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Ortiz N, Díaz C. Preclinical evaluation of fenretinide against primary and metastatic intestinal type‑gastric cancer. Oncol Lett 2024; 28:561. [PMID: 39372665 PMCID: PMC11450695 DOI: 10.3892/ol.2024.14694] [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: 05/15/2024] [Accepted: 08/20/2024] [Indexed: 10/08/2024] Open
Abstract
In recent years there has been a decline in the incidence of gastric cancer, however the high mortality rate has remained constant. The present study evaluated the potential effects of the retinoid fenretinide on the viability and migration of two cell lines, AGS and NCI-N87, that represented primary and metastatic intestinal gastric cancer subtypes, respectively. It was determined that a similar2 dose of fenretinide reduced the viability of both the primary and metastatic cell lines. In addition, it was demonstrated that combined treatment with fenretinide and cisplatin may affect the viability of both primary and metastatic gastric cancer cells. Furthermore, a wound healing assay demonstrated an inhibitory effect for fenretinide on cell migration. As part of the characterization of the mechanism of action, the effect of fenretinide on reactive oxygen species production and lipid droplet content was evaluated, with the latter as an indirect means of assessing autophagy. These results support the hypothesis of combining using fenretinide with conventional therapies to improve survival rates in advanced or metastatic gastric cancer.
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Affiliation(s)
- Natalia Ortiz
- Department of Biochemistry, School of Medicine, University of Costa Rica, San Pedro de Montes de Oca, San José 11501-2060, Costa Rica
| | - Cecilia Díaz
- Department of Biochemistry, School of Medicine, University of Costa Rica, San Pedro de Montes de Oca, San José 11501-2060, Costa Rica
- Institute Clodomiro Picado, Faculty of Microbiology, University of Costa Rica, San Pedro de Montes de Oca, San José 11501-2060, Costa Rica
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2
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Kofman K, Levin M. Bioelectric pharmacology of cancer: A systematic review of ion channel drugs affecting the cancer phenotype. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2024; 191:25-39. [PMID: 38971325 DOI: 10.1016/j.pbiomolbio.2024.07.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 05/21/2024] [Accepted: 07/04/2024] [Indexed: 07/08/2024]
Abstract
Cancer is a pernicious and pressing medical problem; moreover, it is a failure of multicellular morphogenesis that sheds much light on evolutionary developmental biology. Numerous classes of pharmacological agents have been considered as cancer therapeutics and evaluated as potential carcinogenic agents; however, these are spread throughout the primary literature. Here, we briefly review recent work on ion channel drugs as promising anti-cancer treatments and present a systematic review of the known cancer-relevant effects of 109 drugs targeting ion channels. The roles of ion channels in cancer are consistent with the importance of bioelectrical parameters in cell regulation and with the functions of bioelectric signaling in morphogenetic signals that act as cancer suppressors. We find that compounds that are well-known for having targets in the nervous system, such as voltage-gated ion channels, ligand-gated ion channels, proton pumps, and gap junctions are especially relevant to cancer. Our review suggests further opportunities for the repurposing of numerous promising candidates in the field of cancer electroceuticals.
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Affiliation(s)
- Karina Kofman
- Faculty of Dentistry, University of Toronto, Toronto, Canada
| | - Michael Levin
- Allen Discovery Center at Tufts University, USA; Wyss Institute for Biologically Inspired Engineering at Harvard University, USA.
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Guillén-Navarro D, González-Vázquez R, León-Ávila G, Giono-Cerezo S. Quorum Quenching with a Diffusible Signal Factor Analog in Stenotrophomonas maltophilia. Pathogens 2023; 12:1448. [PMID: 38133331 PMCID: PMC10746098 DOI: 10.3390/pathogens12121448] [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: 11/13/2023] [Revised: 12/04/2023] [Accepted: 12/06/2023] [Indexed: 12/23/2023] Open
Abstract
Stenotrophomonas maltophilia is a multidrug-resistant Gram-negative bacillus associated with nosocomial infections in intensive care units, and nowadays, its acquired resistance to trimethoprim-sulfamethoxazole (SXT) by sul genes within class 1 integrons is a worldwide health problem. Biofilm and motility are two of the major virulence factors in this bacterium and are auto-induced by the diffusible signal factor (DSF). In recent studies, retinoids have been used to inhibit (Quorum Quenching) these virulence factors and for their antimicrobial effect. The aim was to reduce biofilm formation and motility with retinoic acid (RA) in S. maltophilia SXT-resistant strains. Eleven SXT-resistant strains and two SXT-susceptible strains were tested for biofilm formation/reduction and planktonic/sessile cell viability with RA and SXT-MIC50/RA; motility (twitching, swimming, swarming) was measured with/without RA; and MLST typing was determined. The biofilm formation of the strains was classified as follows: 15.38% (2/13) as low, 61.54% (8/13) as moderate, and 23.08% (3/13) as high. It was significantly reduced with RA and SXT-MIC50/RA (p < 0.05); cell viability was not significantly reduced with RA (p > 0.05), but it was with SXT-MIC50/RA (p < 0.05); and swimming (p < 0.05) and swarming (p < 0.05) decreased significantly. MLST typing showed the first and novel strains of Mexican S. maltophilia registered in PubMLST (ST479-485, ST497, ST23, ST122, ST175, ST212, and ST300). In conclusion, RA reduced biofilm formation and motility without affecting cell viability; furthermore, antimicrobial synergism with SXT-MIC50/RA in different and novel STs of S. maltophilia was observed.
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Affiliation(s)
- Dafne Guillén-Navarro
- Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Departamento de Microbiología, Prolongación de Carpio y Plan de Ayala S/N, Col. Casco de Santo Tomás, Alcaldía Miguel Hidalgo, Mexico City 11340, Mexico
- Posgrado en Ciencias Quimicobiológicas, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prolongación de Carpio y Plan de Ayala S/N, Col. Casco de Santo Tomás, Alcaldía Miguel Hidalgo, Mexico City 11340, Mexico
| | - Rosa González-Vázquez
- Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Departamento de Microbiología, Prolongación de Carpio y Plan de Ayala S/N, Col. Casco de Santo Tomás, Alcaldía Miguel Hidalgo, Mexico City 11340, Mexico
- Instituto Mexicano del Seguro Social, Unidad Médica de Alta Especialidad, Hospital de Especialidades “Dr. Antonio Fraga Mouret”, Centro Médico Nacional La Raza. Seris y Zaachila S/N, Col. La Raza, Alcaldía Azcapotzalco, Mexico City 04960, Mexico
| | - Gloria León-Ávila
- Posgrado en Ciencias Quimicobiológicas, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prolongación de Carpio y Plan de Ayala S/N, Col. Casco de Santo Tomás, Alcaldía Miguel Hidalgo, Mexico City 11340, Mexico
- Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Departamento de Zoología, Prolongación de Carpio y Plan de Ayala S/N, Col. Casco de Santo Tomás, Alcaldía Miguel Hidalgo, Mexico City 11340, Mexico
| | - Silvia Giono-Cerezo
- Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Departamento de Microbiología, Prolongación de Carpio y Plan de Ayala S/N, Col. Casco de Santo Tomás, Alcaldía Miguel Hidalgo, Mexico City 11340, Mexico
- Posgrado en Ciencias Quimicobiológicas, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prolongación de Carpio y Plan de Ayala S/N, Col. Casco de Santo Tomás, Alcaldía Miguel Hidalgo, Mexico City 11340, Mexico
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Abstract
The full name of the FTO gene is fat mass and obesity-associated gene. In recent years, it has also been found that FTO is involved in m6A demethylation and regulates the progression of multiple cancers, including gastric cancer. The cancer stem cell theory argues that cancer stem cells are key factors in cancer metastasis, and inhibiting the expression of stemness genes is a good method to inhibit metastasis of gastric cancer. Currently, the role of the FTO gene in regulating stemness of gastric cancer cells is still unclear. By analyzing public databases, it was discovered that FTO gene expression was increased in gastric cancer, and high expression of FTO was associated with poor prognosis of patients with gastric cancer. After gastric cancer stem cells were isolated, it was found that FTO protein expression was increased in gastric cancer stem cells; stemness of gastric cancer cells was reduced after the FTO gene knockdown; subcutaneous tumors of nude mice were smaller than those of the control group after FTO knockdown; and stemness of gastric cancer cells was enhanced after FTO was overexpressed by plasmid. By reviewing additional literature and experimental validation, we found that SOX2 may be the factor by which FTO promotes the stemness of gastric cancer cells. Therefore, it was concluded that FTO could promote the stemness of gastric cancer cells, and targeting FTO may be a potential therapeutic approach for patients with metastatic gastric cancer. CTR number: TOP-IACUC-2021-0123.
