical University, Chongqing 400014, China
| | - Wei Liu
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, Departments of General Surgery, Clinical Laboratory Medicine, Orthopaedic Surgery, Plastic Surgery and Burn, and Otolaryngology, Head and Neck Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Bo Huang
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Ministry of Education Key Laboratory of Diagnostic Medicine and School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
- Department of Clinical Laboratory Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, China
| | - Wenping Luo
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, The Affiliated Hospital of Stomatology, Chongqing Medical University, Chongqing 401147, China
| | - Bo Liu
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, Departments of General Surgery, Clinical Laboratory Medicine, Orthopaedic Surgery, Plastic Surgery and Burn, and Otolaryngology, Head and Neck Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Yan Lei
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, Departments of General Surgery, Clinical Laboratory Medicine, Orthopaedic Surgery, Plastic Surgery and Burn, and Otolaryngology, Head and Neck Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Scott Du
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Student Inquiry Research Program, Illinois Mathematics and Science Academy (IMSA), Aurora, IL 60506, USA
| | - Akhila Vuppalapati
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Student Inquiry Research Program, Illinois Mathematics and Science Academy (IMSA), Aurora, IL 60506, USA
| | - Hue H. Luu
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Rex C. Haydon
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Tong-Chuan He
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Guosheng Ren
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, Departments of General Surgery, Clinical Laboratory Medicine, Orthopaedic Surgery, Plastic Surgery and Burn, and Otolaryngology, Head and Neck Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
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22
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STT3-dependent PD-L1 accumulation on cancer stem cells promotes immune evasion. Nat Commun 2018; 9:1908. [PMID: 29765039 PMCID: PMC5954021 DOI: 10.1038/s41467-018-04313-6] [Citation(s) in RCA: 324] [Impact Index Per Article: 46.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Accepted: 04/19/2018] [Indexed: 12/20/2022] Open
Abstract
Enriched PD-L1 expression in cancer stem-like cells (CSCs) contributes to CSC immune evasion. However, the mechanisms underlying PD-L1 enrichment in CSCs remain unclear. Here, we demonstrate that epithelial–mesenchymal transition (EMT) enriches PD-L1 in CSCs by the EMT/β-catenin/STT3/PD-L1 signaling axis, in which EMT transcriptionally induces N-glycosyltransferase STT3 through β-catenin, and subsequent STT3-dependent PD-L1 N-glycosylation stabilizes and upregulates PD-L1. The axis is also utilized by the general cancer cell population, but it has much more profound effect on CSCs as EMT induces more STT3 in CSCs than in non-CSCs. We further identify a non-canonical mesenchymal–epithelial transition (MET) activity of etoposide, which suppresses the EMT/β-catenin/STT3/PD-L1 axis through TOP2B degradation-dependent nuclear β-catenin reduction, leading to PD-L1 downregulation of CSCs and non-CSCs and sensitization of cancer cells to anti-Tim-3 therapy. Together, our results link MET to PD-L1 stabilization through glycosylation regulation and reveal it as a potential strategy to enhance cancer immunotherapy efficacy. PD-L1 accumulates on cancer stem cells and favours immune evasion but the mechanism underlying this accumulation are unknown. Here the authors show that epithelial-mesenchymal transition induces glycosylation and stabilisation of PD-L1; antagonising this process renders cancer cells sensitive to anti-Tim3-therapy.
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23
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Li G, Wang D, Ma W, An K, Liu Z, Wang X, Yang C, Du F, Han X, Chang S, Yu H, Zhang Z, Zhao Z, Zhang Y, Wang J, Sun Y. Transcriptomic and epigenetic analysis of breast cancer stem cells. Epigenomics 2018; 10:765-783. [PMID: 29480027 DOI: 10.2217/epi-2018-0008] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
AIM Cancer stem cells (CSCs) drive triple-negative breast cancer recurrence via their properties of self-renewal, invasiveness and radio/chemotherapy resistance. This study examined how CSCs might sustain these properties. MATERIALS & METHODS Transcriptomes, DNA methylomes and histone modifications were compared between CSCs and non CSCs. RESULTS Transcriptome analysis revealed several pathways that were activated in CSCs, whereas cell cycle regulation pathways were inhibited. Cell development and signaling genes were differentially methylated, with histone methylation analysis suggesting distinct H3K4me2 and H3K27me3 enrichment profiles. An integrated analysis revealed several tumor suppressor genes downregulated in CSCs. CONCLUSION Differential activation of various signaling pathways and genes contributes to the tumor-promoting properties of CSCs. Therapeutic targets identified in the analysis may contribute to improving treatment options for patients.
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Affiliation(s)
- Guochao Li
- Key Laboratory of Genomic & Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, PR China.,University of Chinese Academy of Sciences, Beijing 100049, PR China
| | - Dong Wang
- Key Laboratory of Genomic & Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, PR China.,University of Chinese Academy of Sciences, Beijing 100049, PR China
| | - Wencui Ma
- Heze Third People's Hospital, Shandong 274031, PR China
| | - Ke An
- Key Laboratory of Genomic & Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, PR China.,University of Chinese Academy of Sciences, Beijing 100049, PR China
| | - Zongzhi Liu
- Key Laboratory of Genomic & Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, PR China.,University of Chinese Academy of Sciences, Beijing 100049, PR China
| | - Xinyu Wang
- College of Bioinformatics Science & Technology, Harbin Medical University, Harbin 150081, PR China
| | - Caiyun Yang
- Key Laboratory of Genomic & Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, PR China.,University of Chinese Academy of Sciences, Beijing 100049, PR China
| | - Fengxia Du
- Key Laboratory of Genomic & Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, PR China.,University of Chinese Academy of Sciences, Beijing 100049, PR China
| | - Xiao Han
- Key Laboratory of Genomic & Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, PR China.,University of Chinese Academy of Sciences, Beijing 100049, PR China
| | - Shuang Chang
- Key Laboratory of Genomic & Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, PR China.,University of Chinese Academy of Sciences, Beijing 100049, PR China
| | - Hui Yu
- Key Laboratory of Genomic & Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, PR China.,University of Chinese Academy of Sciences, Beijing 100049, PR China
| | - Zilong Zhang
- Key Laboratory of Genomic & Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, PR China.,University of Chinese Academy of Sciences, Beijing 100049, PR China
| | - Zitong Zhao
- Key Laboratory of Genomic & Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, PR China.,University of Chinese Academy of Sciences, Beijing 100049, PR China
| | - Yan Zhang
- College of Bioinformatics Science & Technology, Harbin Medical University, Harbin 150081, PR China
| | - Junyun Wang
- Key Laboratory of Genomic & Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, PR China.,University of Chinese Academy of Sciences, Beijing 100049, PR China
| | - Yingli Sun
- Key Laboratory of Genomic & Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, PR China.,University of Chinese Academy of Sciences, Beijing 100049, PR China
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24
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Yin L, Gao Y, Zhang X, Wang J, Ding D, Zhang Y, Zhang J, Chen H. Niclosamide sensitizes triple-negative breast cancer cells to ionizing radiation in association with the inhibition of Wnt/β-catenin signaling. Oncotarget 2018; 7:42126-42138. [PMID: 27363012 PMCID: PMC5173121 DOI: 10.18632/oncotarget.9704] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Accepted: 05/16/2016] [Indexed: 01/22/2023] Open
Abstract
Triple-negative breast cancer (TNBC) is one of the most difficult breast cancers to treat because there is no targeted treatment, and conventional cytotoxic chemotherapy followed by adjuvant radiation therapy is the standard of care for patients with TNBC. We herein reported that ionizing radiation (IR) induced Wnt3a, LRP6 and β-catenin expression and consequently activated Wnt/β-catenin signaling in TNBC MDA-MB-231, MDA-MB-468 and Hs578T cells. Moreover, depletion of β-catenin by shRNA sensitized TNBC cells to IR, whereas treatment of Wnt3a protein or overexpression of β-catenin resulted in radioresistance of TNBC cells. Niclosamide, a potent inhibitor of Wnt/β-catenin signaling, not only inhibited constitutive Wnt/β-catenin signaling, but also blocked IR-induced Wnt/β-catenin signaling in TNBC cells. In addition, niclosamide sensitized TNBC cells to IR, prevented Wnt3a-induced radioresistance, and overcame β-catenin-induced radioresistance in TNBC cells. Importantly, animals treated with the combination of niclosamide and γ-ray local tumor irradiation had significant inhibition of MDA-MB-231 tumor growth compared with treated with local tumor irradiation alone. These findings indicate that Wnt/β-catenin signaling pathway plays an important role in the development of radioresistance of TNBC cells, and that niclosamide had significant radiosensitizing effects by inhibiting Wnt/β-catenin signaling in TNBC cells. Our study also provides rationale for further preclinical and clinical evaluation of niclosamide in TNBC management.
