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Meier C, Brieger A. The role of IL-8 in cancer development and its impact on immunotherapy resistance. Eur J Cancer 2025; 218:115267. [PMID: 39899909 DOI: 10.1016/j.ejca.2025.115267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Revised: 01/28/2025] [Accepted: 01/28/2025] [Indexed: 02/05/2025]
Abstract
Tumors are structures of high complexity. Plurality of their structural and functional components - heterogeneity, diversity, directionality, interdependence and integration of signaling pathways - seem to follow isolated local rules, whereby a superordinate structure remains largely unknown. Understanding the complexity of cancer is the mainstay in finding determinants and developing effective therapies. Interleukin 8 (IL-8) is a potent pro-inflammatory chemokine that is significantly elevated in many different tumor entities. In contrast to its initially postulated anti-tumor properties, an increasing number of studies have been published in recent years linking this chemokine with tumor-promoting features and poor prognosis. This review summarizes the current state and diversity of the role of IL-8 in the development of cancer.
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Affiliation(s)
- Clara Meier
- Goethe University Frankfurt, University Hospital, Medical Clinic 1, Biomedical Research Laboratory, Frankfurt am Main, Germany
| | - Angela Brieger
- Goethe University Frankfurt, University Hospital, Medical Clinic 1, Biomedical Research Laboratory, Frankfurt am Main, Germany.
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2
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Bohne A, Grundler E, Knüttel H, Völkel V, Fürst A. Impact of laparoscopic versus open surgery on humoral immunity in patients with colorectal cancer: a systematic review and meta-analysis. Surg Endosc 2024; 38:540-553. [PMID: 38102395 PMCID: PMC10830603 DOI: 10.1007/s00464-023-10582-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Accepted: 11/04/2023] [Indexed: 12/17/2023]
Abstract
BACKGROUND Laparoscopic surgery (LS) is hypothesized to result in milder proinflammatory reactions due to less severe operative trauma, which may contribute to the observed clinical benefits after LS. However, previous systematic reviews and meta-analyses on the impact of LS on immunocompetence are outdated, limited and heterogeneous. Therefore, the humoral response after laparoscopic and open colorectal cancer (CRC) resections was evaluated in a comprehensive systematic review and meta-analysis. METHODS Included were randomized controlled trials (RCTs) measuring parameters of humoral immunity after LS compared to open surgery (OS) in adult patients with CRC of any stage. MEDLINE, Embase, Web of Science (SCI-EXPANDED), Cochrane Library, Google Scholar, ClinicalTrials.gov and ICTRP (World Health Organization) were systematically searched. Risk of bias (RoB) was assessed using the Cochrane RoB2 tool. Weighted inverse variance meta-analysis of mean differences was performed for C-reactive protein (CRP), interleukin (IL)-6, IL-8, tumour necrosis factor (TNF)α and vascular endothelial growth factor (VEGF) using the random-effects method. Methods were prospectively registered in PROSPERO (CRD42021264324). RESULTS Twenty RCTs with 1131 participants were included. Narrative synthesis and meta-analysis up to 8 days after surgery was performed. Quantitative synthesis found concentrations to be significantly lower after LS at 0-2 h after surgery (IL-8), at 3-9 h (CRP, IL-6, IL-8, TNFα) and at postoperative day 1 (CRP, IL-6, IL-8, VEGF). At 3-9 h, IL-6 was notably lower in the LS group by 86.71 pg/ml (mean difference [MD] - 86.71 pg/ml [- 125.05, - 48.37], p < 0.00001). Combined narratively, 13 studies reported significantly lower concentrations of considered parameters in LS patients, whereas only one study reported lower inflammatory markers (for CRP and IL-6) after OS. CONCLUSION The increase in postoperative concentrations of several proinflammatory parameters was significantly less pronounced after LS than after OS in this meta-analysis. Overall, the summarized evidence reinforces the view of a lower induction of inflammation due to LS.
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Affiliation(s)
- A Bohne
- Universität Regensburg, Universitätsstraße 31, 93053, Regensburg, Germany.
| | - E Grundler
- Universität Regensburg, Universitätsstraße 31, 93053, Regensburg, Germany
| | - H Knüttel
- Universität Regensburg, Universitätsbibliothek Regensburg, Universitätsstraße 31, 93053, Regensburg, Germany
| | - V Völkel
- Tumorzentrum Regensburg - Zentrum für Qualitätssicherung und Versorgungsforschung, Universität Regensburg, Am Biopark 9, 93053, Regensburg, Germany
| | - A Fürst
- Caritas Krankenhaus St. Josef Regensburg, Klinik Für Allgemein-, Viszeral-, Thoraxchirurgie und Adipositasmedizin, Landshuter Str. 65, 93053, Regensburg, Germany
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3
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Martins-Gomes C, Nunes FM, Silva AM. Natural Products as Dietary Agents for the Prevention and Mitigation of Oxidative Damage and Inflammation in the Intestinal Barrier. Antioxidants (Basel) 2024; 13:65. [PMID: 38247489 PMCID: PMC10812469 DOI: 10.3390/antiox13010065] [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: 12/07/2023] [Revised: 12/23/2023] [Accepted: 12/29/2023] [Indexed: 01/23/2024] Open
Abstract
Food intake is a basic need to sustain life, but foodborne pathogens and food-related xenobiotics are also the main health concerns regarding intestinal barrier homeostasis. With a predominant role in the well-being of the entire human body, intestinal barrier homeostasis is strictly regulated by epithelial and immune cells. These cells are also the main intervenients in oxidative stress and inflammation-related diseases in the intestinal tract, triggered, for example, by genetic/epigenetic factors, food additives, pesticides, drugs, pathogens, and their metabolites. Nevertheless, the human diet can also be seen as a solution for the problem, mainly via the inclusion of functional foods or nutraceuticals that may act as antioxidant/anti-inflammatory agents to prevent and mitigate acute and chronic oxidative damage and inflammation. A literature analysis of recent advances in this topic highlights the significant role of Nrf2 (nuclear factor erythroid 2-related factor 2) and NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells) pathways in these biological processes, with many natural products and phytochemicals targeting endogenous antioxidant systems and cytokine production and balance. In this review, we summarized and discussed studies using in vitro and in vivo models of the intestinal tract used to reproduce oxidative damage and inflammatory events, as well as the role of natural products as modulators of Nrf2 and NK-kB pathways.