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Affiliation(s)
- Mengqing Li
- Shenzhen Key Laboratory of Gastrointestinal Cancer Translational Research, Department of Oncology, Peking University Shenzhen Hospital, Cancer Institute of Shenzhen PKU-HKUST Medical Center, Shenzhen, China
- Department of Pathology, Peking University Shenzhen Hospital, Shenzhen, China
| | - Xuan Wu
- Shenzhen Key Laboratory of Gastrointestinal Cancer Translational Research, Department of Oncology, Peking University Shenzhen Hospital, Cancer Institute of Shenzhen PKU-HKUST Medical Center, Shenzhen, China
| | - Guan Li
- Department of Gastrointestinal Surgery, Peking University Shenzhen Hospital, Shenzhen, China
| | - Guoqing Lv
- Department of Gastrointestinal Surgery, Peking University Shenzhen Hospital, Shenzhen, China
| | - Shubin Wang
- Shenzhen Key Laboratory of Gastrointestinal Cancer Translational Research, Department of Oncology, Peking University Shenzhen Hospital, Cancer Institute of Shenzhen PKU-HKUST Medical Center, Shenzhen, China
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Microbiota-Derived Natural Products Targeting Cancer Stem Cells: Inside the Gut Pharma Factory. Int J Mol Sci 2023; 24:ijms24054997. [PMID: 36902427 PMCID: PMC10003410 DOI: 10.3390/ijms24054997] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 02/28/2023] [Accepted: 03/02/2023] [Indexed: 03/08/2023] Open
Abstract
Cancer stem cells (CSCs) have drawn much attention as important tumour-initiating cells that may also be crucial for recurrence after chemotherapy. Although the activity of CSCs in various forms of cancer is complex and yet to be fully elucidated, opportunities for therapies targeting CSCs exist. CSCs are molecularly distinct from bulk tumour cells, so they can be targeted by exploiting their signature molecular pathways. Inhibiting stemness has the potential to reduce the risk posed by CSCs by limiting or eliminating their capacity for tumorigenesis, proliferation, metastasis, and recurrence. Here, we briefly described the role of CSCs in tumour biology, the mechanisms involved in CSC therapy resistance, and the role of the gut microbiota in cancer development and treatment, to then review and discuss the current advances in the discovery of microbiota-derived natural compounds targeting CSCs. Collectively, our overview suggests that dietary intervention, toward the production of those identified microbial metabolites capable of suppressing CSC properties, is a promising approach to support standard chemotherapy.
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Ursino H, Zhang B, Ludtka C, Webb A, Allen JB. Hemocompatibility of all-trans retinoic acid-loaded citrate polymer coatings for vascular stents. REGENERATIVE ENGINEERING AND TRANSLATIONAL MEDICINE 2022; 8:579-592. [PMID: 36714809 PMCID: PMC9881644 DOI: 10.1007/s40883-022-00257-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 03/08/2022] [Accepted: 03/18/2022] [Indexed: 02/02/2023]
Abstract
Purpose Current strategies implementing drug-eluting polymer stent coatings fail to fully address the lasting effects of endothelial suppression which ultimately result in delayed reendothelialization and thrombogenic complications. The present study investigates the in vitro hemocompatibility of all-trans retinoic acid loaded poly (1,8-octanediol-co-citrate) coatings (AtRA-POC coatings) for advanced intravascular stent technology. The ability of these materials in supporting endothelial restoration via migration and proliferation while inhibiting smooth muscle cell growth is also explored. Methods Using in vitro models, the hemocompatibility of AtRA-loaded POC-coated cobalt chromium (CoCr) vascular stents was evaluated in terms of platelet and inflammatory activity. Platelet activity was quantified by platelet adhesion and platelet activation, further supported by SEM visualization. Inflammatory activity was quantified by the production of proinflammatory cytokines by THP1 monocytes. Lastly, in vitro wound healing and an 5-Ethynyl-2'deoxyuridine (EdU) and pico green DNA assays were used in quantitating endothelial and smooth muscle cell migration and proliferation. Results Experimental examinations of platelet adhesion and activation demonstrate significant reductions in the platelet response to POC coated AtRA loaded stents when compared to bare CoCr stents. Such findings reveal AtRA-POC coatings to have significantly improved hemocompatibility compared to that of bare metal stents and at least as good as POC alone. Similarly, in reference to LPS-stimulated controls, Human monocyte-like THP1 cells in culture with AtRA-POC-CoCr stents for 24 hours showed reduced detection of proinflammatory cytokines, comparable to that of bare CoCr and untreated controls. This result supports AtRA-POC coatings as possessing limited immunological potential. Observations from in vitro endothelial and smooth muscle cell investigations demonstrate the ability of the drug AtRA to allow cell processes involved in restoration of the endothelium while inhibiting smooth muscle cell processes. Conclusion This study demonstrates AtRA loaded POC coatings are hemocompatible, noninflammatory, and provide a promising strategy in enhancing vascular stent techniques and clinical integration. Possessing hemocompatibility and immunological compatibility that is at least as good as bare metal stents as clinical standards support the use of AtRA-POC coatings for vascular applications. Additionally, selectively reducing smooth muscle cell proliferation while supporting endothelial cell proliferation and migration further demonstrates the potential of these materials in significantly improving the state of vascular stent technology in the area of stent thrombosis and neointimal hyperplasia.
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Affiliation(s)
- Heather Ursino
- Univeristy of Florida, Materials Science and Engineering, Gainesville, FL, USA
| | - Bisheng Zhang
- Univeristy of Florida, Materials Science and Engineering, Gainesville, FL, USA
| | | | - Antonio Webb
- Univeristy of Florida, Materials Science and Engineering, Gainesville, FL, USA
| | - Josephine B. Allen
- Univeristy of Florida, Materials Science and Engineering, Gainesville, FL, USA
- Univeristy of Florida, Biomedical Engineering, Gainesville, FL, USA
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Ma ZL, Ding YL, Jing J, Du LN, Zhang XY, Liu HM, He PX. ATRA promotes PD-L1 expression to control gastric cancer immune surveillance. Eur J Pharmacol 2022; 920:174822. [DOI: 10.1016/j.ejphar.2022.174822] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 01/31/2022] [Accepted: 02/09/2022] [Indexed: 11/03/2022]
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A Novel In Situ Dendritic Cell Vaccine Triggered by Rose Bengal Enhances Adaptive Antitumour Immunity. J Immunol Res 2022; 2022:1178874. [PMID: 35155685 PMCID: PMC8824725 DOI: 10.1155/2022/1178874] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 12/08/2021] [Accepted: 01/15/2022] [Indexed: 02/08/2023] Open
Abstract
Dendritic cell- (DC-) based vaccination has emerged as a promising antitumour immunotherapy. However, overcoming immune tolerance and immunosuppression in the tumour microenvironment (TME) is still a great challenge. Recent studies have shown that Rose Bengal (RB) can effectively induce immunogenic cell death (ICD) in cancer cells, presenting whole tumour antigens for DC processing and presentation. However, the synergistic antitumour effect of combining intralesional RB with immature DCs (RB-iDCs) remains unclear. In the present study, we investigated whether RB-iDCs have superior antitumour effects compared with either single agent and evaluated the immunological mechanism of RB-iDCs in a murine lung cancer model. The results showed that intralesional RB-iDCs suppressed subcutaneous tumour growth and lung metastasis, which resulted in 100% mouse survival and significantly increased TNF-α production by CD8+ T cells. These effects were closely related to the induction of the expression of distinct ICD hallmarks by RB in both bulk cancer cells and cancer stem cells (CSCs), especially calreticulin (CRT), thus enhancing immune effector cell (i.e., CD4+, CD8+, and memory T cells) infiltration and attenuating the accumulation of immunosuppressive cells (i.e., Tregs, macrophages, and myeloid-derived suppressor cells (MDSCs)) in the TME. This study reveals that the RB-iDC vaccine can synergistically destroy the primary tumour, inhibit distant metastasis, and prevent tumour relapse in a lung cancer mouse model, which provides important preclinical data for the development of a novel combinatorial immunotherapy.
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Hsieh HL, Yu MC, Cheng LC, Yeh TS, Tsai MM. Molecular mechanism of therapeutic approaches for human gastric cancer stem cells. World J Stem Cells 2022; 14:76-91. [PMID: 35126829 PMCID: PMC8788185 DOI: 10.4252/wjsc.v14.i1.76] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 05/15/2021] [Accepted: 12/21/2021] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is a primary cause of cancer-related mortality worldwide, and even after therapeutic gastrectomy, survival rates remain poor. The presence of gastric cancer stem cells (GCSCs) is thought to be the major reason for resistance to anticancer treatment (chemotherapy or radiotherapy), and for the development of tumor recurrence, epithelial-mesenchymal transition, and metastases. Additionally, GCSCs have the capacity for self-renewal, differentiation, and tumor initiation. They also synthesize antiapoptotic factors, demonstrate higher performance of drug efflux pumps, and display cell plasticity abilities. Moreover, the tumor microenvironment (TME; tumor niche) that surrounds GCSCs contains secreted growth factors and supports angiogenesis and is thus responsible for the maintenance of the growing tumor. However, the genesis of GCSCs is unclear and exploration of the source of GCSCs is essential. In this review, we provide up-to-date information about GCSC-surface/intracellular markers and GCSC-mediated pathways and their role in tumor development. This information will support improved diagnosis, novel therapeutic approaches, and better prognosis using GCSC-targeting agents as a potentially effective treatment choice following surgical resection or in combination with chemotherapy and radiotherapy. To date, most anti-GCSC blockers when used alone have been reported as unsatisfactory anticancer agents. However, when used in combination with adjuvant therapy, treatment can improve. By providing insights into the molecular mechanisms of GCSCs associated with tumors in GC, the aim is to optimize anti-GCSCs molecular approaches for GC therapy in combination with chemotherapy, radiotherapy, or other adjuvant treatment.
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Affiliation(s)
- Hsi-Lung Hsieh
- Department of Nursing, Division of Basic Medical Sciences, Chang-Gung University of Science and Technology, Taoyuan 333, Taiwan
- Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan
- Department of Neurology, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Ming-Chin Yu
- Department of General Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan 333, Taiwan
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
- Department of General Surgery, New Taipei Municipal TuCheng Hospital, New Taipei 236, Taiwan
| | - Li-Ching Cheng
- Department of Nursing, Division of Basic Medical Sciences, Chang-Gung University of Science and Technology, Taoyuan 333, Taiwan
| | - Ta-Sen Yeh
- Department of General Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan 333, Taiwan
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
| | - Ming-Ming Tsai
- Department of Nursing, Division of Basic Medical Sciences, Chang-Gung University of Science and Technology, Taoyuan 333, Taiwan
- Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan
- Department of General Surgery, Chang Gung Memorial Hospital, Chiayi 613, Taiwan.