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Affiliation(s)
- Lina Yin
- Department of Radiation Biology, Institute of Radiation Medicine, Fudan University, Shanghai, China
| | - Yun Gao
- Department of Radiation Biology, Institute of Radiation Medicine, Fudan University, Shanghai, China
| | - Xuxia Zhang
- Department of Radiation Biology, Institute of Radiation Medicine, Fudan University, Shanghai, China
| | - Jing Wang
- Department of Radiation Biology, Institute of Radiation Medicine, Fudan University, Shanghai, China
| | - Defang Ding
- Department of Radiation Biology, Institute of Radiation Medicine, Fudan University, Shanghai, China
| | - Yaping Zhang
- Department of Radiation Biology, Institute of Radiation Medicine, Fudan University, Shanghai, China
| | - Junxiang Zhang
- Department of Radiation Biology, Institute of Radiation Medicine, Fudan University, Shanghai, China
| | - Honghong Chen
- Department of Radiation Biology, Institute of Radiation Medicine, Fudan University, Shanghai, China
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25
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Chang L, Graham P, Hao J, Ni J, Deng J, Bucci J, Malouf D, Gillatt D, Li Y. Cancer stem cells and signaling pathways in radioresistance. Oncotarget 2017; 7:11002-17. [PMID: 26716904 PMCID: PMC4905454 DOI: 10.18632/oncotarget.6760] [Citation(s) in RCA: 90] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2015] [Accepted: 12/22/2015] [Indexed: 12/17/2022] Open
Abstract
Radiation therapy (RT) is one of the most important strategies in cancer treatment. Radioresistance (the failure to RT) results in locoregional recurrence and metastasis. Therefore, it is critically important to investigate the mechanisms leading to cancer radioresistance to overcome this problem and increase patients' survival. Currently, the majority of the radioresistance-associated researches have focused on preclinical studies. Although the exact mechanisms of cancer radioresistance have not been fully uncovered, accumulating evidence supports that cancer stem cells (CSCs) and different signaling pathways play important roles in regulating radiation response and radioresistance. Therefore, targeting CSCs or signaling pathway proteins may hold promise for developing novel combination modalities and overcoming radioresistance. The present review focuses on the key evidence of CSC markers and several important signaling pathways in cancer radioresistance and explores innovative approaches for future radiation treatment.
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Affiliation(s)
- Lei Chang
- Cancer Care Centre, St George Hospital, Kogarah, NSW, Australia.,St George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Kensington, NSW, Australia
| | - Peter Graham
- Cancer Care Centre, St George Hospital, Kogarah, NSW, Australia.,St George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Kensington, NSW, Australia
| | - Jingli Hao
- Cancer Care Centre, St George Hospital, Kogarah, NSW, Australia.,St George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Kensington, NSW, Australia
| | - Jie Ni
- Cancer Care Centre, St George Hospital, Kogarah, NSW, Australia.,St George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Kensington, NSW, Australia
| | - Junli Deng
- Cancer Care Centre, St George Hospital, Kogarah, NSW, Australia.,St George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Kensington, NSW, Australia
| | - Joseph Bucci
- Cancer Care Centre, St George Hospital, Kogarah, NSW, Australia.,St George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Kensington, NSW, Australia
| | - David Malouf
- Department of Urology, St George Hospital, Kogarah, NSW, Australia
| | - David Gillatt
- Department of Urology, St George Hospital, Kogarah, NSW, Australia.,Australian School of Advanced Medicine, Macquarie University, Sydney, NSW, Australia
| | - Yong Li
- Cancer Care Centre, St George Hospital, Kogarah, NSW, Australia.,St George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Kensington, NSW, Australia
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26
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Wang T, Narayanaswamy R, Ren H, Torchilin VP. Combination therapy targeting both cancer stem-like cells and bulk tumor cells for improved efficacy of breast cancer treatment. Cancer Biol Ther 2017; 17:698-707. [PMID: 27259361 DOI: 10.1080/15384047.2016.1190488] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Many types of tumors are organized in a hierarchy of heterogeneous cell populations. The cancer stem-like cells (CSCs) hypothesis suggests that tumor development and metastasis are driven by a minority population of cells, which are responsible for tumor initiation, growth and recurrences. The inability to efficiently eliminate CSCs during chemotherapy, together with CSCs being highly tumorigenic and invasive, may result in treatment failure due to cancer relapse and metastases. CSCs are emerging as a promising target for the development of translational cancer therapies. Ideal panacea for cancer would kill all malignant cells, including CSCs and bulk tumor cells. Since both chemotherapy and CSCs-specific therapy are insufficient to cure cancer, we propose combination therapy with CSCs-targeted agents and chemotherapeutics for improved breast cancer treatment. We generated in vitro mammosphere of 2 breast cancer cell lines, and demonstrated ability of mammospheres to grow and enrich cancer cells with stem-like properties, including self-renewal, multilineage differentiation and enrichment of cells expressing breast cancer stem-like cell biomarkers CD44(+)/CD24(-/low). The formation of mammospheres was significantly inhibited by salinomycin, validating its pharmacological role against the cancer stem-like cells. In contrast, paclitaxel showed a minimal effect on the proliferation and growth of breast cancer stem-like cells. While combination therapies of salinomycin with conventional chemotherapy (paclitaxel or lipodox) showed a potential to improve tumor cell killing, different subtypes of breast cancer cells showed different patterns in response to the combination therapies. While optimization of combination therapy is warranted, the design of combination therapy should consider phenotypic attributes of breast cancer types.
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Affiliation(s)
- Tao Wang
- a Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University , Boston , MA , USA
| | - Radhika Narayanaswamy
- a Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University , Boston , MA , USA
| | - Huilan Ren
- a Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University , Boston , MA , USA
| | - Vladimir P Torchilin
- a Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University , Boston , MA , USA.,b Department of Biochemistry , Faculty of Science, King Abdulaziz University , Jeddah , Saudi Arabia
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27
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Vallée A, Lecarpentier Y, Guillevin R, Vallée JN. Interactions between TGF-β1, canonical WNT/β-catenin pathway and PPAR γ in radiation-induced fibrosis. Oncotarget 2017; 8:90579-90604. [PMID: 29163854 PMCID: PMC5685775 DOI: 10.18632/oncotarget.21234] [Citation(s) in RCA: 150] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2017] [Accepted: 08/17/2017] [Indexed: 12/16/2022] Open
Abstract
Radiation therapy induces DNA damage and inflammation leading to fibrosis. Fibrosis can occur 4 to 12 months after radiation therapy. This process worsens with time and years. Radiation-induced fibrosis is characterized by fibroblasts proliferation, myofibroblast differentiation, and synthesis of collagen, proteoglycans and extracellular matrix. Myofibroblasts are non-muscle cells that can contract and relax. Myofibroblasts evolve towards irreversible retraction during fibrosis process. In this review, we discussed the interplays between transforming growth factor-β1 (TGF-β1), canonical WNT/β-catenin pathway and peroxisome proliferator-activated receptor gamma (PPAR γ) in regulating the molecular mechanisms underlying the radiation-induced fibrosis, and the potential role of PPAR γ agonists. Overexpression of TGF-β and canonical WNT/β-catenin pathway stimulate fibroblasts accumulation and myofibroblast differentiation whereas PPAR γ expression decreases due to the opposite interplay of canonical WNT/β-catenin pathway. Both TGF-β1 and canonical WNT/β-catenin pathway stimulate each other through the Smad pathway and non-Smad pathways such as phosphatidylinositol 3-kinase/serine/threonine kinase (PI3K/Akt) signaling. WNT/β-catenin pathway and PPAR γ interact in an opposite manner. PPAR γ agonists decrease β-catenin levels through activation of inhibitors of the WNT pathway such as Smad7, glycogen synthase kinase-3 (GSK-3 β) and dickkopf-related protein 1 (DKK1). PPAR γ agonists also stimulate phosphatase and tensin homolog (PTEN) expression, which decreases both TGF-β1 and PI3K/Akt pathways. PPAR γ agonists by activating Smad7 decrease Smads pathway and then TGF-β signaling leading to decrease radiation-induced fibrosis. TGF-β1 and canonical WNT/β-catenin pathway promote radiation-induced fibrosis whereas PPAR γ agonists can prevent radiation-induced fibrosis.
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Affiliation(s)
- Alexandre Vallée
- Experimental and Clinical Neurosciences Laboratory, INSERM U1084, University of Poitiers, Poitiers, France.,Laboratory of Mathematics and Applications (LMA), UMR CNRS 7348, University of Poitiers, Poitiers, France
| | - Yves Lecarpentier
- Centre de Recherche Clinique, Grand Hôpital de l'Est Francilien (GHEF), Meaux, France
| | - Rémy Guillevin
- DACTIM, UMR CNRS 7348, University of Poitiers et CHU de Poitiers, Poitiers, France
| | - Jean-Noël Vallée
- Laboratory of Mathematics and Applications (LMA), UMR CNRS 7348, University of Poitiers, Poitiers, France.,CHU Amiens Picardie, University of Picardie Jules Verne (UPJV), Amiens, France
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29
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Serebryannyy LA, Yemelyanov A, Gottardi CJ, de Lanerolle P. Nuclear α-catenin mediates the DNA damage response via β-catenin and nuclear actin. J Cell Sci 2017; 130:1717-1729. [PMID: 28348105 DOI: 10.1242/jcs.199893] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Accepted: 03/20/2017] [Indexed: 12/29/2022] Open
Abstract
α-Catenin is an F-actin-binding protein widely recognized for its role in cell-cell adhesion. However, a growing body of literature indicates that α-catenin is also a nuclear protein. In this study, we show that α-catenin is able to modulate the sensitivity of cells to DNA damage and toxicity. Furthermore, nuclear α-catenin is actively recruited to sites of DNA damage. This recruitment occurs in a β-catenin-dependent manner and requires nuclear actin polymerization. These findings provide mechanistic insight into the WNT-mediated regulation of the DNA damage response and suggest a novel role for the α-catenin-β-catenin complex in the nucleus.