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Affiliation(s)
- Carlos Martins-Gomes
- Centre for Research and Technology of Agro-Environmental and Biological Sciences (CITAB), Cell Biology and Biochemistry Laboratory, University of Trás-os-Montes and Alto Douro (UTAD), Quinta de Prados, 5000-801 Vila Real, Portugal
- Chemistry Research Centre-Vila Real (CQ-VR), Food and Wine Chemistry Laboratory, University of Trás-os-Montes and Alto Douro (UTAD), Quinta de Prados, 5000-801 Vila Real, Portugal;
| | - Fernando M. Nunes
- Chemistry Research Centre-Vila Real (CQ-VR), Food and Wine Chemistry Laboratory, University of Trás-os-Montes and Alto Douro (UTAD), Quinta de Prados, 5000-801 Vila Real, Portugal;
- Department of Chemistry, School of Life Sciences and Environment, University of Trás-os-Montes and Alto Douro (UTAD), 5000-801 Vila Real, Portugal
| | - Amélia M. Silva
- Centre for Research and Technology of Agro-Environmental and Biological Sciences (CITAB), Cell Biology and Biochemistry Laboratory, University of Trás-os-Montes and Alto Douro (UTAD), Quinta de Prados, 5000-801 Vila Real, Portugal
- Institute for Innovation, Capacity Building and Sustainability of Agri-food Production (Inov4gro), University of Trás-os-Montes and Alto Douro (UTAD), Quinta de Prados, 5000-801 Vila Real, Portugal
- Department of Biology and Environment, School of Life Sciences and Environment, University of Trás-os-Montes and Alto Douro (UTAD), 5000-801 Vila Real, Portugal
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Abdul Kadir FFN, Che Nordin MA, S M N Mydin RB, Choong YS, Che Omar MT. Molecular interaction analysis of anti-IL-8 scFv-10F8-6His against IL-8 monomer through molecular docking and molecular dynamic simulations. J Biomol Struct Dyn 2023; 42:12293-12303. [PMID: 37837430 DOI: 10.1080/07391102.2023.2269254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Accepted: 10/04/2023] [Indexed: 10/16/2023]
Abstract
Elevated interleukin 8 (IL-8) expression has been linked to unfavorable outcomes in a range of inflammatory conditions, such as rheumatoid arthritis, psoriasis, and cancer. The human monoclonal antibody (HuMab) 10F8 and the hybridoma 35B11-B bind to an epitope on human IL-8, respectively. 10F8 inhibited interaction between IL-8 and neutrophils in eczema and pustulosis palmoplantaris patients while 35B11-B decreased size lesion in rat model. The binding interaction of monoclonal antibodies and IL-8, especially how complementarity-determining region (CDR) loops could bind the N-terminal of IL-8, has not been fully deliberated at molecular-level. Here, we used a combination of molecular docking, heated and long coarse-grained molecular dynamics simulations to identify key residues of established interaction. Based on heated MD simulation, docked pose of complexes generated by ClusPro showed good binding stability throughout of 70 ns simulation. Based on long molecular dynamic simulations, key residues for the binding were identified throughout of 1000 ns simulation. TYR-53, ASP-99, and ARG-100 of heavy chain CDR together with TYR-33 of light chain CDR are among the highest contributing energy residues within the binding interaction. Meanwhile, LYS11 and TYR13 of IL-8 are important for the determination of overall binding energy. Furthermore, the result of decomposition residues analysis is in good agreement with the interaction analysis data. Current study provides a list of important interacting residues and further scrutiny on these residues is essential for future development and design of a new and stable recombinant antibody against IL-8.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
| | - Muhamad Alif Che Nordin
- Biological Section, School of Distance Education, Universiti Sains Malaysia, Penang, Malaysia
| | - Rabiatul Basria S M N Mydin
- Biomedical Sciences Department, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Penang, Malaysia
| | - Yee Siew Choong
- Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Penang, Malaysia
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Somu P, Basavegowda N, Gomez LA, Jayaprakash HV, Puneetha GK, Yadav AK, Paul S, Baek KH. Crossroad between the Heat Shock Protein and Inflammation Pathway in Acquiring Drug Resistance: A Possible Target for Future Cancer Therapeutics. Biomedicines 2023; 11:2639. [PMID: 37893013 PMCID: PMC10604354 DOI: 10.3390/biomedicines11102639] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 09/23/2023] [Accepted: 09/25/2023] [Indexed: 10/29/2023] Open
Abstract
The development of multidrug resistance (MDR) against chemotherapeutic agents has become a major impediment in cancer therapy. Understanding the underlying mechanism behind MDR can guide future treatment for cancer with better therapeutic outcomes. Recent studies evidenced that crossroads interaction between the heat shock proteins (HSP) and inflammatory responses under the tumor microenvironment plays a pivotal role in modulating drug responsiveness and drug resistance through a complex cytological process. This review aims to investigate the interrelationship between inflammation and HSP in acquiring multiple drug resistance and investigate strategies to overcome the drug resistance to improve the efficacy of cancer treatment. HSP plays a dual regulatory effect as an immunosuppressive and immunostimulatory agent, involving the simultaneous blockade of multiple signaling pathways in acquiring MDR. For example, HSP27 shows biological effects on monocytes by causing IL10 and TNFα secretion and blocking monocyte differentiation to normal dendritic cells and tumor-associated macrophages to promote cancer progression and chemoresistance. Thus, the HSP function and immune-checkpoint release modalities provide a therapeutic target for a therapeutically beneficial approach for enhancing anti-tumor immune responses. The interconnection between inflammation and HSP, along with the tumor microenvironment in acquiring drug resistance, has become crucial for rationalizing the effect of HSP immunomodulatory activity with immune checkpoint blockade. This relationship can overcome drug resistance and assist in the development of novel combinatorial cancer immunotherapy in fighting cancer with decreasing mortality rates.
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Affiliation(s)
- Prathap Somu
- Department of Biotechnology and Chemical Engineering, School of Civil & Chemical Engineering, Manipal University Jaipur, Dehmi Kalan, Jaipur 303007, India;
| | - Nagaraj Basavegowda
- Department of Biotechnology, Yeungnam University, Gyeongsan 38451, Republic of Korea;
| | - Levin Anbu Gomez
- Department of Biotechnology, School of Agriculture and Bioscience, Karunya Institute of Technology and Sciences (Deemed-to-be University), Karunya Nagar, Coimbatore 641114, India;
| | | | | | - Akhilesh Kumar Yadav
- Department of Environmental Engineering and Management, Chaoyang University of Technology, Taichung 413310, Taiwan;
| | - Subhankar Paul
- Structural Biology and Nanomedicine Laboratory, Department of Biotechnology and Medical Engineering, National Institute of Technology, Rourkela 769008, India
| | - Kwang-Hyun Baek
- Department of Biotechnology, Yeungnam University, Gyeongsan 38451, Republic of Korea;
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Sitaru S, Budke A, Bertini R, Sperandio M. Therapeutic inhibition of CXCR1/2: where do we stand? Intern Emerg Med 2023; 18:1647-1664. [PMID: 37249756 PMCID: PMC10227827 DOI: 10.1007/s11739-023-03309-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 05/10/2023] [Indexed: 05/31/2023]
Abstract
Mounting experimental evidence from in vitro and in vivo animal studies points to an essential role of the CXCL8-CXCR1/2 axis in neutrophils in the pathophysiology of inflammatory and autoimmune diseases. In addition, the pathogenetic involvement of neutrophils and the CXCL8-CXCR1/2 axis in cancer progression and metastasis is increasingly recognized. Consequently, therapeutic targeting of CXCR1/2 or CXCL8 has been intensively investigated in recent years using a wide array of in vitro and animal disease models. While a significant benefit for patients with unwanted neutrophil-mediated inflammatory conditions may be expected from a potential clinical use of inhibitors, their use in severe infections or sepsis might be problematic and should be carefully and thoroughly evaluated in animal models and clinical trials. Translating the approaches using inhibitors of the CXCL8-CXCR1/2 axis to cancer therapy is definitively a new and promising research avenue, which parallels the ongoing efforts to clearly define the involvement of neutrophils and the CXCL8-CXCR1/2 axis in neoplastic diseases. Our narrative review summarizes the current literature on the activation and inhibition of these receptors in neutrophils, key inhibitor classes for CXCR2 and the therapeutic relevance of CXCR2 inhibition focusing here on gastrointestinal diseases.