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Wang S, Liu J, Wu H, Jiang A, Zhao K, Yan K, Wu W, Han H, Zhang Y, Yang W. All-trans retinoic acid (ATRA) inhibits insufficient radiofrequency ablation (IRFA)-induced enrichment of tumor-initiating cells in hepatocellular carcinoma. Chin J Cancer Res 2021; 33:694-707. [PMID: 35125813 PMCID: PMC8742172 DOI: 10.21147/j.issn.1000-9604.2021.06.06] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 10/28/2021] [Indexed: 11/18/2022] Open
Abstract
OBJECTIVE Local recurrence of hepatocellular carcinoma (HCC) after radiofrequency ablation (RFA) treatment remains a serious problem. Tumor-initiating cells (TICs) are thought to be responsible for tumor relapse. Here, we investigated the effect of the TIC differentiation inducer, all-trans retinoic acid (ATRA), on RFA and explored the potential molecular mechanisms. METHODS The proportions of CD133+ and epithelial cell adhesion molecule (EpCAM)+ TICs in recurrent HCC after RFA and primary HCC were first determined in clinic. Then, the effect of heat intervention or insufficient RFA (IRFA) on the malignant potential of HCC cells, including cell migration, sphere formation ability, tumor growth, the proportion of CD133+ and EpCAM+ TICs and expression of stem cell-related genes, was evaluated in vitro andin vivo. Finally, the effect of ATRA on the tumor growth and the proportion of TICs was evaluated. RESULTS In clinical data, a higher proportion of CD133+ and EpCAM+ TICs was found in recurrent tumors than in primary tumors. In vitro heat intervention promoted the cell migration and sphere formation ability. Additionally, it increased the proportion of CD133+ and EpCAM+ TICs and the expression of stem cell-related genes. In addition, after IRFA the residual tumors in xenografts grew faster and had more TICs than untreated tumors. ATRA remarkably inhibited residual tumor growth after IRFA by elimination of TICs though the PI3K/AKT pathway. Combination treatment with ATRA resulted in longer survival outcomes in mouse xenografts than RFA alone. CONCLUSIONS ATRA, as a TIC differentiation inducer, could help to improve the effect of RFA treatment, which was partially attributed to its effect against TICs. The data indicated its potential as an alternative drug in the development of better therapeutic strategies for use in combination with RFA.
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Affiliation(s)
| | | | | | | | | | | | | | - Haibo Han
- Department of Clinical Laboratory, Peking University Cancer Hospital & Institute, Beijing 100142, China
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Wang C, Zhao D, Shu X, Wang K, Wang T, Lin X, Zhang D, Xia T, Qian S, Tang M, Yang W, Hu A, Zhao Q. Protective effects of all-trans retinoic acid against gastric premalignant lesions by repressing exosomal LncHOXA10-pyruvate carboxylase axis. J Cancer Res Clin Oncol 2021; 148:121-135. [PMID: 34632533 DOI: 10.1007/s00432-021-03820-2] [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: 06/17/2021] [Accepted: 09/24/2021] [Indexed: 10/20/2022]
Abstract
PURPOSE Long noncoding RNAs (LncRNAs) play a pivotal role in gastric tumorigenesis, while exosomes facilitate the LncRNAs transferring to recipient cells. However, the roles of exosomal LncRNAs in gastric premalignant lesions (GPL) remain unclear. METHODS We analyzed the expression of LncHOXA10 and its role in GPL progression. The protective effect of all-trans retinoic acid (ATRA) on GPL was explored in vitro and in vivo. RESULTS Here, we found that LncHOXA10 expression was obviously increased in serum exosomes and gastric tissues from individuals with GPL, and exosomal LncHOXA10 from patients with GPL markedly promoted the malignant progression of human gastric epithelial cell line GES-1. Furthermore, RNA-pulldown assay revealed that LncHOXA10 mainly interacted with pyruvate carboxylase (PC), an essential enzyme in various cellular metabolic pathways. In gastric tissues from patients with GPL and gastric cancer (GC), PC was also upregulated and positively correlated with LncHOXA10 expression, which predicted a poor prognosis as well. Moreover, PC silencing attenuated the malignant effects of exosomal LncHOXA10 on GES-1 cells. ATRA also ameliorated the deterioration of GPL and prevented the malignant progression of GPL by reducing exosomal LncHOXA10 and PC expression. CONCLUSIONS Collectively, the LncHOXA10-PC axis participated in the early stage of GC tumorigenesis, and ATRA might be useful to prevent GPL from developing into GC because it targets this axis.
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Affiliation(s)
- Chen Wang
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, China
| | - Didi Zhao
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, China
| | - Xing Shu
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, China
| | - Kexin Wang
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, China
| | - Tingting Wang
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, China
| | - Xiao Lin
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, China
| | - Daoming Zhang
- Department of Gastroenterology, Lujiang County People's Hospital, Hefei, Anhui, China
| | - Tao Xia
- Department of Gastroenterology, Lujiang County People's Hospital, Hefei, Anhui, China
| | - Shiqing Qian
- Department of Pathology, Lujiang County People's Hospital, Hefei, Anhui, China
| | - Min Tang
- Department of Gastroenterology and Hepatology, The Fourth Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Wanshui Yang
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, China
| | - Anla Hu
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, China.
| | - Qihong Zhao
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, China.
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Chen QH, Wu BK, Pan D, Sang LX, Chang B. Beta-carotene and its protective effect on gastric cancer. World J Clin Cases 2021; 9:6591-6607. [PMID: 34447808 PMCID: PMC8362528 DOI: 10.12998/wjcc.v9.i23.6591] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 05/16/2021] [Accepted: 06/22/2021] [Indexed: 02/06/2023] Open
Abstract
Beta-carotene is an important natural pigment that is very beneficial to human health. It is widely found in vegetables and fruits. The three main functions are antioxidant effects, cell gap junction-related functions and immune-related functions. Because of its diverse functions, beta-carotene is believed to prevent and treat many chronic diseases. Gastric cancer is one of the most important diseases it can treat. Gastric cancer is a type of cancer with a high incidence. Its etiology varies, and the pathogenesis is complex. Gastric cancer seriously affects human health. The role of beta-carotene, a natural nutrient, in gastric cancer has been explored by many researchers, including molecular mechanisms and epidemiological studies. Molecular studies have mainly focused on oxidative stress, cell cycle, signal transduction pathways and immune-related mechanisms of beta-carotene in gastric cancer. Many epidemiological surveys and cohort studies of patients with gastric cancer have been conducted, and the results of these epidemiological studies vary due to the use of different research methods and analysis of different regions. This paper will summarize the results of these studies, mainly in terms of molecular mechanisms and epidemiological research results, which will provide a systematic basis for future studies of the treatment and prognosis of gastric cancer. This paper will help researchers identify new research directions.
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Affiliation(s)
- Qian-Hui Chen
- Department of Intensive Care Unit, First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Bao-Kang Wu
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
| | - Dan Pan
- Department of Geriatrics, First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Li-Xuan Sang
- Department of Geriatrics, First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Bing Chang
- Department of Gastroenterology, First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
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Zhu B, Mao X, Man Y. Potential Drug Prediction of Glioblastoma Based on Drug Perturbation-Induced Gene Expression Signatures. BIOMED RESEARCH INTERNATIONAL 2021; 2021:6659701. [PMID: 33575336 PMCID: PMC7857867 DOI: 10.1155/2021/6659701] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 01/11/2021] [Accepted: 01/12/2021] [Indexed: 01/04/2023]
Abstract
OBJECTIVES Glioblastoma (GBM) is a malignant brain tumor which is the most common and aggressive type of central nervous system cancer, with high morbidity and mortality. Despite lots of systematic studies on the molecular mechanism of glioblastoma, the pathogenesis is still unclear, and effective therapies are relatively rare with surgical resection as the frequently therapeutic intervention. Identification of fundamental molecules and gene networks associated with initiation is critical in glioblastoma drug discovery. In this study, an approach for the prediction of potential drug was developed based on perturbation-induced gene expression signatures. METHODS We first collected RNA-seq data of 12 pairs of glioblastoma samples and adjacent normal samples from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified by DESeq2, and coexpression networks were analyzed with weighted gene correlation network analysis (WGCNA). Furthermore, key driver genes were detected based on the differentially expressed genes and potential chemotherapeutic drugs and targeted drugs were found by correlating the gene expression profiles with drug perturbation database. Finally, RNA-seq data of glioblastoma from The Cancer Genome Atlas (TCGA) dataset was collected as an independent validation dataset to verify our findings. RESULTS We identified 1771 significantly DEGs with 446 upregulated genes and 1325 downregulated genes. A total of 24 key drivers were found in the upregulated gene set, and 81 key drivers were found in the downregulated gene set. We screened the Crowd Extracted Expression of Differential Signatures (CREEDS) database to identify drug perturbations that could reverse the key factors of glioblastoma, and a total of 354 drugs were obtained with p value < 10-10. Finally, 7 drugs that could turn down the expression of upregulated factors and 3 drugs that could reverse the expression of downregulated key factors were selected as potential glioblastoma drugs. In addition, similar results were obtained through the analysis of TCGA as independent dataset. CONCLUSIONS In this study, we provided a framework of workflow for potential therapeutic drug discovery and predicted 10 potential drugs for glioblastoma therapy.