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Affiliation(s)
- Leonid A Serebryannyy
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Alex Yemelyanov
- Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Cara J Gottardi
- Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Primal de Lanerolle
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60612, USA
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30
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Da C, Wu L, Liu Y, Wang R, Li R. Effects of irradiation on radioresistance, HOTAIR and epithelial-mesenchymal transition/cancer stem cell marker expression in esophageal squamous cell carcinoma. Oncol Lett 2017; 13:2751-2757. [PMID: 28454462 DOI: 10.3892/ol.2017.5774] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2015] [Accepted: 09/22/2016] [Indexed: 12/29/2022] Open
Abstract
Radiotherapy is a common therapeutic strategy used to treat esophageal squamous cell carcinoma (ESCC). However, tumor cells often develop radioresistance, thereby reducing treatment efficacy. Here, we aimed to identify the mechanisms through which ESCC cells develop radioresistance and identify associated biomarkers. Eca109 cells were exposed to repeated radiation at 2 Gy/fraction for a total dose of 60 Gy (Eca109R60/2Gy cells). MTT and colony formation assays were performed to measure cell proliferation and compare the radiation biology parameters of Eca109 and Eca109R60/2Gy cells. Cell cycle distributions and apoptosis were assessed by flow cytometry. Reverse transcription-quantitative polymerase chain reaction and western blotting were employed to analyze the expression of HOX transcript antisense RNA (HOTAIR), in addition to biomarkers of the epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs). Eca109R60/2Gy cells exhibited increased cell proliferation and clone formation, with significantly higher radiobiological parameters compared with the parental Eca109 cells. The Eca109R60/2Gy cells also exhibited significantly decreased accumulation in G2 phase and increased accumulation in S phase. Additionally, the apoptosis rate was significantly lower in Eca109R60/2Gy cells than in parental Eca109 cells. Finally, HOTAIR expression levels and SNAI1 and β-catenin mRNA and protein expression levels were significantly higher, whereas E-cadherin levels were significantly lower in Eca109R60/2Gy cells than in Eca109 cells. Therefore, our findings demonstrated that radioresistance was affected by the expression of HOTAIR and biomarkers of the EMT and CSCs.
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Affiliation(s)
- Chunli Da
- Radiotherapy Center, Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830000, P.R. China
| | - Li Wu
- Radiotherapy Center, Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830000, P.R. China
| | - Yuting Liu
- Department of Anesthesiology, Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830000, P.R. China
| | - Ruozheng Wang
- Radiotherapy Center, Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830000, P.R. China
| | - Ruiguang Li
- Endoscopic Diagnosis and Treatment Center, Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830000, P.R. China
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31
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Lee SY, Jeong EK, Ju MK, Jeon HM, Kim MY, Kim CH, Park HG, Han SI, Kang HS. Induction of metastasis, cancer stem cell phenotype, and oncogenic metabolism in cancer cells by ionizing radiation. Mol Cancer 2017; 16:10. [PMID: 28137309 PMCID: PMC5282724 DOI: 10.1186/s12943-016-0577-4] [Citation(s) in RCA: 385] [Impact Index Per Article: 48.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Accepted: 12/25/2016] [Indexed: 12/12/2022] Open
Abstract
Radiation therapy is one of the major tools of cancer treatment, and is widely used for a variety of malignant tumours. Radiotherapy causes DNA damage directly by ionization or indirectly via the generation of reactive oxygen species (ROS), thereby destroying cancer cells. However, ionizing radiation (IR) paradoxically promotes metastasis and invasion of cancer cells by inducing the epithelial-mesenchymal transition (EMT). Metastasis is a major obstacle to successful cancer therapy, and is closely linked to the rates of morbidity and mortality of many cancers. ROS have been shown to play important roles in mediating the biological effects of IR. ROS have been implicated in IR-induced EMT, via activation of several EMT transcription factors—including Snail, HIF-1, ZEB1, and STAT3—that are activated by signalling pathways, including those of TGF-β, Wnt, Hedgehog, Notch, G-CSF, EGFR/PI3K/Akt, and MAPK. Cancer cells that undergo EMT have been shown to acquire stemness and undergo metabolic changes, although these points are debated. IR is known to induce cancer stem cell (CSC) properties, including dedifferentiation and self-renewal, and to promote oncogenic metabolism by activating these EMT-inducing pathways. Much accumulated evidence has shown that metabolic alterations in cancer cells are closely associated with the EMT and CSC phenotypes; specifically, the IR-induced oncogenic metabolism seems to be required for acquisition of the EMT and CSC phenotypes. IR can also elicit various changes in the tumour microenvironment (TME) that may affect invasion and metastasis. EMT, CSC, and oncogenic metabolism are involved in radioresistance; targeting them may improve the efficacy of radiotherapy, preventing tumour recurrence and metastasis. This study focuses on the molecular mechanisms of IR-induced EMT, CSCs, oncogenic metabolism, and alterations in the TME. We discuss how IR-induced EMT/CSC/oncogenic metabolism may promote resistance to radiotherapy; we also review efforts to develop therapeutic approaches to eliminate these IR-induced adverse effects.
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Affiliation(s)
- Su Yeon Lee
- Department of Molecular Biology, College of Natural Sciences, Pusan National University, Pusan, 609-735, Korea
| | - Eui Kyong Jeong
- Department of Molecular Biology, College of Natural Sciences, Pusan National University, Pusan, 609-735, Korea
| | - Min Kyung Ju
- Department of Molecular Biology, College of Natural Sciences, Pusan National University, Pusan, 609-735, Korea
| | - Hyun Min Jeon
- Department of Molecular Biology, College of Natural Sciences, Pusan National University, Pusan, 609-735, Korea
| | - Min Young Kim
- Research Center, Dongnam Institute of Radiological and Medical Science (DIRAMS), Pusan, 619-953, Korea
| | - Cho Hee Kim
- Department of Molecular Biology, College of Natural Sciences, Pusan National University, Pusan, 609-735, Korea.,DNA Identification Center, National Forensic Service, Seoul, 158-707, Korea
| | - Hye Gyeong Park
- Nanobiotechnology Center, Pusan National University, Pusan, 609-735, Korea
| | - Song Iy Han
- The Division of Natural Medical Sciences, College of Health Science, Chosun University, Gwangju, 501-759, Korea
| | - Ho Sung Kang
- Department of Molecular Biology, College of Natural Sciences, Pusan National University, Pusan, 609-735, Korea.
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32
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Gemenetzidis E, Gammon L, Biddle A, Emich H, Mackenzie IC. Invasive oral cancer stem cells display resistance to ionising radiation. Oncotarget 2016; 6:43964-77. [PMID: 26540568 PMCID: PMC4791279 DOI: 10.18632/oncotarget.6268] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2015] [Accepted: 10/06/2015] [Indexed: 11/28/2022] Open
Abstract
There is a significant amount of evidence to suggest that human tumors are driven and maintained by a sub-population of cells, known as cancer stem cells (CSC). In the case of head and neck cancer, such cells have been characterised by high expression levels of CD44 cell surface glycoprotein, while we have previously shown the presence of two diverse oral CSC populations in vitro, with different capacities for cell migration and proliferation. Here, we examined the response of oral CSC populations to ionising radiation (IR), a front-line measure for the treatment of head and neck tumors. We show that oral CSC initially display resistance to IR-induced growth arrest as well as relative apoptotic resistance. We propose that this is a result of preferential activation of the DNA damagerepair pathway in oral CSC with increased activation of ATM and BRCA1, elevated levels of DNA repair proteins RAD52, XLF, and a significantly faster rate of DNA double-strand-breaks clearance 24 hours following IR. By visually identifying CSC sub-populations undergoing EMT, we show that EMT-CSC represent the majority of invasive cells, and are more radio-resistant than any other population in re-constructed 3D tissues. We provide evidence that IR is not sufficient to eliminate CSC in vitro, and that sensitization of CD44hi/ESAlow cells to IR, followed by secondary EMT blockade, could be critical in order to reduce primary tumor recurrence, but more importantly to be able to eradicate cells capable of invasion and distant metastasis.