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Affiliation(s)
- Sebastian Sitaru
- Institute of Cardiovascular Physiology and Pathophysiology, Walter Brendel Center of Experimental Medicine, University Hospital, Ludwig-Maximilian University, Großhaderner Str. 9, Planegg-Martinsried, 82152, Munich, Germany
- Department of Dermatology and Allergy, School of Medicine, Technical University of Munich, Munich, Germany
| | - Agnes Budke
- Institute of Cardiovascular Physiology and Pathophysiology, Walter Brendel Center of Experimental Medicine, University Hospital, Ludwig-Maximilian University, Großhaderner Str. 9, Planegg-Martinsried, 82152, Munich, Germany
| | | | - Markus Sperandio
- Institute of Cardiovascular Physiology and Pathophysiology, Walter Brendel Center of Experimental Medicine, University Hospital, Ludwig-Maximilian University, Großhaderner Str. 9, Planegg-Martinsried, 82152, Munich, Germany.
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Golbashirzadeh M, Heidari HR, Aghamolayi AA, Fattahi Y, Talebi M, Khosroushahi AY. In vitro siRNA-mediated GPX4 and AKT1 silencing in oxaliplatin resistance cancer cells induces ferroptosis and apoptosis. Med Oncol 2023; 40:279. [PMID: 37632628 DOI: 10.1007/s12032-023-02130-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 02/21/2022] [Indexed: 08/28/2023]
Abstract
Oxaliplatin is a member of platinum-based chemotherapy drugs frequently used in colorectal cancer (CRC). However, resistance to oxaliplatin causes tumor progression and metastasis. Akt1 and Gpx4 are essential regulator genes of apoptosis and ferroptosis pathways. Inhibition of these genes might eradicate oxaliplatin resistance in resistant CRC cells. We compared two cell death strategies to reverse drug resistance in Caco-2 and HT-29 oxaliplatin-resistant cell lines. We used the AKT1-specific siRNA to induce apoptosis. Also, GPX4-specific siRNA and FIN56 were utilized to generate ferroptosis. The effect of these treatments was assessed by reactive oxygen species (ROS) formation, cell viability, and protein expression level assays. Besides, the expression of GPX4, CoQ10, and NRF2 was assessed in both cell lines after treatments. Correctly measuring the expression of these responsible genes and proteins confirms the occurrence of different types of cell death. In addition, the ability of Akt1/ GPX4 siRNA in resensitizing HT-29 and Caco-2 oxaliplatin resistance cells was evaluated. Our finding showed that the upregulation of GPX4/siRNA caused a reduction in GPX4 and CoQ10 expressions in both cell lines. However, the expression level of NRF2 showed the same level in our cell lines, so we observed a downregulation of NRF2 in resistant CRC cell lines. Cell viability assay indicated that induction of ferroptosis by GPX4/siRNA or FIN56 and apoptosis by Akt1/siRNA in resistant cell lines could reverse the oxaliplatin resistance. We concluded that downregulation of Akt1 or Gpx4 could increase the efficacy of oxaliplatin to overcome the resistance compared to FIN56.
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Affiliation(s)
- Morteza Golbashirzadeh
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, P.O. 14766-51664, Tabriz, Iran
| | - Hamid Reza Heidari
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, P.O. 14766-51664, Tabriz, Iran.
| | - Ali Asghar Aghamolayi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, P.O. 14766-51664, Tabriz, Iran
| | - Yasin Fattahi
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, P.O. 14766-51664, Tabriz, Iran
| | - Mehdi Talebi
- Hematology and Oncology Research Center, Department of Applied Cell Sciences, School of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ahmad Yari Khosroushahi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Department of Medical Nanotechnology, Faculty of Advanced Medical Science, Tabriz University of Medical Sciences, Daneshgah Street, P.O.Box 51548-53431, Tabriz, Iran.
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Jain A, Bhattacharya S. Recent advances in nanomedicine preparative methods and their therapeutic potential for colorectal cancer: a critical review. Front Oncol 2023; 13:1211603. [PMID: 37427139 PMCID: PMC10325729 DOI: 10.3389/fonc.2023.1211603] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 06/05/2023] [Indexed: 07/11/2023] Open
Abstract
Colorectal cancer (CRC) is a prevalent malignancy that affects a large percentage of the global population. The conventional treatments for CRC have a number of limitations. Nanoparticles have emerged as a promising cancer treatment method due to their ability to directly target cancer cells and regulate drug release, thereby enhancing therapeutic efficacy and minimizing side effects. This compilation examines the use of nanoparticles as drug delivery systems for CRC treatment. Different nanomaterials can be used to administer anticancer drugs, including polymeric nanoparticles, gold nanoparticles, liposomes, and solid lipid nanoparticles. In addition, we discuss recent developments in nanoparticle preparation techniques, such as solvent evaporation, salting-out, ion gelation, and nanoprecipitation. These methods have demonstrated high efficacy in penetrating epithelial cells, a prerequisite for effective drug delivery. This article focuses on the various targeting mechanisms utilized by CRC-targeted nanoparticles and their recent advancements in this field. In addition, the review offers descriptive information regarding numerous nano-preparative procedures for colorectal cancer treatments. We also discuss the outlook for innovative therapeutic techniques in the management of CRC, including the potential application of nanoparticles for targeted drug delivery. The review concludes with a discussion of current nanotechnology patents and clinical studies used to target and diagnose CRC. The results of this investigation suggest that nanoparticles have great potential as a method of drug delivery for the treatment of colorectal cancer.