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Affiliation(s)
- Bochi Zhu
- Department of Neurology, The Second Hospital of Jilin University, Changchun City, Jilin Province, 130041, China
| | - Xijing Mao
- Department of Neurology, The Second Hospital of Jilin University, Changchun City, Jilin Province, 130041, China
| | - Yuhong Man
- Department of Neurology, The Second Hospital of Jilin University, Changchun City, Jilin Province, 130041, China
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Soltanian S, Sheikhbahaei M. Effect of Menadione and Combination of Gemcitabine and Cisplatin on Cancer Stem Cells in Human Non-small Cell Lung Cancer (NSCLC) Cell Line A549. IRANIAN JOURNAL OF PHARMACEUTICAL RESEARCH : IJPR 2021; 20:105-117. [PMID: 34400945 PMCID: PMC8170754 DOI: 10.22037/ijpr.2020.112373.13715] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 04/12/2023]
Abstract
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Chemotherapy-induced adverse effects and resistance of NSCLC to conventional drugs reduce the efficacy of current therapies. Tumors contain a small population of cancer stem cells (CSCs) that play a critical role in tumor initiation, maintenance, and drug resistance that finally lead to cancer recurrence. Therefore, CSC-targeting therapies can offer the best hope for developing curative cancer therapies. Vitamins have a high potential for cancer prevention and treatment. Vitamins also ameliorate the side effects which occur in chemo-radio therapy. Menadione (2-methyl-1,4-naphthoquinone/vitamin-K3) is a synthetic form of vitamin K that indicated antitumor activities. The purpose of this study was to evaluate the anti-CSCs effect of menadione and combination of cisplatin and gemcitabine as a first-line treatment in patients with NSCLC on the NSCLC cell line A549. MTT results displayed decreased cell survival after treatment with cisplatin/gemcitabine for 48 h treatment (IC50 values 0.25 µM for cisplatin and 5 µM for gemcitabine). Menadione also inhibited the cell growth in A549 cells (IC50: 16 µM). Quantitative RT-PCR showed significant downregulation of CSC markers (Oct4, Nanog, Sox2, Aldh1, Abcb1, CD44, and CD133) and Snail, epithelial-mesenchymal transition marker, after treatment with menadione and cisplatin/gemcitabine. Flow cytometry showed CD44-positive cells that constitute a high percentage (70%) of A549 cells reduced significantly after treatment with cisplatin/gemcitabine or menadione. However, A549 cells did not show a significant population positive for CD133 and ABCB1 (less than 0.05%), and these fractions did not change after treatment with two agents.
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Vav1 Sustains the In Vitro Differentiation of Normal and Tumor Precursors to Insulin Producing Cells Induced by all-Trans Retinoic Acid (ATRA). Stem Cell Rev Rep 2020; 17:673-684. [PMID: 33165749 PMCID: PMC8036226 DOI: 10.1007/s12015-020-10074-x] [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] [Accepted: 10/27/2020] [Indexed: 02/07/2023]
Abstract
All-trans retinoic acid (ATRA) promotes the development and the function of insulin producing cells and induces partial differentiation of pancreatic tumor cells. A number of evidences clearly indicate that the ATRA mediated signaling may have a substantial role in therapeutic approaches based on restoration of functional β-cells. Among the proteins up-regulated by ATRA, Vav1 is involved in maturation and function of haematopoietic cells and is essential for retinoids induced differentiation of tumor promyelocytes. The presence of Vav1 in solid tissues, including pancreas, is considered ectopic and no role in the differentiation of human epithelial cells has so far been described. We demonstrated here that Vav1 sustains the maturation to β-cells of the normal precursors human Biliary Tree Stem/progenitor Cells (hBTSCs) induced by a differentiation medium containing ATRA and that, in the mature normal pancreas, insulin-producing cells express variable levels of Vav1. Using pancreatic ductal adenocarcinoma (PDAC)-derived cells, we also revealed that the ATRA induced up-modulation of Vav1 is essential for the retinoid-induced trans-differentiation of neoplastic cells into insulin producing cells. The results of this study identify Vav1 as crucial molecule in ATRA induced maturation of insulin producing cells and suggest this protein as a marker for new strategies ended to restore functional β-cells.
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Fang S, Hu C, Xu L, Cui J, Tao L, Gong M, Wang Y, He Y, He T, Bi Y. All-trans-retinoic acid inhibits the malignant behaviors of hepatocarcinoma cells by regulating autophagy. Am J Transl Res 2020; 12:6793-6810. [PMID: 33194073 PMCID: PMC7653590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 09/24/2020] [Indexed: 06/11/2023]
Abstract
Hepatocellular carcinoma is the fourth leading cause of cancer-related deaths due to its high rate of recurrence and metastasis. All-trans-retinoic acid (ATRA) can inhibit the malignant behaviors of hepatocarcinoma cells. Autophagy is reportedly involved in the migration and metastasis of various cancer cells. This study aimed to investigate the effect of autophagy on the function of ATRA on hepatocarcinoma cells, and to explore its possible underlying mechanism. Hepatocarcinoma cell lines, Hepa1-6 and HepG2, were treated with ATRA and autophagy inhibitors, including 3-methyladenine (3-MA) and Bafilomycin (Baf). Transmission electron microscopy, laser scanning, western blot, and real-time PCR demonstrated that ATRA induces autophagy in hepatocarcinoma cells. Trypan blue staining, a wound healing assay, and a transwell assay showed that 3-MA and Baf reverses the inhibitory functions of ATRA on the proliferation, migration, and invasion of hepatocarcinoma cells. Flow cytometry, Hoechst staining, periodic acid-Schiff staining, and indocyanine green uptake validated that 3-MA and Baf reverses the function of ATRA on apoptosis and the differentiation of hepatocarcinoma cells. Real-time PCR, western blot, and an immunofluorescence assay demonstrated that the reversal of the epithelial-mesenchymal transition (EMT) process by ATRA is weakened when autophagy is inhibited. Additionally, we confirmed that Bcl-2 is associated with the induction of ATRA-induced autophagy instead of the PI3K/Akt/mTOR pathway. These findings suggest that ATRA induces autophagy and autophagic cell death through the Bcl-2/Beclin1 pathway. Furthermore, ATRA-induced autophagy is involved in the inhibitory effect of ATRA on the malignant behaviors of hepatocarcinoma cells by reversing the EMT process.
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Affiliation(s)
- Shuyu Fang
- Department of Pediatric Research Institute of Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of PediatricsChongqing, P.R. China
| | - Chaoqun Hu
- Department of Pediatric Research Institute of Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of PediatricsChongqing, P.R. China
| | - Lei Xu
- Department of Microbiology, Chongqing Medical UniversityChongqing, P.R. China
| | - Jiejie Cui
- Department of Pediatric Research Institute of Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of PediatricsChongqing, P.R. China
| | - Li Tao
- Department of Pediatric Research Institute of Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of PediatricsChongqing, P.R. China
| | - Mengjia Gong
- Department of Pediatric Research Institute of Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of PediatricsChongqing, P.R. China
| | - Yi Wang
- Department of Pediatric Research Institute of Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of PediatricsChongqing, P.R. China
| | - Yun He
- Department of Pediatric Research Institute of Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of PediatricsChongqing, P.R. China
| | - Tongchuan He
- Molecular Oncology Laboratory, The University of Chicago Medical CenterChicago, IL 60637, USA
| | - Yang Bi
- Department of Pediatric Research Institute of Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of PediatricsChongqing, P.R. China
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Wang C, Zhao D, Wang K, Gao L, He Y, Wu H, Ruan L, Chen W, Zhang D, Xia T, Qian S, Liu Z, Yang Y, Yang W, Hu A, Zhao Q. All-Trans Retinoic Acid Rescues the Tumor Suppressive Role of RAR-β by Inhibiting LncHOXA10 Expression in Gastric Tumorigenesis. Nutr Cancer 2020; 73:2065-2077. [PMID: 32959699 DOI: 10.1080/01635581.2020.1823006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Numerous long noncoding RNAs (LncRNAs) were having recently been shown to be involved in cancer development, including gastric cancer (GC). However, the precise mechanism and treatments to target these molecules have rarely been studied. Thus, we aimed to investigate the function of LncHOXA10 in gastric tumorigenesis and targeted therapy. First, we measured the differences in LncHOXA10 and retinoic acid receptor β (RAR-β) levels in gastric cancer tissues and cell lines compared with those in noncancerous tissues and cell lines. We observed that LncHOXA10 was significantly upregulated in gastric cancer tissues and cell lines, whereas RAR-β showed the opposite trend. Subsequently, loss and gain of LncHOXA10 cell lines were constructed to determine whether LncHOXA10 plays a role in gastric tumorigenesis. The results showed that LncHOXA10 promoted the proliferation, migration, and invasion of cells, whereas apoptosis was markedly inhibited. Subsequently, mechanistic investigations revealed that LncHOXA10 can repress RAR-β expression and that all-trans retinoic acid (ATRA) can rescue the expression of RAR-β. Finally, we showed that ATRA can reverse the pro-cancerous function of LncHOXA10. We showed that LncHOXA10 may be a prognostic and therapeutic factor of gastric cancer by negatively regulating RAR-β. Furthermore, ATRA can inhibit the role of LncHOXA10 in gastric tumorigenesis.