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Affiliation(s)
- Emilios Gemenetzidis
- Blizard Institute Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Luke Gammon
- Blizard Institute Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Adrian Biddle
- Blizard Institute Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Helena Emich
- Blizard Institute Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Ian C Mackenzie
- Blizard Institute Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
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Niwa O, Barcellos-Hoff MH, Globus RK, Harrison JD, Hendry JH, Jacob P, Martin MT, Seed TM, Shay JW, Story MD, Suzuki K, Yamashita S. ICRP Publication 131: Stem Cell Biology with Respect to Carcinogenesis Aspects of Radiological Protection. Ann ICRP 2016; 44:7-357. [PMID: 26637346 DOI: 10.1177/0146645315595585] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
This report provides a review of stem cells/progenitor cells and their responses to ionising radiation in relation to issues relevant to stochastic effects of radiation that form a major part of the International Commission on Radiological Protection's system of radiological protection. Current information on stem cell characteristics, maintenance and renewal, evolution with age, location in stem cell 'niches', and radiosensitivity to acute and protracted exposures is presented in a series of substantial reviews as annexes concerning haematopoietic tissue, mammary gland, thyroid, digestive tract, lung, skin, and bone. This foundation of knowledge of stem cells is used in the main text of the report to provide a biological insight into issues such as the linear-no-threshold (LNT) model, cancer risk among tissues, dose-rate effects, and changes in the risk of radiation carcinogenesis by age at exposure and attained age. Knowledge of the biology and associated radiation biology of stem cells and progenitor cells is more developed in tissues that renew fairly rapidly, such as haematopoietic tissue, intestinal mucosa, and epidermis, although all the tissues considered here possess stem cell populations. Important features of stem cell maintenance, renewal, and response are the microenvironmental signals operating in the niche residence, for which a well-defined spatial location has been identified in some tissues. The identity of the target cell for carcinogenesis continues to point to the more primitive stem cell population that is mostly quiescent, and hence able to accumulate the protracted sequence of mutations necessary to result in malignancy. In addition, there is some potential for daughter progenitor cells to be target cells in particular cases, such as in haematopoietic tissue and in skin. Several biological processes could contribute to protecting stem cells from mutation accumulation: (a) accurate DNA repair; (b) rapidly induced death of injured stem cells; (c) retention of the DNA parental template strand during divisions in some tissue systems, so that mutations are passed to the daughter differentiating cells and not retained in the parental cell; and (d) stem cell competition, whereby undamaged stem cells outcompete damaged stem cells for residence in the niche. DNA repair mainly occurs within a few days of irradiation, while stem cell competition requires weeks or many months depending on the tissue type. The aforementioned processes may contribute to the differences in carcinogenic radiation risk values between tissues, and may help to explain why a rapidly replicating tissue such as small intestine is less prone to such risk. The processes also provide a mechanistic insight relevant to the LNT model, and the relative and absolute risk models. The radiobiological knowledge also provides a scientific insight into discussions of the dose and dose-rate effectiveness factor currently used in radiological protection guidelines. In addition, the biological information contributes potential reasons for the age-dependent sensitivity to radiation carcinogenesis, including the effects of in-utero exposure.
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34
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Lowndes M, Rotherham M, Price JC, El Haj AJ, Habib SJ. Immobilized WNT Proteins Act as a Stem Cell Niche for Tissue Engineering. Stem Cell Reports 2016; 7:126-37. [PMID: 27411105 PMCID: PMC4944585 DOI: 10.1016/j.stemcr.2016.06.004] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2015] [Revised: 06/07/2016] [Accepted: 06/08/2016] [Indexed: 11/18/2022] Open
Abstract
The timing, location, and level of WNT signaling are highly regulated during embryonic development and for the maintenance of adult tissues. Consequently the ability to provide a defined and directed source of WNT proteins is crucial to fully understand its role in tissue development and to mimic its activity in vitro. Here we describe a one-step immobilization technique to covalently bind WNT3A proteins as a basal surface with easy storage and long-lasting activity. We show that this platform is able to maintain adult and embryonic stem cells while also being adaptable for 3D systems. Therefore, this platform could be used for recapitulating specific stem cell niches with the goal of improving tissue engineering.
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Affiliation(s)
- Molly Lowndes
- Centre for Stem Cells and Regenerative Medicine, King's College London, London SE1 9RT, UK
| | - Michael Rotherham
- Institute for Science and Technology in Medicine, Guy Hilton Research Centre, Keele University, Stoke-on-Trent ST4 7QB, UK
| | - Joshua C Price
- Centre for Stem Cells and Regenerative Medicine, King's College London, London SE1 9RT, UK; Institute for Science and Technology in Medicine, Guy Hilton Research Centre, Keele University, Stoke-on-Trent ST4 7QB, UK
| | - Alicia J El Haj
- Institute for Science and Technology in Medicine, Guy Hilton Research Centre, Keele University, Stoke-on-Trent ST4 7QB, UK
| | - Shukry J Habib
- Centre for Stem Cells and Regenerative Medicine, King's College London, London SE1 9RT, UK.
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35
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Wnt/β-catenin signaling in melanoma: Preclinical rationale and novel therapeutic insights. Cancer Treat Rev 2016; 49:1-12. [PMID: 27395773 DOI: 10.1016/j.ctrv.2016.06.009] [Citation(s) in RCA: 81] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2016] [Revised: 06/20/2016] [Accepted: 06/21/2016] [Indexed: 01/25/2023]
Abstract
WNT signaling regulates embryonic development and tissue homeostasis in the adult stage. Evolutionarily, activation of the WNT pathway is triggered by a large family of cytokines and activates a broad spectrum of downstream targets through two independent branches mediated by β-catenin (defined as canonical pathway) or PLC and small GTPase (defined as non-canonical pathway), respectively. Recent studies revealed the crucial role of WNT in the maintenance of cell metabolism and stemness as well as its deregulation in tumourigenesis and malignant transformation through oncogenic reprogramming, which contributes to cancer cell proliferation and differentiation, survival, stress response and resistance. In addition, multiple functional mutations discovered in human tumours have been reported to cause malignancy, indicating this pathway as a novel therapeutic target in oncology. Notably, emerging data highlights its involvement in the crosstalk between immune and cancer cells. However, contradictory effects have been also observed in different pre-clinical models when strategic(???) inhibitors are tested. In this review, we address the multifaceted regulatory mechanisms of WNT signaling in cancer, with a particular focus on current melanoma therapy, which has witnessed dramatic improvement in the last five years.
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36
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Zhang Q, Gao M, Luo G, Han X, Bao W, Cheng Y, Tian W, Yan M, Yang G, An J. Enhancement of Radiation Sensitivity in Lung Cancer Cells by a Novel Small Molecule Inhibitor That Targets the β-Catenin/Tcf4 Interaction. PLoS One 2016; 11:e0152407. [PMID: 27014877 PMCID: PMC4807779 DOI: 10.1371/journal.pone.0152407] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2015] [Accepted: 03/14/2016] [Indexed: 02/07/2023] Open
Abstract
Radiation therapy is an important treatment choice for unresectable advanced human lung cancers, and a critical adjuvant treatment for surgery. However, radiation as a lung cancer treatment remains far from satisfactory due to problems associated with radiation resistance in cancer cells and severe cytotoxicity to non-cancer cells, which arise at doses typically administered to patients. We have recently identified a promising novel inhibitor of β-catenin/Tcf4 interaction, named BC-23 (C21H14ClN3O4S), which acts as a potent cell death enhancer when used in combination with radiation. Sequential exposure of human p53-null non-small cell lung cancer (NSCLC) H1299 cells to low doses of x-ray radiation, followed 1 hour later by administration of minimally cytotoxic concentrations of BC-23, resulted in a highly synergistic induction of clonogenic cell death (combination index <1.0). Co-treatment with BC-23 at low concentrations effectively inhibits Wnt/β-catenin signaling and down-regulates c-Myc and cyclin D1 expression. S phase arrest and ROS generation are also involved in the enhancement of radiation effectiveness mediated by BC-23. BC-23 therefore represents a promising new class of radiation enhancer.