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Joshi S, Pandey R, Kumar A, Gupta V, Arya N. Targeted blockade of interleukin-8 negates metastasis and chemoresistance via Akt/Erk-NFκB axis in oral cancer. Cytokine 2023; 166:156155. [PMID: 37088002 DOI: 10.1016/j.cyto.2023.156155] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 01/18/2023] [Accepted: 02/11/2023] [Indexed: 04/25/2023]
Abstract
BACKGROUND The tumor microenvironment plays a significant role in tumor growth, metastasis and chemoresistance via dysregulated signaling pathways. Toward this, an inflammatory chemokine, interleukin-8 (IL-8), is overexpressed in various cancers and is involved in tumor progression and chemoresistance. However, the mechanistic role of IL-8 in mediating metastasis and chemoresistance in oral squamous cell carcinoma (OSCC) is not known. METHODS AND RESULTS In the present study, we evaluated the effect of IL-8 in regulating metastasis as well as chemoresistance in OSCC cell lines. For this, IL-8 was blocked exogenously using neutralizing IL-8 monoclonal antibody and IL-8 levels were enhanced by exogenous supply of recombinant human IL-8 (rhIL-8) to OSCC cells. The epithelial-to-mesenchymal transition (EMT) was evaluated using qPCR, migration by scratch/wound healing assay and invasion ability using transwell assay. rIL-8 induced chemoresistance was studied by apoptosis assay and the nuclear localization of NFκB using immunocytochemistry. IL-8 was significantly overexpressed in OSCC patients and cell lines. While exogenous blockade of IL-8 significantly reduced EMT, migration and invasion potential in OSCC cells, IL-8 overexpression upregulated these cellular traits thereby confirming the role of IL-8 in OSCC metastasis. Exogenous blockade of IL-8 also reversed chemoresistance in cisplatin resistant OSCC subline via NFκB signaling. CONCLUSION IL-8 plays a crucial role in OSCC metastasis and its targeted blockade can help in management of cisplatin resistance.
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Affiliation(s)
- Swarali Joshi
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Ahmedabad, Gujarat, India
| | - Ritu Pandey
- Department of Biochemistry, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India
| | - Ashok Kumar
- Department of Biochemistry, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India
| | - Vikas Gupta
- Department of Otorhinolaryngology (ENT) - Head & Neck Surgery, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India
| | - Neha Arya
- Department of Medical Devices, National Institute of Pharmaceutical Education and Research, Ahmedabad, Gujarat, India; Department of Translational Medicine, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India.
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Molczyk C, Singh RK. CXCR1: A Cancer Stem Cell Marker and Therapeutic Target in Solid Tumors. Biomedicines 2023; 11:biomedicines11020576. [PMID: 36831112 PMCID: PMC9953306 DOI: 10.3390/biomedicines11020576] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 02/10/2023] [Accepted: 02/14/2023] [Indexed: 02/18/2023] Open
Abstract
Therapy resistance is a significant concern while treating malignant disease. Accumulating evidence suggests that a subset of cancer cells potentiates tumor survival, therapy resistance, and relapse. Several different pathways regulate these purported cancer stem cells (CSCs). Evidence shows that the inflammatory tumor microenvironment plays a crucial role in maintaining the cancer stem cell pool. Typically, in the case of the tumor microenvironment, inflammatory pathways can be utilized by the tumor to aid in tumor progression; one such pathway is the CXCR1/2 pathway. The CXCR1 and CXCR2 receptors are intricately related, with CXCR1 binding two ligands that also bind CXCR2. They have the same downstream pathways but potentially separate roles in the tumor microenvironment. CXCR1 is becoming more well known for its role as a cancer stem cell identifier and therapeutic target. This review elucidates the role of the CXCR1 axis as a CSC marker in several solid tumors and discusses the utility of CXCR1 as a therapeutic target.
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11
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Santolla MF, Talia M, Cirillo F, Scordamaglia D, De Rosis S, Spinelli A, Miglietta AM, Nardo B, Filippelli G, De Francesco EM, Belfiore A, Lappano R, Maggiolini M. The AGEs/RAGE Transduction Signaling Prompts IL-8/CXCR1/2-Mediated Interaction between Cancer-Associated Fibroblasts (CAFs) and Breast Cancer Cells. Cells 2022; 11:2402. [PMID: 35954247 PMCID: PMC9368521 DOI: 10.3390/cells11152402] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 07/29/2022] [Accepted: 08/02/2022] [Indexed: 01/27/2023] Open
Abstract
Advanced glycation end products (AGEs) and the cognate receptor, named RAGE, are involved in metabolic disorders characterized by hyperglycemia, type 2 diabetes mellitus (T2DM) and obesity. Moreover, the AGEs/RAGE transduction pathway prompts a dysfunctional interaction between breast cancer cells and tumor stroma toward the acquisition of malignant features. However, the action of the AGEs/RAGE axis in the main players of the tumor microenvironment, named breast cancer-associated fibroblasts (CAFs), remains to be fully explored. In the present study, by chemokine array, we first assessed that interleukin-8 (IL-8) is the most up-regulated pro-inflammatory chemokine upon AGEs/RAGE activation in primary CAFs, obtained from breast tumors. Thereafter, we ascertained that the AGEs/RAGE signaling promotes a network cascade in CAFs, leading to the c-Fos-dependent regulation of IL-8. Next, using a conditioned medium from AGEs-exposed CAFs, we determined that IL-8/CXCR1/2 paracrine activation induces the acquisition of migratory and invasive features in MDA-MB-231 breast cancer cells. Altogether, our data provide new insights on the involvement of IL-8 in the AGEs/RAGE transduction pathway among the intricate connections linking breast cancer cells to the surrounding stroma. Hence, our findings may pave the way for further investigations to define the role of IL-8 as useful target for the better management of breast cancer patients exhibiting metabolic disorders.
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Affiliation(s)
- Maria Francesca Santolla
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy
| | - Marianna Talia
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy
| | - Francesca Cirillo
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy
| | - Domenica Scordamaglia
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy
| | - Salvatore De Rosis
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy
| | - Asia Spinelli
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy
| | - Anna Maria Miglietta
- Breast and General Surgery Unit, Regional Hospital Cosenza, 87100 Cosenza, Italy
| | - Bruno Nardo
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy
- Breast and General Surgery Unit, Regional Hospital Cosenza, 87100 Cosenza, Italy
| | | | - Ernestina Marianna De Francesco
- Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, 95122 Catania, Italy
| | - Antonino Belfiore
- Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, 95122 Catania, Italy
| | - Rosamaria Lappano
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy
| | - Marcello Maggiolini
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy
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Nano-Drug Delivery Systems Based on Different Targeting Mechanisms in the Targeted Therapy of Colorectal Cancer. Molecules 2022; 27:molecules27092981. [PMID: 35566331 PMCID: PMC9099628 DOI: 10.3390/molecules27092981] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 04/23/2022] [Accepted: 05/03/2022] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is a usual digestive tract malignancy and the third main cause of cancer death around the world, with a high occurrence rate and mortality rate. Conventional therapies for CRC have certain side effects and restrictions. However, the exciting thing is that with the rapid development of nanotechnology, nanoparticles have gradually become more valuable drug delivery systems than traditional therapies because of their capacity to control drug release and target CRC. This also promotes the application of nano-drug targeted delivery systems in the therapy of CRC. Moreover, to make nanoparticles have a better colon targeting effect, many approaches have been used, including nanoparticles targeting CRC and in response to environmental signals. In this review, we focus on various targeting mechanisms of CRC-targeted nanoparticles and their latest research progress in the last three years, hoping to give researchers some inspiration on the design of CRC-targeted nanoparticles.