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Affiliation(s)
- Chen Wang
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, China
| | - Didi Zhao
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, China
| | - Kexin Wang
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, China
| | - Lei Gao
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, China
| | - Yue He
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, China
| | - Hanhan Wu
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, China
| | - Liang Ruan
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, China
| | - Wenjun Chen
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, China
| | - Daoming Zhang
- Department of Gastroenterology, Lujiang County People's Hospital, Hefei, Anhui Province, China
| | - Tao Xia
- Department of Gastroenterology, Lujiang County People's Hospital, Hefei, Anhui Province, China
| | - Shiqing Qian
- Department of Pathology, Lujiang County People's Hospital, Hefei, Anhui Province, China
| | - Zhining Liu
- Department of General Surgery, the Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yi Yang
- Department of Pathology, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Wanshui Yang
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, China
| | - Anla Hu
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, China
| | - Qihong Zhao
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, China
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Maucort C, Di Giorgio A, Azoulay S, Duca M. Differentiation of Cancer Stem Cells by Using Synthetic Small Molecules: Toward New Therapeutic Strategies against Therapy Resistance. ChemMedChem 2020; 16:14-29. [PMID: 32803855 DOI: 10.1002/cmdc.202000251] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 07/19/2020] [Indexed: 12/12/2022]
Abstract
Despite the existing arsenal of anti-cancer drugs, 10 million people die each year worldwide due to cancers; this highlights the need to discover new therapies based on innovative modes of action against these pathologies. Current chemotherapies are based on the use of cytotoxic agents, targeted drugs, monoclonal antibodies or immunotherapies that are able to reduce or stop the proliferation of cancer cells. However, tumor eradication is often hampered by the presence of resistant cells called cancer stem-like cells or cancer stem cells (CSCs). Several strategies have been proposed to specifically target CSCs such as the use of CSC-specific antibodies, small molecules able to target CSC signaling pathways or drugs able to induce CSC differentiation rendering them sensitive to classical chemotherapy. These latter compounds are the focus of the present review, which aims to report recent advances in anticancer-differentiation strategies. This therapeutic approach was shown to be particularly promising for eradicating tumors in which CSCs are the main reason for therapeutic failure. This general view of the chemistry and mechanism of action of compounds inducing the differentiation of CSCs could be particularly useful for a broad range of researchers working in the field of anticancer therapies as the combination of compounds that induce differentiation with classical chemotherapy could represent a successful approach for future therapeutic applications.
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Affiliation(s)
- Chloé Maucort
- Université Côte d'Azur, CNRS, Institute of Chemistry of Nice (ICN), 28 avenue Valrose, 06108, Nice, France
| | - Audrey Di Giorgio
- Université Côte d'Azur, CNRS, Institute of Chemistry of Nice (ICN), 28 avenue Valrose, 06108, Nice, France
| | - Stéphane Azoulay
- Université Côte d'Azur, CNRS, Institute of Chemistry of Nice (ICN), 28 avenue Valrose, 06108, Nice, France
| | - Maria Duca
- Université Côte d'Azur, CNRS, Institute of Chemistry of Nice (ICN), 28 avenue Valrose, 06108, Nice, France
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Soltanian S, Sheikhbahaei M, Ziasistani M. Phytol Down-Regulates Expression of Some Cancer Stem Cell Markers and Decreases Side Population Proportion in Human Embryonic Carcinoma NCCIT Cells. Nutr Cancer 2020; 73:1520-1533. [PMID: 32700607 DOI: 10.1080/01635581.2020.1795695] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Cancer stem cells (CSCs), a subgroup of cancer cells, have self-renewal capacity and differentiation potential and drive tumor growth. CSCs are highly-resistant to conventional chemo-radio therapy. Phytochemicals were shown to be able to eliminate CSCs. Phytol is a diterpene alcohol with demonstrated anticancer effects. The current study compared the effect of phytol with retinoic acid (RA) as a well-known inducers of CSC differentiation and cisplatin, a common chemotherapy drug, on CSC markers in human embryonic carcinoma NCCIT cells. NCCIT cells were exposed to 10 mM RA for 14 day to induce differentiation. Moreover, NCCIT cells were treated with IC50 dose of cisplatin (12 µM) and phytol (40 µM) for 7 day. Real-time PCR showed that phytol was more effective that RA and cisplatin in down-regulating the CSC markers OCT4, NANOG, SOX2, ALDH1, ABCB1, CD44 and CD133. Percentage of SP (13%) and ABCB1+ (0.34%) in NCCIT cells decreased to 7% and 0.1% respectively after treatment with phytol. A very small proportion of NCCIT cells were positive for CD44 (0.2%) and CD133 (0.48%) and this fraction did not change significantly after treatment with three agents. In conclusion, phytol has the greatest inhibitory effect on CSC population and markers than RA and cisplatin.
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Affiliation(s)
- Sara Soltanian
- Department of Biology, Faculty of Science, Shahid Bahonar University of Kerman, Kerman, Iran
| | - Mahboubeh Sheikhbahaei
- Department of Biology, Faculty of Science, Shahid Bahonar University of Kerman, Kerman, Iran
| | - Mahsa Ziasistani
- Pathology and Stem Cell Research Center, Afzalipour Medical School, Kerman University of Medical Sciences, Kerman, Iran
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20
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Luo JY, Yan SB, Chen G, Chen P, Liang SW, Xu QQ, Gu JH, Huang ZG, Qin LT, Lu HP, Mo WJ, Luo YG, Chen JB. RNA-Sequencing, Connectivity Mapping, and Molecular Docking to Investigate Ligand-Protein Binding for Potential Drug Candidates for the Treatment of Wilms Tumor. Med Sci Monit 2020; 26:e920725. [PMID: 32214060 PMCID: PMC7119447 DOI: 10.12659/msm.920725] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Background Wilms tumor, or nephroblastoma, is a malignant pediatric embryonal renal tumor that has a poor prognosis. This study aimed to use bioinformatics data, RNA-sequencing, connectivity mapping, molecular docking, and ligand-protein binding to identify potential targets for drug therapy in Wilms tumor. Material/Methods Wilms tumor and non-tumor samples were obtained from high throughput gene expression databases, and differentially expressed genes (DEGs) were analyzed using the voom method in the limma package. The overlapping DEGs were obtained from the intersecting drug target genes using the Connectivity Map (CMap) database, and systemsDock was used for molecular docking. Gene databases were searched for gene expression profiles for complementary analysis, analysis of clinical significance, and prognosis analysis to refine the study. Results From 177 cases of Wilms tumor, there were 648 upregulated genes and 342 down-regulated genes. Gene Ontology (GO) enrichment analysis showed that the identified DEGs that affected the cell cycle. After obtaining 21 candidate drugs, there were seven overlapping genes with 75 drug target genes and DEGs. Molecular docking results showed that relatively high scores were obtained when retinoic acid and the cyclin-dependent kinase inhibitor, alsterpaullone, were docked to the overlapping genes. There were significant standardized mean differences for three overlapping genes, CDK2, MAP4K4, and CRABP2. However, four upregulated overlapping genes, CDK2, MAP4K4, CRABP2, and SIRT1 had no prognostic significance. Conclusions RNA-sequencing, connectivity mapping, and molecular docking to investigate ligand-protein binding identified retinoic acid and alsterpaullone as potential drug candidates for the treatment of Wilms tumor.
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Affiliation(s)
- Jia-Yuan Luo
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China (mainland)
| | - Shi-Bai Yan
- Department of Medical Oncology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China (mainland)
| | - Gang Chen
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China (mainland)
| | - Peng Chen
- Department of Pediatric Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China (mainland)
| | - Song-Wu Liang
- Department of Pediatric Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China (mainland)
| | - Qiong-Qian Xu
- Department of Pediatric Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China (mainland)
| | - Jin-Han Gu
- Department of Pediatric Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China (mainland)
| | - Zhi-Guang Huang
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China (mainland)
| | - Li-Ting Qin
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China (mainland)
| | - Hui-Ping Lu
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China (mainland)
| | - Wei-Jia Mo
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China (mainland)
| | - Yi-Ge Luo
- Department of Pediatric Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China (mainland)
| | - Jia-Bo Chen
- Department of Pediatric Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China (mainland)
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Zhang ZZ, Yu WX, Zheng M, Liao XH, Wang JC, Yang DY, Lu WX, Wang L, Zhang S, Liu HK, Zhou XZ, Lu KP. PIN1 Inhibition Sensitizes Chemotherapy in Gastric Cancer Cells by Targeting Stem Cell-like Traits and Multiple Biomarkers. Mol Cancer Ther 2020; 19:906-919. [PMID: 31879364 DOI: 10.1158/1535-7163.mct-19-0656] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Revised: 09/25/2019] [Accepted: 12/19/2019] [Indexed: 11/16/2022]
Abstract
Gastric cancer is the third leading cause of cancer-related death worldwide. Diffuse type gastric cancer has the worst prognosis due to notorious resistance to chemotherapy and enrichment of cancer stem-like cells (CSC) associated with the epithelial-to-mesenchymal transition (EMT). The unique proline isomerase PIN1 is a common regulator of oncogenic signaling networks and is important for gastric cancer development. However, little is known about its roles in CSCs and drug resistance in gastric cancer. In this article, we demonstrate that PIN1 overexpression is closely correlated with advanced tumor stages, poor chemo-response and shorter recurrence-free survival in diffuse type gastric cancer in human patients. Furthermore, shRNA-mediated genetic or all-trans retinoic acid-mediated pharmaceutical inhibition of PIN1 in multiple human gastric cancer cells potently suppresses the EMT, cell migration and invasion, and lung metastasis. Moreover, PIN1 genetic or pharmaceutical inhibition potently eliminates gastric CSCs and suppresses their self-renewal and tumorigenicity in vitro and in vivo Consistent with these phenotypes, are that PIN1 biochemically targets multiple signaling molecules and biomarkers in EMT and CSCs and that genetic and pharmaceutical PIN1 inhibition functionally and drastically enhances the sensitivity of gastric cancer to multiple chemotherapy drugs in vitro and in vivo These results demonstrate that PIN1 inhibition sensitizes chemotherapy in gastric cancer cells by targeting CSCs, and suggest that PIN1 inhibitors may be used to overcome drug resistance in gastric cancer.