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Affiliation(s)
- Qinghao Zhang
- Department of Pharmacology, State University of New York, Upstate Medical University, Syracuse, New York, United States of America.,SUNY Upstate Cancer Research Institute, State University of New York, Upstate Medical University, Syracuse, New York, United States of America
| | - Mei Gao
- Department of Pharmacology, State University of New York, Upstate Medical University, Syracuse, New York, United States of America.,SUNY Upstate Cancer Research Institute, State University of New York, Upstate Medical University, Syracuse, New York, United States of America
| | - Guifen Luo
- Department of Pharmacology, State University of New York, Upstate Medical University, Syracuse, New York, United States of America.,SUNY Upstate Cancer Research Institute, State University of New York, Upstate Medical University, Syracuse, New York, United States of America
| | - Xiaofeng Han
- Department of Pharmacology, State University of New York, Upstate Medical University, Syracuse, New York, United States of America.,SUNY Upstate Cancer Research Institute, State University of New York, Upstate Medical University, Syracuse, New York, United States of America
| | - Wenjing Bao
- Department of Pharmacology, State University of New York, Upstate Medical University, Syracuse, New York, United States of America.,SUNY Upstate Cancer Research Institute, State University of New York, Upstate Medical University, Syracuse, New York, United States of America.,Department of Medicine, Liaoning University of Chinese Traditional Medicine, No. 33 Beiling Street, Huanggu District, Shenyang, China
| | - Yanyan Cheng
- Department of Pharmacology, State University of New York, Upstate Medical University, Syracuse, New York, United States of America.,SUNY Upstate Cancer Research Institute, State University of New York, Upstate Medical University, Syracuse, New York, United States of America.,Department of Medicine, Liaoning University of Chinese Traditional Medicine, No. 33 Beiling Street, Huanggu District, Shenyang, China
| | - Wang Tian
- Department of Pharmacology, State University of New York, Upstate Medical University, Syracuse, New York, United States of America.,SUNY Upstate Cancer Research Institute, State University of New York, Upstate Medical University, Syracuse, New York, United States of America
| | - Maocai Yan
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, United States of America
| | - Guanlin Yang
- Department of Medicine, Liaoning University of Chinese Traditional Medicine, No. 33 Beiling Street, Huanggu District, Shenyang, China
| | - Jing An
- Department of Pharmacology, State University of New York, Upstate Medical University, Syracuse, New York, United States of America.,SUNY Upstate Cancer Research Institute, State University of New York, Upstate Medical University, Syracuse, New York, United States of America.,Department of Medicine, University of California San Diego, La Jolla, California, United States of America
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37
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Jun S, Jung YS, Suh HN, Wang W, Kim MJ, Oh YS, Lien EM, Shen X, Matsumoto Y, McCrea PD, Li L, Chen J, Park JI. LIG4 mediates Wnt signalling-induced radioresistance. Nat Commun 2016; 7:10994. [PMID: 27009971 PMCID: PMC4820809 DOI: 10.1038/ncomms10994] [Citation(s) in RCA: 86] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2015] [Accepted: 02/05/2016] [Indexed: 01/13/2023] Open
Abstract
Despite the implication of Wnt signalling in radioresistance, the underlying mechanisms are unknown. Here we find that high Wnt signalling is associated with radioresistance in colorectal cancer (CRC) cells and intestinal stem cells (ISCs). We find that LIG4, a DNA ligase in DNA double-strand break repair, is a direct target of β-catenin. Wnt signalling enhances non-homologous end-joining repair in CRC, which is mediated by LIG4 transactivated by β-catenin. During radiation-induced intestinal regeneration, LIG4 mainly expressed in the crypts is conditionally upregulated in ISCs, accompanied by Wnt/β-catenin signalling activation. Importantly, among the DNA repair genes, LIG4 is highly upregulated in human CRC cells, in correlation with β-catenin hyperactivation. Furthermore, blocking LIG4 sensitizes CRC cells to radiation. Our results reveal the molecular mechanism of Wnt signalling-induced radioresistance in CRC and ISCs, and further unveils the unexpected convergence between Wnt signalling and DNA repair pathways in tumorigenesis and tissue regeneration. The Wnt/β-catenin signalling pathway contributes to radio resistance in intestinal stem cells but the underlying mechanism is currently unknown. In this study, the authors demonstrate that LIG4, a DNA ligase involved in the DNA repair process, is a direct target of β-catenin and it specifically mediates non-homologous end joining repair in colorectal cancer cells.
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Affiliation(s)
- Sohee Jun
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| | - Youn-Sang Jung
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| | - Han Na Suh
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| | - Wenqi Wang
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| | - Moon Jong Kim
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| | - Young Sun Oh
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| | - Esther M Lien
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| | - Xi Shen
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| | - Yoshihisa Matsumoto
- Research Laboratory for Nuclear Reactors, Tokyo Institute of Technology, Tokyo 152-8550, Japan
| | - Pierre D McCrea
- Department of Molecular Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.,Graduate School of Biomedical Sciences at Houston, The University of Texas Health Science Center and MD Anderson Cancer Center, Houston, Texas 77030, USA.,Program in Genes and Development, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| | - Lei Li
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.,Graduate School of Biomedical Sciences at Houston, The University of Texas Health Science Center and MD Anderson Cancer Center, Houston, Texas 77030, USA.,Program in Genes and Development, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| | - Junjie Chen
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.,Graduate School of Biomedical Sciences at Houston, The University of Texas Health Science Center and MD Anderson Cancer Center, Houston, Texas 77030, USA.,Program in Genes and Development, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| | - Jae-Il Park
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.,Graduate School of Biomedical Sciences at Houston, The University of Texas Health Science Center and MD Anderson Cancer Center, Houston, Texas 77030, USA.,Program in Genes and Development, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
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38
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Malik A, Sultana M, Qazi A, Qazi MH, Parveen G, Waquar S, Ashraf AB, Rasool M. Role of Natural Radiosensitizers and Cancer Cell Radioresistance: An Update. Anal Cell Pathol (Amst) 2016; 2016:6146595. [PMID: 26998418 PMCID: PMC4779816 DOI: 10.1155/2016/6146595] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2016] [Accepted: 02/01/2016] [Indexed: 11/17/2022] Open
Abstract
Cancer originates from genetic mutations accumulation. Cancer stem cells have been depicted as tumorigenic cells that can differentiate and self-renew. Cancer stem cells are thought to be resistant to conventional therapy like chemotherapy and radiation therapy. Radiation therapy and chemotherapy damage carcinomic DNA cells. Because of the ability of cancer stem cells to self-renew and reproduce malignant tumors, they are the subject of intensive research. In this review, CSCs radioresistant mechanisms which include DNA damage response and natural radiosensitizers have been summed up. Reactive oxygen species play an important role in different physiological processes. ROS scavenging is responsible for regulation of reactive oxygen species generation. A researcher has proved that microRNAs regulate tumor radiation resistance. Ionizing radiation does not kill the cancer cells; rather, IR just slows down the signs and symptoms. Ionizing radiation damages DNA directly/indirectly. IR is given mostly in combination with other chemo/radiotherapies. We briefly described here the behavior of cancer stem cells and radioresistance therapies in cancer treatment. To overcome radioresistance in treatment of cancer, strategies like fractionation modification, treatment in combination, inflammation modification, and overcoming hypoxic tumor have been practiced. Natural radiosensitizers, for example, curcumin, genistein, and quercetin, are more beneficial than synthetic compounds.
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Affiliation(s)
- Arif Malik
- Institute of Molecular Biology and Biotechnology (IMBB), The University of Lahore, Pakistan
| | - Misbah Sultana
- Institute of Molecular Biology and Biotechnology (IMBB), The University of Lahore, Pakistan
| | - Aamer Qazi
- Center for Research in Molecular Medicine (CRiMM), The University of Lahore, Pakistan
| | - Mahmood Husain Qazi
- Center for Research in Molecular Medicine (CRiMM), The University of Lahore, Pakistan
| | - Gulshan Parveen
- Institute of Molecular Biology and Biotechnology (IMBB), The University of Lahore, Pakistan
| | - Sulayman Waquar
- Institute of Molecular Biology and Biotechnology (IMBB), The University of Lahore, Pakistan
| | - Abdul Basit Ashraf
- University College of Medicine and Dentistry, The University of Lahore, Pakistan
| | - Mahmood Rasool
- Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University, Jeddah, Saudi Arabia
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39
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WNT signaling in glioblastoma and therapeutic opportunities. J Transl Med 2016; 96:137-50. [PMID: 26641068 DOI: 10.1038/labinvest.2015.140] [Citation(s) in RCA: 195] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2015] [Revised: 09/19/2015] [Accepted: 10/06/2015] [Indexed: 12/20/2022] Open
Abstract
WNTs and their downstream effectors regulate proliferation, death, and migration and cell fate decision. Deregulation of WNT signaling is associated with various cancers including GBM, which is the most malignant primary brain cancer. In this review, we will summarize the experimental evidence supporting oncogenic roles of WNT signaling in GBM and discuss current progress in the targeting of WNT signaling as an anti-cancer approach. In particular, we will focus on (1) genetic and epigenetic alterations that lead to aberrant WNT pathway activation in GBM, (2) WNT-mediated control of GBM stem cell maintenance and invasion, and (3) cross-talk between WNT and other signaling pathways in GBM. We will then review the discovery of agents that can inhibit WNT signaling in preclinical models and the current status of human clinical trials.