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13
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Li L, Chen C, Xiang Q, Fan S, Xiao T, Chen Y, Zheng D. Transient Receptor Potential Cation Channel Subfamily V Member 1 Expression Promotes Chemoresistance in Non-Small-Cell Lung Cancer. Front Oncol 2022; 12:773654. [PMID: 35402237 PMCID: PMC8990814 DOI: 10.3389/fonc.2022.773654] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Accepted: 03/02/2022] [Indexed: 12/23/2022] Open
Abstract
Approximately 85% of lung cancer cases are non-small-cell lung cancer (NSCLC). Chemoresistance is a leading cause of chemotherapy failure in NSCLC treatment. Transient receptor potential cation channel subfamily V, member 1 (TRPV1), a non-selective cation channel, plays multiple roles in tumorigenesis and tumor development, including tumor cell proliferation, death, and metastasis as well as the response to therapy. In this study, we found TRPV1 expression was increased in NSCLC. TRPV1 overexpression induced cisplatin (DDP) and fluorouracil (5-FU) resistance in A549 cells independent of its channel function. TRPV1 expression was upregulated in A549-DDP/5-FU resistant cells, and DDP/5-FU sensitivity was restored by TRPV1 knockdown. TRPV1 overexpression mediated DDP and 5-FU resistance by upregulation of ABCA5 drug transporter gene expression, thereby increasing drug efflux, enhancing homologous recombination (HR) DNA repair pathway to alleviate apoptosis and activating IL-8 signaling to promote cell survival. These findings demonstrate an essential role of TRPV1 in chemoresistance in NSCLC and implicate TRPV1 as a potential chemotherapeutic target.
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Affiliation(s)
- Li Li
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Shenzhen University International Cancer Center, Department of Cell Biology and Genetics, School of Medicine, Shenzhen University, Shenzhen, China
| | - Cheng Chen
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Shenzhen University International Cancer Center, Department of Cell Biology and Genetics, School of Medicine, Shenzhen University, Shenzhen, China
| | - Qin Xiang
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Shenzhen University International Cancer Center, Department of Cell Biology and Genetics, School of Medicine, Shenzhen University, Shenzhen, China
| | - Songqing Fan
- Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Tian Xiao
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Shenzhen University International Cancer Center, Department of Cell Biology and Genetics, School of Medicine, Shenzhen University, Shenzhen, China
| | - Yangchao Chen
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Duo Zheng
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Shenzhen University International Cancer Center, Department of Cell Biology and Genetics, School of Medicine, Shenzhen University, Shenzhen, China
- *Correspondence: Duo Zheng,
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14
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Identification of Growth Factors, Cytokines and Mediators Regulated by Artemisia annua L. Polyphenols (pKAL) in HCT116 Colorectal Cancer Cells: TGF-β1 and NGF-β Attenuate pKAL-Induced Anticancer Effects via NF-κB p65 Upregulation. Int J Mol Sci 2022; 23:ijms23031598. [PMID: 35163520 PMCID: PMC8835737 DOI: 10.3390/ijms23031598] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 01/26/2022] [Accepted: 01/28/2022] [Indexed: 11/30/2022] Open
Abstract
The anticancer effects of natural phytochemicals are relevant to the modulation of cytokine signaling pathways in various cancer cells with stem-like properties as well as immune cells. The aim of this study was to elucidate a novel anticancer mechanism of Artemisia annua L. polyphenols (pKAL) involved in the regulation of growth factors, cytokines and mediators in stem-like HCT116 colorectal cancer cells. Through RayBiotech human L-1000 antibody array and bioinformatics analysis, we show here that pKAL-induced anticancer effects are associated with downregulation of growth factor and cytokine signaling proteins including TGFA, FGF16, PDGFC, CCL28, CXCR3, IRF6 and SMAD1. Notably, we found that TGF-β signaling proteins such as GDF10, ENG and TGFBR2 and well-known survival proteins such as NGF-β, VEGFD and insulin were significantly upregulated by pKAL. Moreover, the results of hematoxylin staining, cell viability assay and Western blot analysis demonstrated that TGF-β1 and NGF-β attenuated pKAL-induced anticancer effects by inhibiting pKAL-induced downregulation of caspase-8, NF-κB p65 and cyclin D1. These results suggest that certain survival mediators may be activated by pKAL through the TGF-β1 and NGF-β signaling pathways during pKAL-induced cell death and thus, strategies to inhibit the survival signaling are inevitably required for more effective anticancer effects of pKAL.
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15
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Hameed Y, Usman M, Liang S, Ejaz S. Novel diagnostic and prognostic biomarkers of colorectal cancer: Capable to overcome the heterogeneity-specific barrier and valid for global applications. PLoS One 2021; 16:e0256020. [PMID: 34473751 PMCID: PMC8412268 DOI: 10.1371/journal.pone.0256020] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Accepted: 07/28/2021] [Indexed: 02/05/2023] Open
Abstract
INTRODUCTION The heterogeneity-specific nature of the available colorectal cancer (CRC) biomarkers is significantly contributing to the cancer-associated high mortality rate worldwide. Hence, this study was initiated to investigate a system of novel CRC biomarkers that could commonly be employed to the CRC patients and helpful to overcome the heterogenetic-specific barrier. METHODS Initially, CRC-related hub genes were extracted through PubMed based literature mining. A protein-protein interaction (PPI) network of the extracted hub genes was constructed and analyzed to identify few more closely CRC-related hub genes (real hub genes). Later, a comprehensive bioinformatics approach was applied to uncover the diagnostic and prognostic role of the identified real hub genes in CRC patients of various clinicopathological features. RESULTS Out of 210 collected hub genes, in total 6 genes (CXCL12, CXCL8, AGT, GNB1, GNG4, and CXCL1) were identified as the real hub genes. We further revealed that all the six real hub genes were significantly dysregulated in colon adenocarcinoma (COAD) patients of various clinicopathological features including different races, cancer stages, genders, age groups, and body weights. Additionally, the dysregulation of real hub genes has shown different abnormal correlations with many other parameters including promoter methylation, overall survival (OS), genetic alterations and copy number variations (CNVs), and CD8+T immune cells level. Finally, we identified a potential miRNA and various chemotherapeutic drugs via miRNA, and real hub genes drug interaction network that could be used in the treatment of CRC by regulating the expression of real hub genes. CONCLUSION In conclusion, we have identified six real hub genes as potential biomarkers of CRC patients that could help to overcome the heterogenetic-specific barrier across different clinicopathological features.