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Affiliation(s)
- Zhen-Zhen Zhang
- Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, Fujian Medical University, Fuzhou, Fujian, China.
- Department of Pathology of the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China
| | - Wei-Xing Yu
- Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, Fujian Medical University, Fuzhou, Fujian, China
| | - Min Zheng
- Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, Fujian Medical University, Fuzhou, Fujian, China
| | - Xin-Hua Liao
- Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, Fujian Medical University, Fuzhou, Fujian, China
| | - Ji-Chuang Wang
- Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, Fujian Medical University, Fuzhou, Fujian, China
| | - Da-Yun Yang
- Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, Fujian Medical University, Fuzhou, Fujian, China
| | - Wen-Xian Lu
- Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, Fujian Medical University, Fuzhou, Fujian, China
| | - Long Wang
- Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, Fujian Medical University, Fuzhou, Fujian, China
| | - Sheng Zhang
- Department of Pathology of the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China
| | - He-Kun Liu
- Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, Fujian Medical University, Fuzhou, Fujian, China
| | - Xiao Zhen Zhou
- Division of Translational Therapeutics, Department of Medicine and Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Kun Ping Lu
- Division of Translational Therapeutics, Department of Medicine and Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
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22
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All-trans retinoic acid suppressed GES-1 cell proliferation induced by exosomes from patients with precancerous lesions by arresting the cell cycle in S-phase. Eur J Cancer Prev 2020; 30:113-119. [PMID: 32032154 DOI: 10.1097/cej.0000000000000571] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
We aimed to detect the expression of specific LncRNAs in exosomes isolated from the serum of patients with precancerous lesions and to study the effect of these serum exosomes on the activity of GES-1 cells in patients with precancerous lesions, as well as the activity of all-trans retinoic acid on GES-1 cells with or without the exosomes. Exosomes were extracted from the serum of patients with precancerous lesions and normal controls. Based on our previous sequencing results, quantitative real time-PCR was used to detect differentially expressed LncRNAs. Exosomes from the serum of patients with precancerous lesions were cocultured with GES-1 cells, and 5 μM all-trans retinoic acid was added as an intervention. Changes in cell viability and expression of LncHOXA10 were observed. Compared with the blank group, the proliferation activity of GES-1 cells cocultured with exosomes derived from the serum of patients with precancerous lesions was increased (P < 0.01), the proportion of cells in S phase was increased (P < 0.05). After adding 5 μM all-trans retinoic acid, the viability of cells decreased significantly (P < 0.01), the proportion of cells in S phase decreased significantly (P < 0.05). The expression of LncHOXA10 was decreased (P < 0.05). All-trans retinoic acid can conduct its chemopreventive effects by inhibiting the expression of LncHOXA10, thereby reducing the activity of LncHOXA10 in GES-1 cells cocultured with serum exosomes from patients with precancerous lesions.
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Xiang S, Zhao Z, Zhang T, Zhang B, Meng M, Cao Z, Zhou Q. Triptonide effectively suppresses gastric tumor growth and metastasis through inhibition of the oncogenic Notch1 and NF-κB signaling pathways. Toxicol Appl Pharmacol 2020; 388:114870. [PMID: 31866380 DOI: 10.1016/j.taap.2019.114870] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Revised: 12/02/2019] [Accepted: 12/17/2019] [Indexed: 12/25/2022]
Abstract
Gastric cancer ranks as the third leading cause of cancer-related death worldwide. The uncontrolled tumor growth and robust metastasis are key factors to cause the cancer patient death. Mechanistically, aberrant activation of Notch and NF-κB signaling pathways plays pivotal roles in the initiation and metastasis of gastric cancer. Despite great efforts have been made in recent decades, the effective drug against the advanced and metastatic gastric cancer is still lacking in the clinical setting. In this study, we found that triptonide, a small molecule (MW358) purified from the traditional Chinese medicinal herb Tripterygium wilfordii Hook F, effectively suppressed tumor growth and metastasis in xenograft mice without obvious toxicity at the doses we tested, resulting in potent anti-gastric cancer effect with low toxicity. Triptonide markedly inhibited human metastatic gastric cancer cell migration, invasion, proliferation, and tumorigenicity. Molecular mechanistic studies revealed that triptonide significantly reduced Notch1 protein levels in metastatic gastric cancer cells through degrading the oncogenic protein Notch1 via the ubiquitin-proteasome pathway. Consequently, the levels of Notch1 downstream proteins RBPJ, IKKα, IKKβ were significantly diminished, and nuclear factor-kappa B (NF-κB) phosphorylation was significantly reduced. Together, triptonide effectively suppresses gastric cancer growth and metastasis via inhibition of the oncogenic Notch1 and NF-κB signaling pathways. Our findings provide a new strategy and drug candidate for treatment of the advanced and metastatic gastric cancer.
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Affiliation(s)
- Shufen Xiang
- Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu 215123, PR China
| | - Zhe Zhao
- Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu 215123, PR China
| | - Tong Zhang
- Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu 215123, PR China
| | - Bin Zhang
- Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu 215123, PR China
| | - Mei Meng
- Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu 215123, PR China
| | - Zhifei Cao
- Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu 215123, PR China
| | - Quansheng Zhou
- Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu 215123, PR China.
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24
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Zhang DM, Luo Y, Yishake D, Liu ZY, He TT, Luo Y, Zhang YJ, Fang AP, Zhu HL. Prediagnostic dietary intakes of vitamin A and β-carotene are associated with hepatocellular-carcinoma survival. Food Funct 2020; 11:759-767. [DOI: 10.1039/c9fo02468a] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Vitamin A and its precursor (β-carotene) have been linked with cancer incidence and mortality.
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Affiliation(s)
- Dao-ming Zhang
- Department of Nutrition
- School of Public Health
- Sun Yat-sen University
- Guangzhou 510080
- People's Republic of China
| | - Yun Luo
- Department of Nutrition
- School of Public Health
- Sun Yat-sen University
- Guangzhou 510080
- People's Republic of China
| | - Dinuerguli Yishake
- Department of Nutrition
- School of Public Health
- Sun Yat-sen University
- Guangzhou 510080
- People's Republic of China
| | - Zhao-yan Liu
- Department of Nutrition
- School of Public Health
- Sun Yat-sen University
- Guangzhou 510080
- People's Republic of China
| | - Tong-tong He
- Department of Nutrition
- School of Public Health
- Sun Yat-sen University
- Guangzhou 510080
- People's Republic of China
| | - Yan Luo
- Department of Nutrition
- School of Public Health
- Sun Yat-sen University
- Guangzhou 510080
- People's Republic of China
| | - Yao-jun Zhang
- Department of Hepatobiliary Oncology
- Sun Yat-sen University Cancer Center
- Guangzhou 510060
- People's Republic of China
- State Key Laboratory of Oncology in South China
| | - Ai-ping Fang
- Department of Nutrition
- School of Public Health
- Sun Yat-sen University
- Guangzhou 510080
- People's Republic of China
| | - Hui-lian Zhu
- Department of Nutrition
- School of Public Health
- Sun Yat-sen University
- Guangzhou 510080
- People's Republic of China
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25
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Sexton RE, Hallak MNA, Uddin MH, Diab M, Azmi AS. Gastric Cancer Heterogeneity and Clinical Outcomes. Technol Cancer Res Treat 2020; 19:1533033820935477. [PMID: 32799763 PMCID: PMC7432987 DOI: 10.1177/1533033820935477] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 04/16/2020] [Accepted: 05/22/2020] [Indexed: 12/21/2022] Open
Abstract
Gastric adenocarcinoma is a highly aggressive disease with poor overall survival. The aggressive nature of this disease is in part due to the high intra and inter tumoral heterogeneity and also due to the late diagnosis at presentation. Once progression occurs, treatment is more difficult due to the adaptation of tumors, which acquires resistance to commonly used chemotherapeutics. In this report, using publicly available data sets and pathway analysis, we highlight the vast heterogeneity of gastric cancer by investigating genes found to be significantly perturbed. We found several upregulated genes in the diffuse gastric cancer subtypes share similarity to gastric cancer as a whole which can be explained by the increase in this subtype of gastric cancer throughout the world. We report significant downregulation of genes that are underrepresented within the literature, such as ADH7, GCNT2, and LIF1, while other genes have not been explored within gastric cancer to the best of our knowledge such as METTL7A, MAL, CWD43, and SLC2A12. We identified gender to be another heterogeneous component of this disease and suggested targeted treatment strategies specific to this heterogeneity. In this study, we provide an in-depth exploration of the molecular landscape of gastric cancer in order to shed light onto novel areas of gastric cancer research and explore potential new therapeutic targets.