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40
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Lamb R, Harrison H, Smith DL, Townsend PA, Jackson T, Ozsvari B, Martinez-Outschoorn UE, Pestell RG, Howell A, Lisanti MP, Sotgia F. Targeting tumor-initiating cells: eliminating anabolic cancer stem cells with inhibitors of protein synthesis or by mimicking caloric restriction. Oncotarget 2016; 6:4585-601. [PMID: 25671304 PMCID: PMC4467101 DOI: 10.18632/oncotarget.3278] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2014] [Accepted: 01/21/2015] [Indexed: 01/03/2023] Open
Abstract
We have used an unbiased proteomic profiling strategy to identify new potential therapeutic targets in tumor-initiating cells (TICs), a.k.a., cancer stem cells (CSCs). Towards this end, the proteomes of mammospheres from two breast cancer cell lines were directly compared to attached monolayer cells. This allowed us to identify proteins that were highly over-expressed in CSCs and/or progenitor cells. We focused on ribosomal proteins and protein folding chaperones, since they were markedly over-expressed in mammospheres. Overall, we identified >80 molecules specifically associated with protein synthesis that were commonly upregulated in mammospheres. Most of these proteins were also transcriptionally upregulated in human breast cancer cells in vivo, providing evidence for their potential clinical relevance. As such, increased mRNA translation could provide a novel mechanism for enhancing the proliferative clonal expansion of TICs. The proteomic findings were functionally validated using known inhibitors of protein synthesis, via three independent approaches. For example, puromycin (which mimics the structure of tRNAs and competitively inhibits protein synthesis) preferentially targeted CSCs in both mammospheres and monolayer cultures, and was ~10-fold more potent for eradicating TICs, than “bulk” cancer cells. In addition, rapamycin, which inhibits mTOR and hence protein synthesis, was very effective at reducing mammosphere formation, at nanomolar concentrations. Finally, mammosphere formation was also markedly inhibited by methionine restriction, which mimics the positive effects of caloric restriction in cultured cells. Remarkably, mammosphere formation was >18-fold more sensitive to methionine restriction and replacement, as directly compared to monolayer cell proliferation. Methionine is absolutely required for protein synthesis, since every protein sequence starts with a methionine residue. Thus, the proliferation and survival of CSCs is very sensitive to the inhibition of protein synthesis, using multiple independent approaches. Our findings have important clinical implications, since they may also explain the positive therapeutic effects of PI3-kinase inhibitors and AKT inhibitors, as they ultimately converge on mTOR signaling and would block protein synthesis. We conclude that inhibition of mRNA translation by pharmacological or protein/methionine restriction may be effective strategies for eliminating TICs. Our data also indicate a novel mechanism by which caloric/protein restriction may reduce tumor growth, by targeting protein synthesis in anabolic tumor-initiating cancer cells.
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Affiliation(s)
- Rebecca Lamb
- The Manchester Centre for Cellular Metabolism (MCCM), Institute of Cancer Sciences, University of Manchester, UK.,The Breakthrough Breast Cancer Research Unit, Institute of Cancer Sciences, University of Manchester, UK
| | - Hannah Harrison
- The Manchester Centre for Cellular Metabolism (MCCM), Institute of Cancer Sciences, University of Manchester, UK.,The Breakthrough Breast Cancer Research Unit, Institute of Cancer Sciences, University of Manchester, UK
| | - Duncan L Smith
- The Cancer Research UK Manchester Institute, University of Manchester, UK
| | - Paul A Townsend
- The Manchester Centre for Cellular Metabolism (MCCM), Institute of Cancer Sciences, University of Manchester, UK
| | - Thomas Jackson
- The Manchester Centre for Cellular Metabolism (MCCM), Institute of Cancer Sciences, University of Manchester, UK
| | - Bela Ozsvari
- The Manchester Centre for Cellular Metabolism (MCCM), Institute of Cancer Sciences, University of Manchester, UK.,The Breakthrough Breast Cancer Research Unit, Institute of Cancer Sciences, University of Manchester, UK
| | | | | | - Anthony Howell
- The Manchester Centre for Cellular Metabolism (MCCM), Institute of Cancer Sciences, University of Manchester, UK.,The Breakthrough Breast Cancer Research Unit, Institute of Cancer Sciences, University of Manchester, UK
| | - Michael P Lisanti
- The Manchester Centre for Cellular Metabolism (MCCM), Institute of Cancer Sciences, University of Manchester, UK.,The Breakthrough Breast Cancer Research Unit, Institute of Cancer Sciences, University of Manchester, UK
| | - Federica Sotgia
- The Manchester Centre for Cellular Metabolism (MCCM), Institute of Cancer Sciences, University of Manchester, UK.,The Breakthrough Breast Cancer Research Unit, Institute of Cancer Sciences, University of Manchester, UK
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41
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Chang HW, Nam HY, Kim HJ, Moon SY, Kim MR, Lee M, Kim GC, Kim SW, Kim SY. Effect of β-catenin silencing in overcoming radioresistance of head and neck cancer cells by antagonizing the effects of AMPK on Ku70/Ku80. Head Neck 2015; 38 Suppl 1:E1909-17. [PMID: 26713771 DOI: 10.1002/hed.24347] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2015] [Revised: 09/09/2015] [Accepted: 10/17/2015] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND We attempted to elucidate the mechanism of cell death after radiation by studying how β-catenin silencing controls the radiation sensitivity of radioresistant head and neck cancer cells. METHODS The most radioresistant cancer cell line (AMC-HN-9) was selected for study. Targeted silencing of β-catenin was used on siRNAs. Sensitivity to radiation was examined using clonogenic and methylthiazol tetrazolium (MTT) assays. RESULTS A combination of irradiation plus β-catenin silencing led to a significant reduction in the inherent radioresistance of AMC-HN-9 cells. Although expression of Ku70/80 was upregulated in AMC-HN-9 cells after irradiation, Ku70/80 was dramatically decreased in a combination of irradiation and β-catenin silencing. Interestingly, irradiation-induced Ku70/80 was completely prevented by β-catenin silencing-induced LKB1/AMP-activated protein kinase (LKB1/AMPK) signal. CONCLUSION The LKB1/AMPK pathway might relay the signal between the Wnt/β-catenin pathway and the Ku70/Ku80 DNA repair machinery, and play a decisive role in fine-tuning the responses of cancer cells to irradiation. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1909-E1917, 2016.
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Affiliation(s)
- Hyo Won Chang
- Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Hae Yun Nam
- Departments of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Hyo Jung Kim
- Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - So Young Moon
- Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Mi Ra Kim
- Department of Otorhinolaryngology-Head and Neck Surgery, Inje University College of Medicine, Haeundae Paik Hospital, Busan, Republic of Korea
| | - Myungjin Lee
- Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Gui Chul Kim
- Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Seong Who Kim
- Departments of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Sang Yoon Kim
- Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.,Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea
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42
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Wang L, Tian H, Yuan J, Wu H, Wu J, Zhu X. CONSORT: Sam68 Is Directly Regulated by MiR-204 and Promotes the Self-Renewal Potential of Breast Cancer Cells by Activating the Wnt/Beta-Catenin Signaling Pathway. Medicine (Baltimore) 2015; 94:e2228. [PMID: 26656364 PMCID: PMC5008509 DOI: 10.1097/md.0000000000002228] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Breast cancer stem cells (BCSCs) are considered to be responsible for recurrence in breast cancer. The 68 kDa Src-associated protein in mitosis (Sam68) has been linked to the development and progression of breast cancer; however, the posttranscriptional regulation and role of Sam68 in BCSC self-renewal remain unclear.Sam68 was ectopically overexpressed or knocked down using a siRNA; the self-renewal potential of breast cancer cell lines was assessed using flow cytometry, in vitro mammosphere culture and a xenograft model in NOD/SCID mice. Activation of beta-catenin was assessed by immunohistochemical staining, Western blotting, and luciferase reporter gene assays. The ArrayExpress dataset GSE45666 was used to identify conserved microRNAs downregulated in breast cancer; real-time PCR, Western blotting, luciferase reporter assay, and xenografted tumor model were used to confirm miR-204 regulated Sam68.We found that endogenous Sam68 expression correlated positively with the self-renewal potential of breast cancer cell lines. Overexpression of Sam68 promoted, whereas knockdown reduced, breast cancer cell self-renewal potential in vitro and tumorigenicity in vivo. The Wnt/beta-catenin pathway was identified as a functional mediator of Sam68-induced self-renewal in SKBR-3 and MCF-7 cells. Furthermore, miR-204 was found to be frequently downregulated in human breast cancer and confirmed to directly target Sam68; miR-204 inhibited the self-renewal of breast cancer cell lines by targeting and suppressing Sam68.Our study reveals that Sam68 is regulated by miR-204 and may play an important role in the self-renewal of BCSCs via activating the Wnt/beta-catenin pathway. Sam68 may represent a novel therapeutic target for breast cancer.