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Affiliation(s)
- Yasir Hameed
- Department of Biotechnology, Institute of Biochemistry, Biotechnology and Bioinformatics, The Islamia University of Bahawalpur, Bahawalpur, Pakistan
| | - Muhammad Usman
- Department of Biotechnology, Institute of Biochemistry, Biotechnology and Bioinformatics, The Islamia University of Bahawalpur, Bahawalpur, Pakistan
| | - Shufang Liang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, P.R. China
| | - Samina Ejaz
- Department of Biochemistry, Institute of Biochemistry, Biotechnology and Bioinformatics, The Islamia University of Bahawalpur, Bahawalpur, Pakistan
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16
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Comprehensive Omics Analysis of a Novel Small-Molecule Inhibitor of Chemoresistant Oncogenic Signatures in Colorectal Cancer Cell with Antitumor Effects. Cells 2021; 10:cells10081970. [PMID: 34440739 PMCID: PMC8392328 DOI: 10.3390/cells10081970] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 07/27/2021] [Accepted: 07/30/2021] [Indexed: 01/10/2023] Open
Abstract
Tumor recurrence from cancer stem cells (CSCs) and metastasis often occur post-treatment in colorectal cancer (CRC), leading to chemoresistance and resistance to targeted therapy. MYC is a transcription factor in the nuclei that modulates cell growth and development, and regulates immune response in an antitumor direction by mediating programmed death ligand 1 (PD-L1) and promoting CRC tumor recurrence after adjuvant chemotherapy. However, the molecular mechanism through which c-MYC maintains stemness and confers treatment resistance still remains elusive in CRC. In addition, recent reports demonstrated that CRC solid colon tumors expresses C-X-C motif chemokine ligand 8 (CXCL8). Expression of CXCL8 in CRC was reported to activate the expression of PD-L1 immune checkpoint through c-MYC, this ultimately induces chemoresistance in CRC. Accumulating studies have also demonstrated increased expression of CXCL8, matrix metalloproteinase 7 (MMP7), tissue inhibitor of metalloproteinase 1 (TIMP1), and epithelial-to-mesenchymal transition (EMT) components, in CRC tumors suggesting their potential collaboration to promote EMT and CSCs. TIMP1 is MMP-independent and regulates cell development and apoptosis in various cancer cell types, including CRC. Recent studies showed that TIMP1 cleaves CXCL8 on its chemoattractant, thereby influencing its mechanistic response to therapy. This therefore suggests crosstalk among the c-MYC/CXCL8/TIMP1 oncogenic signatures. In this study, we explored computer simulations through bioinformatics to identify and validate that the MYC/CXCL8/TIMP1 oncogenic signatures are overexpressed in CRC, Moreover, our docking results exhibited putative binding affinities of the above-mentioned oncogenes, with our novel small molecule, RV59, Finally, we demonstrated the anticancer activities of RV59 against NCI human CRC cancer cell lines both as single-dose and dose-dependent treatments, and also demonstrated the MYC/CXCL8/TIMP1 signaling pathway as a potential RV59 drug target.
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17
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Cheng KJ, Mejia Mohammed EH, Khong TL, Mohd Zain S, Thavagnanam S, Ibrahim ZA. IL-1α and colorectal cancer pathogenesis: Enthralling candidate for anti-cancer therapy. Crit Rev Oncol Hematol 2021; 163:103398. [PMID: 34147647 DOI: 10.1016/j.critrevonc.2021.103398] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 06/08/2021] [Accepted: 06/09/2021] [Indexed: 01/04/2023] Open
Abstract
Inflammation has been well-established as a hallmark of colorectal cancer (CRC). Interleukin-1 alpha (IL-1α) is one of the primary inflammatory mediators driving the pathogenesis of inflammation-associated CRC. This systematic review presents the roles of IL-1α in the pathogenesis of the disease. Bibliographic databases PubMed, Science Direct, Scopus and Web of Science were systematically searched for articles that addresses the relationship between IL-1α and colorectal cancer. We highlighted various mechanisms by which IL-1α promotes the pathogenesis of CRC including enhancement of angiogenesis, metastasis, resistance to therapy, and inhibition of tumour suppressive genes. We also discussed the potential mechanisms by which IL-1α expression is induced or secreted in various studies. Beyond these, the systematic review also highlights several potential therapeutic strategies which should be further explored in the future; to target IL-1α and/or its associated pathways; paving our way in finding effective treatments for CRC patients.
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Affiliation(s)
- Kim Jun Cheng
- Department of Pharmacology, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | | | - Tak Loon Khong
- Department of Surgery, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | - Shamsul Mohd Zain
- Department of Pharmacology, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | - Surendran Thavagnanam
- Department of Paediatrics, Royal London Hospital, Whitechapel Rd, Whitechapel, E1 1FR London, United Kingdom
| | - Zaridatul Aini Ibrahim
- Department of Pharmacology, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia.
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18
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Markiewicz LH, Ogrodowczyk AM, Wiczkowski W, Wróblewska B. Phytate and Butyrate Differently Influence the Proliferation, Apoptosis and Survival Pathways in Human Cancer and Healthy Colonocytes. Nutrients 2021; 13:1887. [PMID: 34072741 PMCID: PMC8230256 DOI: 10.3390/nu13061887] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 05/19/2021] [Accepted: 05/28/2021] [Indexed: 12/12/2022] Open
Abstract
The colonic epithelium is never exposed to a single factor, therefore studies on the effect of combinations of factors naturally and persistently present in the intestines are of special importance for understanding the phenomena occurring at this place. The aim of the study was to investigate the combined effect of 1 mM phytate and 1 mM butyrate (PA1B1) on cell lines derived from cancer (HCT116 and HT-29) and healthy (NCM460D) human colonic epithelium. Colorimetric and flow cytometry methods were used to determine the proliferation rate, cell cycle, and apoptosis. Selected markers of proliferation, inflammatory, and survival pathways were investigated at the mRNA and/or protein level. The combination of phytate and butyrate disturbed the cell cycle and triggered apoptosis and/or death in both studied cancer colonocytes to a higher extent compared to healthy colonocytes. Moreover, in healthy colonocytes, phytate activated the survival pathway without stimulation of inflammatory response. This may indicate that the response of healthy colonocytes to phytate protects colonic epithelium from the loss of integrity and tightness that would occur if inflammation developed. Based on the obtained results we postulate that studies on both cancer and/or healthy colonocytes should be carried out in the presence of butyrate as the permanent component of colonic contents. This should be of special importance when anti-proliferative/pro-apoptotic activity or inflammatory status of colonocytes is to be investigated.
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Affiliation(s)
- Lidia Hanna Markiewicz
- Department of Immunology and Food Microbiology, Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Tuwima 10, 10-748 Olsztyn, Poland; (A.M.O.); (B.W.)
| | - Anna Maria Ogrodowczyk
- Department of Immunology and Food Microbiology, Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Tuwima 10, 10-748 Olsztyn, Poland; (A.M.O.); (B.W.)
| | - Wiesław Wiczkowski
- Department of Chemistry and Biodynamics of Food, Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Tuwima 10, 10-748 Olsztyn, Poland;
| | - Barbara Wróblewska
- Department of Immunology and Food Microbiology, Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Tuwima 10, 10-748 Olsztyn, Poland; (A.M.O.); (B.W.)