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Affiliation(s)
- Rachel E. Sexton
- Department of Oncology, Wayne State University School of
Medicine, Detroit, MI, USA
| | | | - Md. Hafiz Uddin
- Department of Oncology, Wayne State University School of
Medicine, Detroit, MI, USA
| | - Maria Diab
- Department of Oncology, Wayne State University School of
Medicine, Detroit, MI, USA
| | - Asfar S. Azmi
- Department of Oncology, Wayne State University School of
Medicine, Detroit, MI, USA
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26
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Reduction of Serum Concentrations and Synergy between Retinol, β-Carotene, and Zinc According to Cancer Staging and Different Treatment Modalities Prior to Radiation Therapy in Women with Breast Cancer. Nutrients 2019; 11:nu11122953. [PMID: 31817125 PMCID: PMC6950526 DOI: 10.3390/nu11122953] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Revised: 09/01/2019] [Accepted: 09/15/2019] [Indexed: 12/25/2022] Open
Abstract
The procedures used for breast cancer treatment are able to increase the level of oxidative stress and cause depletion of antioxidants. Objectives: To investigate the relationship between serum concentrations of retinol, β-carotene, and zinc, according to breast cancer staging, considering different treatment modalities prior to radiation therapy and the synergistic action between these micronutrients. Methods: This is a cross-sectional observational study comprising a cohort of patients with breast cancer which was carried out prior to radiation therapy. Patients were divided into 3 groups: G1 comprised women who had undergone breast-conserving surgery, G2 comprised those who had undergone chemotherapy, and G3 those who had undergone breast-conserving surgery and chemotherapy. Serum concentrations of retinol, β-carotene, and zinc were quantified. Breast cancer staging was based on the TNM (Tumor, Node, Metastasis) classification of malignant tumors, a type of staging tool for different cancers. Results: A total of 230 patients were assessed. A decrease of the serum concentrations of the micronutrients assessed as the staging level of the disease increased was observed. Surgery alone had a greater negative impact on serum concentrations of retinol. Considering the treatments prior to radiotherapy, patients undergoing surgery alone and chemotherapy associated with surgery had higher percentages of deficiency of β-carotene and retinol. There was a positive correlation between the concentrations of zinc, retinol, and β-carotene, showing a synergy between these micronutrients. Conclusion: A significant reduction in the serum concentrations of the assessed micronutrients was observed, according to the increase in breast cancer staging. The synergy between the micronutrients must be considered in order to maximize the benefits and minimize the adverse effects of irradiation to normal cells.
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27
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The Effect of Arsenic Trioxide on All-trans Retinoic Acid Binding to Human Serum Albumin. J Fluoresc 2019; 29:1277-1283. [DOI: 10.1007/s10895-019-02458-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Accepted: 10/31/2019] [Indexed: 01/30/2023]
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28
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A Shifty Target: Tumor-Initiating Cells and Their Metabolism. Int J Mol Sci 2019; 20:ijms20215370. [PMID: 31661927 PMCID: PMC6862122 DOI: 10.3390/ijms20215370] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Revised: 10/25/2019] [Accepted: 10/26/2019] [Indexed: 12/20/2022] Open
Abstract
Tumor-initiating cells (TICs), or cancer stem cells, constitute highly chemoresistant, asymmetrically dividing, and tumor-initiating populations in cancer and are thought to play a key role in metastatic and chemoresistant disease. Tumor-initiating cells are isolated from cell lines and clinical samples based on features such as sphere formation in stem cell medium and expression of TIC markers, typically a set of outer membrane proteins and certain transcription factors. Although both bulk tumor cells and TICs show an adaptive metabolic plasticity, TIC metabolism is thought to differ and likely in a tumor-specific and growth condition-dependent pattern. In the context of some common solid tumor diseases, we here review reports on how TIC isolation methods and markers associate with metabolic features, with some focus on oxidative metabolism, including fatty acid and lipid metabolism. These have emerged as significant factors in TIC phenotypes, and in tumor biology as a whole. Other sections address mitochondrial biogenesis and dynamics in TICs, and the influence of the tumor microenvironment. Further elucidation of the complex biology of TICs and their metabolism will require advanced methodologies.
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29
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Zhang LH, Wang Y, Fan QQ, Liu YK, Li LH, Qi XW, Mao Y, Hua D. Up-regulated Wnt1-inducible signaling pathway protein 1 correlates with poor prognosis and drug resistance by reducing DNA repair in gastric cancer. World J Gastroenterol 2019; 25:5814-5825. [PMID: 31636474 PMCID: PMC6801184 DOI: 10.3748/wjg.v25.i38.5814] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Revised: 08/16/2019] [Accepted: 09/13/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Wnt1-inducible signaling pathway protein 1 (WISP1) is upregulated in several types of human cancer, and has been implicated in cancer progression. However, its clinical implications in gastric cancer (GC) remain unclear.
AIM To explore the expression pattern and clinical significance of WISP1 in GC.
METHODS Public data portals, including Oncomine, The Cancer Genome Atlas database, Coexpedia, and Kaplan-Meier plotter, were analyzed for the expression and clinical significance of WISP1 mRNA levels in GC. One hundred and fifty patients who underwent surgery for GC between February 2010 and October 2012 at the Affiliated Hospital of Jiangnan University were selected for validation study. WISP1 levels were measured at both the mRNA and protein levels by RT-qPCR, Western blot analysis, and immunohistochemistry (IHC). In addition, the in situ expression of WISP1 in the GC tissues was determined by IHC, and the patients were accordingly classified into high- and low-expression groups. The correlation of WISP1 expression status with patient prognosis was then determined by univariate and multivariate Cox regression analyses. WISP1 was knocked down by RNA interference. The 50% inhibitory concentration of oxaliplatin was detected by CellTiter-Blue assay.
RESULTS WISP1 levels at both the mRNA and protein levels were remarkably upregulated in GC tissues compared to normal tissues. Moreover, IHC revealed that WISP1 expression was associated with T stage and chemotherapy outcome, but not with lymph node metastasis, age, gender, histological grade, or histological type. GC patients with high WISP1 expression showed a poor overall survival. Multivariate survival analysis indicated that WISP1 was an important prognostic factor for GC patients. Mechanistically, knock-down of WISP1 expression enhanced sensitivity to oxaliplatin by reducing DNA repair and enhancing DNA damage.
CONCLUSION Significantly upregulated WISP1 expression is associated with cancer progression, chemotherapy outcome, and prognosis in GC. Mechanistically, knock-down of WISP1 expression enhances oxaliplatin sensitivity by reducing DNA repair and enhancing DNA damage. WISP1 may be a potential therapeutic target for GC treatment or a potential biomarker for diagnosis and prognosis.
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Affiliation(s)
- Li-Hua Zhang
- Department of Oncology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi 214062, Jiangsu Province, China
- School of Pharmaceutical Sciences, Jiangnan University, Wuxi 214122, Jiangsu Province, China
- Wuxi Medical College, Jiangnan University, Wuxi 214122, Jiangsu Province, China
| | - Yan Wang
- Wuxi Medical College, Jiangnan University, Wuxi 214122, Jiangsu Province, China
| | - Qian-Qian Fan
- Department of Oncology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi 214062, Jiangsu Province, China
- Department of Gynecology, Zaozhuang Maternal and Child Health Hospital, Zaozhuang 277100, Shandong Province, China
| | - Yan-Kui Liu
- Department of Pathology, Affiliated Hospital of Jiangnan University, Wuxi 214062, Jiangsu Province, China
| | - Long-Hai Li
- Wuxi Medical College, Jiangnan University, Wuxi 214122, Jiangsu Province, China
| | - Xiao-Wei Qi
- Department of Pathology, Affiliated Hospital of Jiangnan University, Wuxi 214062, Jiangsu Province, China
| | - Yong Mao
- Department of Oncology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi 214062, Jiangsu Province, China
| | - Dong Hua
- Department of Oncology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi 214062, Jiangsu Province, China
- School of Pharmaceutical Sciences, Jiangnan University, Wuxi 214122, Jiangsu Province, China
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30
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Francisco V, Lino M, Ferreira L. A near infrared light-triggerable modular formulation for the delivery of small biomolecules. J Nanobiotechnology 2019; 17:97. [PMID: 31526377 PMCID: PMC6747754 DOI: 10.1186/s12951-019-0530-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Accepted: 09/10/2019] [Indexed: 12/02/2022] Open
Abstract
Background Externally triggered drug delivery systems hold considerable promise for improving the treatment of many diseases, in particular, diseases where the spatial–temporal release of the drug is critical to maximize their biological effect whilst minimizing undesirable, off-target, side effects. Results Herein, we developed a light-triggerable formulation that takes advantage of host–guest chemistry to complex drugs functionalized with a guest molecule and release it after exposure to near infrared (NIR) light due to the disruption of the non-covalent host–guest interactions. The system is composed by a gold nanorod (AuNR), which generates plasmonic heat after exposure to NIR, a thin layer of hyaluronic acid immobilized to the AuNR upon functionalization with a macrocycle, cucurbit[6]uril (CB[6]), and a drug functionalized with a guest molecule that interacts with the macrocycle. For proof of concept, we have used this formulation for the intracellular release of a derivative of retinoic acid (RA), a molecule known to play a key role in tissue development and homeostasis as well as during cancer treatment. We showed that the formulation was able to conjugate approximately 65 μg of RA derivative per mg of CB[6] @AuNR and released it within a few minutes after exposure to a NIR laser. Importantly, the bioactivity of RA released from the formulation was demonstrated in a reporter cell line expressing luciferase under the control of the RA receptor. Conclusions This NIR light-triggered supramolecular-based modular platform holds great promise for theranostic applications.
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Affiliation(s)
- Vitor Francisco
- CNC-Center for Neurosciences and Cell Biology, University of Coimbra, 3004-517, Coimbra, Portugal
| | - Miguel Lino
- Faculty of Medicine, University of Coimbra, 3000-548, Coimbra, Portugal
| | - Lino Ferreira
- CNC-Center for Neurosciences and Cell Biology, University of Coimbra, 3004-517, Coimbra, Portugal. .,Faculty of Medicine, University of Coimbra, 3000-548, Coimbra, Portugal.