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Affiliation(s)
- Lan Wang
- From the Department of Pathogen Biology and Immunology, School of Basic Courses, Guangdong Pharmaceutical University, Guangzhou, China (LW, HW); Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China (HT, XZ); and Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong, China (HT, JY, JW, XZ)
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43
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Yang ZX, Sun YH, He JG, Cao H, Jiang GQ. Increased activity of CHK enhances the radioresistance of MCF-7 breast cancer stem cells. Oncol Lett 2015; 10:3443-3449. [PMID: 26788148 PMCID: PMC4665200 DOI: 10.3892/ol.2015.3777] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2014] [Accepted: 07/16/2015] [Indexed: 01/02/2023] Open
Abstract
The resistance of breast cancer to radiotherapy remains a major obstacle to successful cancer management. Radiotherapy may result in DNA damage and activate breast cancer stem cells. DNA damage may lead to activation of the checkpoint kinase (CHK) signaling pathway, of which debromohymenialdisine (DBH) is a specific inhibitor. Radiotherapy also increases the expression of phosphorylated CHK1/2 (pCHK1/2) in the breast cancer cell line, MCF-7, in vitro in a dose-dependent manner. DBH is a relatively stable effective inhibitor that significantly reduces pCHK1/2 expression and MCF-7 proliferation. Low-dose radiotherapy combined with DBH resulted in a higher MCF-7 inhibition rate compared with high-dose radiation alone. This result indicates that the inhibition of the CHK1/2 signal pathway may significantly reduce DNA damage within radiated cells. Radiotherapy may also regulate the proportion of CD44+/CD24− MCF-7 cancer stem cells in a dose- and time-dependent manner. However, the stem cell proportion of MCF-7 cells was significantly reduced by treatment with DBH. The inhibition is relatively stable and time dependent. Significant reductions were observed after 3 days of culture (P<0.01). The results of the present study indicate that the DBH-induced downregulation of CHK may provide a novel method of enhancing the effect of radiotherapy and reducing stem cell survival in the MCF-7 cell line.
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Affiliation(s)
- Zhi-Xue Yang
- Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China
| | - Yi-Hui Sun
- Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China
| | - Jian-Gang He
- Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China
| | - Hua Cao
- Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China
| | - Guo-Qin Jiang
- Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China
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44
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Williams KE, Bundred NJ, Landberg G, Clarke RB, Farnie G. Focal adhesion kinase and Wnt signaling regulate human ductal carcinoma in situ stem cell activity and response to radiotherapy. Stem Cells 2015; 33:327-41. [PMID: 25187396 DOI: 10.1002/stem.1843] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2014] [Accepted: 08/15/2014] [Indexed: 12/23/2022]
Abstract
Cancer stem cells (CSCs) can avoid or efficiently repair DNA damage from radio and chemotherapy, which suggests they play a role in disease recurrence. Twenty percentage of patients treated with surgery and radiotherapy for ductal carcinoma in situ (DCIS) of the breast recur and our previous data show that high grade DCIS have increased numbers of CSCs. Here, we investigate the role of focal adhesion kinase (FAK) and Wnt pathways in DCIS stem cells and their capacity to survive irradiation. Using DCIS cell lines and patient samples, we demonstrate that CSC-enriched populations are relatively radioresistant and possess high FAK activity. Immunohistochemical studies of active FAK in DCIS tissue show high expression was associated with a shorter median time to recurrence. Treatment with a FAK inhibitor or FAK siRNA in nonadherent and three-dimensional matrigel culture reduced mammosphere formation, and potentiated the effect of 2 Gy irradiation. Moreover, inhibition of FAK in vitro and in vivo decreased self-renewal capacity, levels of Wnt3a and B-Catenin revealing a novel FAK-Wnt axis regulating DCIS stem cell activity. Overall, these data establish that the FAK-Wnt axis is a promising target to eradicate self-renewal capacity and progression of human breast cancers.
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Affiliation(s)
- Kathryn E Williams
- Surgical Oncology, University Hospital of South Manchester NHS Foundation Trust, Wythenshawe Hospital, Education and Research Centre, Manchester, United Kingdom; Cancer Stem Cell Research, University of Manchester, Institute of Cancer Sciences, Manchester Academic Health Science Centre, The Christie NHS Foundation Trust, Manchester, United Kingdom
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45
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Penthala NR, Crooks PA, Freeman ML, Sekhar KR. Development and validation of a novel assay to identify radiosensitizers that target nucleophosmin 1. Bioorg Med Chem 2015; 23:3681-6. [PMID: 25922180 PMCID: PMC4418231 DOI: 10.1016/j.bmc.2015.04.018] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2015] [Revised: 03/21/2015] [Accepted: 04/03/2015] [Indexed: 10/23/2022]
Abstract
A series of indole analogs that are synthesized using the scaffold of a potent radiosensitizer, YTR107, were tested for their ability to alter the solubility of phosphorylated nucleophosmin 1 (pNPM1). NPM1 is critical for DNA double strand break (DSB) repair. In response to formation of DNA DSBs, phosphorylated T199 NPM1 binds to ubiquitinated chromatin, in a RNF8/RNF168-dependent manner, forming irradiation-induced foci (IRIF) that promote repair of DNA DSBs. A Western blot assay was developed using lead molecule, YTR107, for the purpose of screening newly synthesized molecules that target pNPM1 in irradiated cells. A colony formation assay was used to demonstrate the radiosensitization properties of the compounds. Compounds that enhanced the extractability of pNPM1 upon radiation treatment possessed radiosensitization properties.
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Affiliation(s)
- Narsimha R Penthala
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - Peter A Crooks
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - Michael L Freeman
- Department of Radiation Oncology, Vanderbilt University School Medicine, Nashville, TN 37232, USA
| | - Konjeti R Sekhar
- Department of Radiation Oncology, Vanderbilt University School Medicine, Nashville, TN 37232, USA.
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46
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Wei W, Lewis MT. Identifying and targeting tumor-initiating cells in the treatment of breast cancer. Endocr Relat Cancer 2015; 22:R135-55. [PMID: 25876646 PMCID: PMC4447610 DOI: 10.1530/erc-14-0447] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/07/2015] [Indexed: 01/05/2023]
Abstract
Breast cancer is the most common cancer in women (excluding skin cancer), and it is the second leading cause of cancer-related deaths. Although conventional and targeted therapies have improved survival rates, there are still considerable challenges in treating breast cancer, including treatment resistance, disease recurrence, and metastasis. Treatment resistance can be either de novo - because of traits that tumor cells possess before treatment - or acquired - because of traits that tumor cells gain in response to treatment. A recently proposed mechanism of de novo resistance invokes the existence of a specialized subset of cancer cells defined as tumor-initiating cells (TICs), or cancer stem cells (CSCs). TICs have the capacity to self-renew and to generate new tumors that consist entirely of clonally derived cell types present in the parental tumor. There are data to suggest that TICs are resistant to many conventional cancer therapies and that they can survive treatment in spite of dramatic shrinkage of the tumor. Residual TICs can then eventually regrow, which results in disease relapse. It has also been hypothesized that TIC may be responsible for metastatic disease. If these hypotheses are correct, targeting TICs may be imperative for achieving a cure. In the present review, we discuss evidence for breast TICs and their apparent resistance to conventional chemotherapy and radiotherapy as well as to various targeted therapies. We also address the potential impact of breast TIC plasticity and metastatic potential on therapeutic strategies. Finally, we describe several genes and signaling pathways that appear to be important for TIC function and may represent promising therapeutic targets.
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Affiliation(s)
- Wei Wei
- Baylor College of MedicineLester and Sue Smith Breast Center, Houston, Texas, USADepartments of Molecular and Cellular BiologyRadiologyBaylor College of Medicine, One Baylor Plaza, BCM600, Room N1210, Houston, Texas 77030, USA Baylor College of MedicineLester and Sue Smith Breast Center, Houston, Texas, USADepartments of Molecular and Cellular BiologyRadiologyBaylor College of Medicine, One Baylor Plaza, BCM600, Room N1210, Houston, Texas 77030, USA
| | - Michael T Lewis
- Baylor College of MedicineLester and Sue Smith Breast Center, Houston, Texas, USADepartments of Molecular and Cellular BiologyRadiologyBaylor College of Medicine, One Baylor Plaza, BCM600, Room N1210, Houston, Texas 77030, USA Baylor College of MedicineLester and Sue Smith Breast Center, Houston, Texas, USADepartments of Molecular and Cellular BiologyRadiologyBaylor College of Medicine, One Baylor Plaza, BCM600, Room N1210, Houston, Texas 77030, USA Baylor College of MedicineLester and Sue Smith Breast Center, Houston, Texas, USADepartments of Molecular and Cellular BiologyRadiologyBaylor College of Medicine, One Baylor Plaza, BCM600, Room N1210, Houston, Texas 77030, USA
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47
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Kazemi T, Younesi V, Jadidi-Niaragh F, Yousefi M. Immunotherapeutic approaches for cancer therapy: An updated review. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2015; 44:769-79. [PMID: 25801036 DOI: 10.3109/21691401.2015.1019669] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
In spite of specific immune effector mechanisms raised against tumor cells, there are mechanisms employed by the tumor cells to keep them away from immune recognition and elimination; some of these mechanisms have been identified, while others are still poorly understood. Manipulation or augmentation of specific antitumor immune responses are now the preferred approaches for treatment of malignancies, and traditional therapeutic approaches are being replaced by the use of agents which potentiate immune effector mechanisms, broadly called "immunotherapy". Cancer immunotherapy is generally classified into two main classes including active and passive methods. Interventions to augment the immune system of the patient, for example, vaccination or adjuvant therapy, actively promote antitumor effector mechanisms to improve cancer elimination. On the other hand, administration of specific monoclonal antibodies (mAbs) against different tumor antigens and adoptive transfer of genetically-modified specific T cells are currently the most rapidly developing approaches for cancer targeted therapy. In this review, we will discuss the different modalities for active and passive immunotherapy for cancer.