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19
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Zheng Z, Xie J, Xiong L, Gao M, Qin L, Dai C, Liang Z, Wang Y, Xue J, Wang Q, Wang W, Li X. Identification of candidate biomarkers and therapeutic drugs of colorectal cancer by integrated bioinformatics analysis. Med Oncol 2020; 37:104. [PMID: 33078282 DOI: 10.1007/s12032-020-01425-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Accepted: 09/26/2020] [Indexed: 12/18/2022]
Abstract
Most colorectal cancer (CRC) patients are diagnosed with advanced stages and low prognosis. We aimed to identify potential diagnostic and prognostic biomarkers, as well as active small molecules of CRC. Microarray data (GSE9348, GSE35279, and GSE106582) were obtained from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified by the GEO2R platform. Common DEGs were selected for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Cytoscape software was used to construct protein-protein interaction networks and identify hub genes. Hub genes were evaluated by Kaplan-Meier survival analysis in the GEPIA database and validated in two independent microarray data (GSE74602 and GSE83889). Common DEGs were used to select active small molecules by the connectivity map database. A total of 166 DEGs were identified as common DEGs. GO analysis demonstrated that common DEGs were significantly enriched in the apoptotic process, cell proliferation, and cell adhesion. KEGG analysis indicated that the most enriched pathways were the PI3K-Akt signaling pathway and extracellular matrix-receptor interaction. COL1A2, THBS2, TIMP1, and CXCL8 significantly upregulated in colorectal tumor. High expressions of COL1A2, THBS2, and TIMP1 were associated with poor survival, while high expressions of CXCL8 were associated with better survival. We selected 11 small molecules for CRC therapy. In conclusion, we found key dysregulated genes associated with CRC and potential small molecules to reverse them. COL1A2, THBS2, TIMP1, and CXCL8 may act as diagnostic and prognostic biomarkers of CRC.
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Affiliation(s)
- Zhuoling Zheng
- Department of Pharmacy, The Sixth Affiliated Hospital, Sun Yat-Sen University, 26 Erheng Road of Yuan Village, Guangzhou, 510655, China
| | - Jingwen Xie
- Department of Pharmacy, The Sixth Affiliated Hospital, Sun Yat-Sen University, 26 Erheng Road of Yuan Village, Guangzhou, 510655, China
| | - Lixiong Xiong
- Department of Pharmacy, The Sixth Affiliated Hospital, Sun Yat-Sen University, 26 Erheng Road of Yuan Village, Guangzhou, 510655, China
| | - Min Gao
- Department of Pharmacy, The Sixth Affiliated Hospital, Sun Yat-Sen University, 26 Erheng Road of Yuan Village, Guangzhou, 510655, China
| | - Li Qin
- Department of Pharmacy, The Sixth Affiliated Hospital, Sun Yat-Sen University, 26 Erheng Road of Yuan Village, Guangzhou, 510655, China
| | - Chunmei Dai
- Department of Pharmacy, The Sixth Affiliated Hospital, Sun Yat-Sen University, 26 Erheng Road of Yuan Village, Guangzhou, 510655, China
| | - Zhikun Liang
- Department of Pharmacy, The Sixth Affiliated Hospital, Sun Yat-Sen University, 26 Erheng Road of Yuan Village, Guangzhou, 510655, China
| | - Yiting Wang
- Department of Pharmacy, The Sixth Affiliated Hospital, Sun Yat-Sen University, 26 Erheng Road of Yuan Village, Guangzhou, 510655, China
| | - Jing Xue
- Department of Pharmacy, The Sixth Affiliated Hospital, Sun Yat-Sen University, 26 Erheng Road of Yuan Village, Guangzhou, 510655, China
| | - Qinbo Wang
- Department of Pharmacy, The Sixth Affiliated Hospital, Sun Yat-Sen University, 26 Erheng Road of Yuan Village, Guangzhou, 510655, China
| | - Wenhui Wang
- Network Information Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, 26 Erheng Road of Yuan Village, Guangzhou, 510655, China. .,National Engineering Research Center of Digital Life, Sun Yat-Sen University, 132 Waihuan Dong Road, University City, Guangzhou, 510006, China.
| | - Xiaoyan Li
- Department of Pharmacy, The Sixth Affiliated Hospital, Sun Yat-Sen University, 26 Erheng Road of Yuan Village, Guangzhou, 510655, China.
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20
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Fousek K, Horn LA, Palena C. Interleukin-8: A chemokine at the intersection of cancer plasticity, angiogenesis, and immune suppression. Pharmacol Ther 2020; 219:107692. [PMID: 32980444 DOI: 10.1016/j.pharmthera.2020.107692] [Citation(s) in RCA: 199] [Impact Index Per Article: 39.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 09/17/2020] [Indexed: 12/11/2022]
Abstract
Tumor progression relies on the ability of cancer cells to effectively invade surrounding tissues and propagate. Among the many mechanisms that contribute to tumor progression is the epithelial-to-mesenchymal transition (EMT), a phenotypic plasticity phenomenon that increases the cancer cells' motility and invasiveness and influences their surrounding microenvironment by promoting the secretion of a variety of soluble factors. One such factor is IL-8, a chemokine with multiple pro-tumorigenic roles within the tumor microenvironment (TME), including stimulating proliferation or transformation of tumor cells into a migratory or mesenchymal phenotype. Further, IL-8 can increase tumor angiogenesis or recruit larger numbers of immunosuppressive cells to the tumor. Prognostically, observations in many tumor types show that patients with higher levels of IL-8 at baseline experience worse clinical outcomes. Additionally, studies have shown that the chemokine directly contributes to the development of resistance to both chemotherapy and molecularly targeted agents. More recently, clinical studies evaluating levels of IL-8 in patients receiving immune checkpoint inhibition (ICI) therapy deduced that myeloid tumor infiltration driven by IL-8 contributes to resistance to ICI agents and that peripheral IL-8 can predict outcomes to ICI therapy. Further, pre-clinical data demonstrate that targeting IL-8 or its receptors enables improved tumor killing by immune cells, and treatment strategies combining blockade of the IL-8/IL-8R axis with ICI ultimately improve anti-tumor efficacy. Based on these results and the prognostic capacity of IL-8, there are a number of ongoing clinical trials evaluating the addition of IL-8 targeting strategies to immune-based therapies.
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Affiliation(s)
- Kristen Fousek
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Lucas A Horn
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Claudia Palena
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
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21
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Blondy S, David V, Verdier M, Mathonnet M, Perraud A, Christou N. 5-Fluorouracil resistance mechanisms in colorectal cancer: From classical pathways to promising processes. Cancer Sci 2020; 111:3142-3154. [PMID: 32536012 PMCID: PMC7469786 DOI: 10.1111/cas.14532] [Citation(s) in RCA: 305] [Impact Index Per Article: 61.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 06/06/2020] [Accepted: 06/09/2020] [Indexed: 12/11/2022] Open
Abstract
Colorectal cancer (CRC) is a public health problem. It is the third most common cancer in the world, with nearly 1.8 million new cases diagnosed in 2018. The only curative treatment is surgery, especially for early tumor stages. When there is locoregional or distant invasion, chemotherapy can be introduced, in particular 5-fluorouracil (5-FU). However, the disease can become tolerant to these pharmaceutical treatments: resistance emerges, leading to early tumor recurrence. Different mechanisms can explain this 5-FU resistance. Some are disease-specific, whereas others, such as drug efflux, are evolutionarily conserved. These mechanisms are numerous and complex and can occur simultaneously in cells exposed to 5-FU. In this review, we construct a global outline of different mechanisms from disruption of 5-FU-metabolic enzymes and classic cellular processes (apoptosis, autophagy, glucose metabolism, oxidative stress, respiration, and cell cycle perturbation) to drug transporters and epithelial-mesenchymal transition induction. Particular interest is directed to tumor microenvironment function as well as epigenetic alterations and miRNA dysregulation, which are the more promising processes that will be the subject of much research in the future.