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31
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Lima L, de Melo TCT, Marques D, de Araújo JNG, Leite ISF, Alves CX, Genre J, Silbiger VN. Modulation of all-trans retinoic acid-induced MiRNA expression in neoplastic cell lines: a systematic review. BMC Cancer 2019; 19:866. [PMID: 31470825 PMCID: PMC6717326 DOI: 10.1186/s12885-019-6081-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Accepted: 08/23/2019] [Indexed: 12/13/2022] Open
Abstract
Background Cancer is a genetic and epigenetic disease that involves inactivation of tumor suppressor genes and activation of proto-oncogenes. All-trans retinoic acid (ATRA) is an isomer of retinoic acid involved in the onset of differentiation and apoptosis of a number of normal and cancer cells, functioning as an anti-cancer agent in several neoplasms. Ectopic changes in the expression of certain microRNAs (miRNAs) occur in response to ATRA, leading to phenotypic alterations in neoplastic cell lines. Moreover, the modulation of miRNA patterns upon ATRA-treatment may represent an effective chemopreventive and anti-cancer therapy strategy. The present systematic review was performed to provide an overview of the modulation of ATRA-induced miRNA expression in different types of neoplastic cells and identify the efficacy of intervention factors (i.e., concentration and duration of treatment) and how they influence expression profiles of oncogenesis-targeting miRNAs. Methods A systematic search was conducted according to the PRISMA statement via the US National Library of Medicine MEDLINE/PubMed bibliographic search engine. Results The search identified 31 experimental studies involving human cell lines from nine different cancer types (neuroblastoma, acute myeloid leukemia, breast cancer, lung cancer, pancreatic cancer, glioma, glioblastoma, embryonal carcinoma, and colorectal cancer) treated with ATRA at concentrations ranging from 10− 3 μmol/L to 102 μmol mol/L for 24 h to 21 days. Conclusion The concentrations used and the duration of treatment of cancer cells with ATRA varied widely. The presence of ATRA in the culture medium of cancer cells was able to modulate the expression of more than 300 miRNAs, and inhibit invasive behavior and deregulated growth of cancer cells, resulting in total tumor remission in some cases. ATRA may thus be broadly effective for neoplasm treatment and prevention, although these studies may not accurately represent in vivo conditions. Additional studies are required to elucidate ATRA-induced miRNA modulation during neoplasm treatment.
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Affiliation(s)
- Lara Lima
- Postgraduate Program in Nutrition, Federal University of Rio Grande do Norte, Natal, Brazil.,Laboratory of Bioanalysis and Molecular Biotechnology, Federal University of Rio Grande do Norte, Natal, Brazil
| | | | - Diego Marques
- Laboratory of Bioanalysis and Molecular Biotechnology, Federal University of Rio Grande do Norte, Natal, Brazil
| | - Jéssica Nayara Góes de Araújo
- Laboratory of Bioanalysis and Molecular Biotechnology, Federal University of Rio Grande do Norte, Natal, Brazil.,Postgraduate Program in Pharmaceutical Sciences, Federal University of Rio Grande do Norte, Natal, Brazil
| | | | - Camila Xavier Alves
- Postgraduate Program in Pharmaceutical Sciences, Federal University of Rio Grande do Norte, Natal, Brazil
| | - Julieta Genre
- Postgraduate Program in Pharmaceutical Sciences, Federal University of Rio Grande do Norte, Natal, Brazil
| | - Vivian Nogueira Silbiger
- Postgraduate Program in Nutrition, Federal University of Rio Grande do Norte, Natal, Brazil. .,Laboratory of Bioanalysis and Molecular Biotechnology, Federal University of Rio Grande do Norte, Natal, Brazil. .,Postgraduate Program in Pharmaceutical Sciences, Federal University of Rio Grande do Norte, Natal, Brazil. .,Department of Clinical and Toxicological Analysis, Federal University of Rio Grande do Norte, Av. General Gustavo Cordeiro de Faria S/N, Petrópolis, Natal - RN, 59012-570, Brazil.
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32
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Zhang Z, Yu W, Zheng M, Liao X, Wang J, Yang D, Lu W, Wang L, Zhang S, Liu H, Zhou XZ, Lu KP. Pin1 inhibition potently suppresses gastric cancer growth and blocks PI3K/AKT and Wnt/β-catenin oncogenic pathways. Mol Carcinog 2019; 58:1450-1464. [PMID: 31026381 DOI: 10.1002/mc.23027] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Revised: 03/29/2019] [Accepted: 04/09/2019] [Indexed: 12/15/2022]
Abstract
Gastric cancer is the second leading cause of cancer-related mortality and the fourth most common cancer globally. High intratumor heterogeneity of advanced gastric cancer poses great challenges to targeted therapy due to simultaneous activation of many redundant cancer-driving pathways. A central common signaling mechanism in cancer is proline-directed phosphorylation, which is further regulated by the unique proline isomerase Pin1. Pin1 inhibition exerts anticancer activity by blocking multiple cancer-driving pathways in some cancers, but its role in gastric cancer is not fully understood. Here we detected Pin1 protein expression in 1065 gastric cancer patients and paired normal tissues using immunohistochemistry and Western blot, and then examined the effects of Pin1 overexpression, and genetic and chemical Pin1 inhibition using Pin1 short hairpin RNA or small molecule inhibitor all-trans retinoic acid (ATRA) on tumorigenesis of human gastric cancer in vitro and in vivo, followed by biochemical analyses to elucidate Pin1 regulated oncogenic pathways. We found that Pin1 was significantly overexpressed in primary and metastasized tumors, with Pin1 overexpression being correlated with advanced stage and poor prognosis. Furthermore, whereas Pin1 overexpression promoted the transformed phenotype in immortalized and nontransformed human gastric cells, either genetic or chemical Pin1 inhibition in multiple human gastric cancer cells potently suppressed cell growth, G1/S transition and colony formation in vitro, as well as tumor growth in xenograft tumor models in vivo, which were further supported by downregulation of multiple key oncoproteins in PI3K/AKT and Wnt/β-catenin signaling pathways. These results not only provide the first evidence for a critical role of Pin1 in the tumorigenesis of gastric cancer but also suggest that targeting Pin1 using ATRA or other inhibitors offers an effective new therapeutic approach for treating advanced gastric cancer.
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Affiliation(s)
- Zhenzhen Zhang
- Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, Fujian Medical University, Fuzhou, Fujian, China.,Department of Pathology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Weixing Yu
- Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, Fujian Medical University, Fuzhou, Fujian, China
| | - Min Zheng
- Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, Fujian Medical University, Fuzhou, Fujian, China
| | - Xinhua Liao
- Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, Fujian Medical University, Fuzhou, Fujian, China
| | - Jichuang Wang
- Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, Fujian Medical University, Fuzhou, Fujian, China
| | - Dayun Yang
- Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, Fujian Medical University, Fuzhou, Fujian, China
| | - Wenxian Lu
- Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, Fujian Medical University, Fuzhou, Fujian, China
| | - Long Wang
- Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, Fujian Medical University, Fuzhou, Fujian, China
| | - Sheng Zhang
- Department of Pathology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Hekun Liu
- Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, Fujian Medical University, Fuzhou, Fujian, China
| | - Xiao Zhen Zhou
- Division of Translational Therapeutics, Department of Medicine and Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Kun Ping Lu
- Division of Translational Therapeutics, Department of Medicine and Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
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Shu F, Zou X, Tuo H, She S, Huang J, Ren H, Hu H, Peng S, Wang J, Yang Y. Stathmin gene silencing suppresses proliferation, migration and invasion of gastric cancer cells via AKT/sCLU and STAT3 signaling. Int J Oncol 2019; 54:1086-1098. [PMID: 30628664 DOI: 10.3892/ijo.2019.4674] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Accepted: 11/02/2018] [Indexed: 11/06/2022] Open
Abstract
Globally, gastric cancer is the fifth most common malignancy, with high rates of incidence and mortality. The high mortality rate and poor prognosis of gastric cancer are closely associated with its profound invasiveness, high incidence of metastasis, rapid proliferation, and high rate of recurrence. Previous studies have confirmed that stathmin (STMN) has an important role in the occurrence, development and prognosis of gastric cancer. However, the detailed mechanisms by which STMN affects these processes remain unclear. The aim of the present study was to determine how STMN promotes invasion, migration and proliferation in gastric cancer tumor cells. The results of immunohistochemistry indicated that STMN is overexpressed in stomach neoplasm tissues, and that it is associated with migration, invasion, proliferation and anti‑apoptotic states of gastric cancer cells. The secretory proteins of gastric cancer cells with or without STMN knockdown were further analyzed using the isobaric tags for relative and absolute quantitation method to identify differentially expressed proteins verified by reverse transcription‑quantitative polymerase chain reaction and western blot analysis. Inhibition of STMN decreases the levels of clusterin, cystatin C and matrix metalloproteinases, followed by inhibiting the protein kinase B and signal transducer and activation of transcription activation. These findings suggest that STMN could be a promising therapeutic target for gastric cancer.
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Affiliation(s)
- Feng Shu
- Department of Infectious Diseases, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China
| | - Xiaoqin Zou
- Department of Infectious Diseases, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China
| | - Huan Tuo
- Department of Infectious Diseases, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China
| | - Sha She
- Department of Infectious Diseases, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China
| | - Juan Huang
- Department of Infectious Diseases, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China
| | - Hong Ren
- Department of Infectious Diseases, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China
| | - Huaidong Hu
- Department of Infectious Diseases, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China
| | - Shifang Peng
- Department of Infectious Diseases, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China
| | - Jiandong Wang
- Department of Infectious Diseases, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China
| | - Yixuan Yang
- Department of Infectious Diseases, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China
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