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Affiliation(s)
- Tohid Kazemi
- a Immunology Research Center, Tabriz University of Medical Sciences , Tabriz , Iran.,b Department of Immunology , Faculty of Medicine, Tabriz University of Medical Sciences , Tabriz , Iran
| | - Vahid Younesi
- c Department of Immunology , School of Public Health, Tehran University of Medical Sciences , Tehran , Iran
| | - Farhad Jadidi-Niaragh
- c Department of Immunology , School of Public Health, Tehran University of Medical Sciences , Tehran , Iran
| | - Mehdi Yousefi
- a Immunology Research Center, Tabriz University of Medical Sciences , Tabriz , Iran.,b Department of Immunology , Faculty of Medicine, Tabriz University of Medical Sciences , Tabriz , Iran
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48
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Zhang H, Luo H, Hu Z, Peng J, Jiang Z, Song T, Wu B, Yue J, Zhou R, Xie R, Chen T, Wu S. Targeting WISP1 to sensitize esophageal squamous cell carcinoma to irradiation. Oncotarget 2015; 6:6218-34. [PMID: 25749038 PMCID: PMC4467433 DOI: 10.18632/oncotarget.3358] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2014] [Accepted: 01/13/2015] [Indexed: 01/12/2023] Open
Abstract
Radiotherapy is a primary treatment modality for esophageal squamous cell carcinoma (ESCC). However, most of patients benefited little from radiotherapy due to refractory radioresistance. We found that WISP1, a downstream target gene of Wnt/β-catenin pathway, was re-expressed in 67.3% of ESCC patients as an oncofetal gene. Expression of WISP1 predicted prognosis of ESCC patients treated with radiotherapy. Overall survival in WISP1-positive patients was significantly poorer than in WISP1-negative patients. Serum concentration of WISP1 after radiotherapy reversely correlated with relapse-free survival. Gain and loss of function studies confirmed that WISP1 mediated radioresistance both in esophageal squamous cancer cells and in xenograft tumor models. Further studies revealed that WISP1 contributed to radioresistance primarily by repressing irradiation-induced DNA damage and activating PI3K kinase. LncRNA BOKAS was up-regulated following radiation and promoted WISP1 expression and resultant radioresistance. Furthermore, WISP1 facilitated its own expression in response to radiation, creating a positive feedback loop and increased radioresistance. Our study revealed WISP1 as a potential target to overcome radioresistance in ESCC.
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Affiliation(s)
- Hongfang Zhang
- Hangzhou Cancer Institution, Hangzhou Cancer Hospital, Hangzhou, China
| | - Honglei Luo
- Department of Radiotherapy, Huai'an First People's Hospital, Huai'an, China
| | - Zhaoyang Hu
- Hangzhou Cancer Institution, Hangzhou Cancer Hospital, Hangzhou, China
| | - Jin Peng
- Department of Radiotherapy, Huai'an First People's Hospital, Huai'an, China
| | - Zhenzhen Jiang
- Hangzhou Cancer Institution, Hangzhou Cancer Hospital, Hangzhou, China
| | - Tao Song
- Hangzhou Cancer Institution, Hangzhou Cancer Hospital, Hangzhou, China
| | - Bo Wu
- Hangzhou Cancer Institution, Hangzhou Cancer Hospital, Hangzhou, China
| | - Jing Yue
- Hangzhou Cancer Institution, Hangzhou Cancer Hospital, Hangzhou, China
| | - Rongjing Zhou
- Department of Pathology, Hangzhou Cancer Hospital, Hangzhou, China
| | - Ruifei Xie
- Hangzhou Cancer Institution, Hangzhou Cancer Hospital, Hangzhou, China
- Department of Bio-Informatics, Hangzhou Cancer Hospital, Hangzhou, China
| | - Tian Chen
- Hangzhou Cancer Institution, Hangzhou Cancer Hospital, Hangzhou, China
| | - Shixiu Wu
- Hangzhou Cancer Institution, Hangzhou Cancer Hospital, Hangzhou, China
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49
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Debeb BG, Smith DL, Li L, Larson R, Xu W, Woodward WA. Differential effect of phosphorylation-defective survivin on radiation response in estrogen receptor-positive and -negative breast cancer. PLoS One 2015; 10:e0120719. [PMID: 25763854 PMCID: PMC4357387 DOI: 10.1371/journal.pone.0120719] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2014] [Accepted: 01/26/2015] [Indexed: 01/18/2023] Open
Abstract
Survivin is a key member of the inhibitor of apoptosis protein family, and is considered a promising therapeutic target due to its universal overexpression in cancers. Survivin is implicated in cellular radiation response through its role in apoptosis, cell division, and DNA damage response. In the present study, analysis of publically available data sets showed that survivin gene expression increased with breast cancer stage (p < 0.00001) and was significantly higher in estrogen receptor-negative cancers as compared to estrogen receptor-positive cancers (p = 9e-46). However, survivin was prognostic in estrogen receptor-positive tumors (p = 0.03) but not in estrogen receptor-negative tumors (p = 0.28). We assessed the effect of a survivin dominant-negative mutant on colony-formation (2D) and mammosphere-formation (3D) efficiency, and radiation response in the estrogen receptor-positive MCF7 and estrogen receptor-negative SUM149 breast cancer cell lines. The colony-formation efficiency was significantly lower in the dominant-negative survivin-transduced cells versus control MCF7 cells (0.42 vs. 0.58, p < 0.01), but it was significantly higher in dominant-negative population versus control-transduced SUM149 cells (0.29 vs. 0.20, p < 0.01). A similar, non-significant, trend in mammosphere-formation efficiency was observed. We compared the radiosensitivity of cells stably expressing dominant-negative survivin with their controls in both cell lines under 2D and 3D culture conditions following exposure to increasing doses of radiation. We found that the dominant-negative populations were radioprotective in MCF7 cells but radiosensitive in SUM149 cells compared to the control-transduced population; further, Taxol was synergistic with the survivin mutant in SUM149 but not MCF7. Our data suggests that survivin modulation influences radiation response differently in estrogen receptor-positive and estrogen receptor-negative breast cancer subtypes, warranting further investigation.
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Affiliation(s)
- Bisrat G. Debeb
- Department of Radiation Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX, United States of America
| | - Daniel L. Smith
- Department of Radiation Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX, United States of America
| | - Li Li
- Department of Radiation Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX, United States of America
| | - Richard Larson
- Department of Radiation Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX, United States of America
| | - Wei Xu
- Department of Radiation Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX, United States of America
| | - Wendy A. Woodward
- Department of Radiation Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX, United States of America
- * E-mail:
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50
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Ma J, Cheng J, Gong Y, Tian L, Huang Q. Downregulation of Wnt signaling by sonic hedgehog activation promotes repopulation of human tumor cell lines. Dis Model Mech 2015; 8:385-91. [PMID: 25713298 PMCID: PMC4381337 DOI: 10.1242/dmm.018887] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2014] [Accepted: 02/12/2015] [Indexed: 12/12/2022] Open
Abstract
Tumor repopulation after radiotherapy is a big obstacle for clinical cancer therapy. The molecular mechanisms of tumor cell repopulation after radiotherapy remain unclear. This study investigated the role of sonic hedgehog (SHH) and Wnt signaling pathways in tumor repopulation after radiotherapy in an in vitro repopulation model. In this model, irradiated dying tumor cells functioned as feeder cells, whereas luciferase-labeled living tumor cells acted as reporter cells. Proliferation of reporter cells was measured by bioluminescence imaging. Results showed that irradiated dying HT29 and Panc1 tumor cells significantly stimulated the repopulation of living cells in their respective cultures. In HT29 and Panc1 cells, radiation significantly inhibited Wnt activity. In the irradiated dying HT29 and Panc1 cells, the level of the activated nuclear β-catenin was significantly decreased. Treatment with the Wnt agonist 68166 significantly decreased, whereas treatment with Wnt antagonist significantly increased, repopulation in HT29 and Panc1 tumor cells in a dose-dependent manner. β-catenin short-hairpin RNA (shRNA) also significantly promoted tumor cell repopulation. The level of secreted frizzled related protein-1 (SFRP1), hedgehog and Gli1 were increased in irradiated cells. Our results highlight the interaction between Wnt and SHH signaling pathways in dying tumor cells and suggest that downregulation of Wnt signaling after SHH activation is negatively associated with tumor repopulation.
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Affiliation(s)
- Jingjing Ma
- The Comprehensive Cancer Center & Shanghai Key Laboratory for Pancreatic Diseases, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 201620, China. Department of Pharmacy, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Jin Cheng
- The Comprehensive Cancer Center & Shanghai Key Laboratory for Pancreatic Diseases, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 201620, China
| | - Yanping Gong
- Experimental Research Center, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 201620, China
| | - Ling Tian
- Experimental Research Center, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 201620, China.
| | - Qian Huang
- The Comprehensive Cancer Center & Shanghai Key Laboratory for Pancreatic Diseases, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 201620, China.
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