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Affiliation(s)
- Sabrina Blondy
- Faculty of Medicine, Laboratoire EA3842 CAPTuR "Control of cell activation, Tumor progression and Therapeutic resistance", Limoges cedex, France
| | - Valentin David
- Faculty of Medicine, Laboratoire EA3842 CAPTuR "Control of cell activation, Tumor progression and Therapeutic resistance", Limoges cedex, France.,Department of pharmacy, University Hospital of Limoges, Limoges, France
| | - Mireille Verdier
- Faculty of Medicine, Laboratoire EA3842 CAPTuR "Control of cell activation, Tumor progression and Therapeutic resistance", Limoges cedex, France
| | - Muriel Mathonnet
- Faculty of Medicine, Laboratoire EA3842 CAPTuR "Control of cell activation, Tumor progression and Therapeutic resistance", Limoges cedex, France.,Service de Chirurgie Digestive, Department of Digestive, General and Endocrine Surgery, University Hospital of Limoges, Limoges, France
| | - Aurélie Perraud
- Faculty of Medicine, Laboratoire EA3842 CAPTuR "Control of cell activation, Tumor progression and Therapeutic resistance", Limoges cedex, France.,Service de Chirurgie Digestive, Department of Digestive, General and Endocrine Surgery, University Hospital of Limoges, Limoges, France
| | - Niki Christou
- Faculty of Medicine, Laboratoire EA3842 CAPTuR "Control of cell activation, Tumor progression and Therapeutic resistance", Limoges cedex, France.,Service de Chirurgie Digestive, Department of Digestive, General and Endocrine Surgery, University Hospital of Limoges, Limoges, France
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22
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Najdaghi S, Razi S, Rezaei N. An overview of the role of interleukin-8 in colorectal cancer. Cytokine 2020; 135:155205. [PMID: 32721849 DOI: 10.1016/j.cyto.2020.155205] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2020] [Revised: 07/08/2020] [Accepted: 07/09/2020] [Indexed: 02/07/2023]
Abstract
Colorectal Cancer (CRC), a common malignancy, is developing globally among people. Mutagenic insults activate peripheral nucleated cells to secrete chemokines in order to cause an inflammatory state. Despite the presence of multi-retrieving factors, elevated production of minor cytokines may speed-up the sever stages of the baseline inflammation targeting normal compensatory mechanism. IL-8 is a pro-inflammatory cytokine that is believed to be up-regulated in CRC to proceed primary condition into tumor behavior via induction of proliferation, angiogenesis and metastasis. Here, we assess the role of IL-8 in every step of CRC from signaling pathway and formation to invasion and discuss around new perspective therapy that targets IL-8 to manage CRC worldwide incidence and survival rate, more precisely.
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Affiliation(s)
- Soroush Najdaghi
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Isfahan Neurosciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Sepideh Razi
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Student Research Committee, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Sheffield, UK.
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23
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Li J, Huang L, Zhao H, Yan Y, Lu J. The Role of Interleukins in Colorectal Cancer. Int J Biol Sci 2020; 16:2323-2339. [PMID: 32760201 PMCID: PMC7378639 DOI: 10.7150/ijbs.46651] [Citation(s) in RCA: 93] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2020] [Accepted: 05/30/2020] [Indexed: 12/13/2022] Open
Abstract
Despite great progress has been made in treatment strategies, colorectal cancer (CRC) remains the predominant life-threatening malignancy with the feature of high morbidity and mortality. It has been widely acknowledged that the dysfunction of immune system, including aberrantly expressed cytokines, is strongly correlated with the pathogenesis and progression of colorectal cancer. As one of the most well-known cytokines that were discovered centuries ago, interleukins are now uncovering new insights into colorectal cancer therapy. Herein, we divide currently known interleukins into 6 families, including IL-1 family, IL-2 family, IL-6 family, IL-8 family, IL-10 family and IL-17 family. In addition, we comprehensively reviewed the oncogenic or antitumour function of each interleukin involved in CRC pathogenesis and progression by elucidating the underlying mechanisms. Furthermore, by providing interleukins-associated clinical trials, we have further driven the profound prospect of interleukins in the treatment of colorectal cancer.
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Affiliation(s)
- Jingjing Li
- Department of Clinical Medicine, Grade 2017, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, Henan, China
| | - Ling Huang
- Department of Clinical Medicine, Grade 2017, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, Henan, China
| | - Hanzhang Zhao
- Department of Clinical Medicine, Grade 2017, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, Henan, China
| | - Yuheng Yan
- Department of Clinical Medicine, Grade 2017, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, Henan, China
| | - Jing Lu
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, Henan, China
- Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou University, Zhengzhou 450001, Henan, China
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou 450001, Henan, China
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24
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Limpakan Yamada S, Wongsirisin P, Yodkeeree S, Chakrabandhu B, Chongruksut W, Limtrakul Dejkriengkraikul P. Interleukin-8 associated with chemosensitivity and poor chemotherapeutic response to gastric cancer. J Gastrointest Oncol 2020; 10:1120-1132. [PMID: 31949929 DOI: 10.21037/jgo.2019.09.02] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Background Gastric cancer (GC) patients have been found to have developed chemotherapy resistance that has resulted in a lowering of their overall survival rates. Interleukin-6 (IL-6) and interleukin-8 (IL-8) could be responsible as the predictive biomarkers in monitoring drug resistance. We have developed a protocol to monitor drug treatment by testing ex vivo chemosensitivity and cytokine levels of primary gastric cultures obtained from endoscopic biopsies. Methods We studied 49 patients with distal GC who underwent primary surgical resection between June 2014 and December 2016 in the northern endemic region of Thailand. The clinical and pathological data of patients were recorded, and the cancer sub-type was classified. The correlation of cytokine IL-6 and IL-8 protein expression levels and chemotherapy sensitivity in primary gastric cultures was investigated. Endoscopic biopsies were collected before and/or after chemotherapy treatment followed by FOLFOXIV regimen (oxaliplatin + 5-FU/leucovorin). The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed to examine ex vivo chemosensitivity to cisplatin, oxaliplatin, 5-fluorouracil (5-FU) and irinotecan. Enzyme-linked immunosorbent assay (ELISA) was performed to investigate cytokine levels. Results Ex vivo drug treatment of 49 primary gastric cultures from naive patients revealed a significant correlation between basal levels of IL-8 and chemosensitivity to cisplatin (P=0.001) and oxaliplatin (P=0.001). IL-8 protein expression levels were significantly decreased in the early phase after cisplatin and oxaliplatin treatments leading to an increase in cell sensitivity to drug treatments. Among 49 patients, 11 patients were classified as partial or poor responders after drug interventions, in which case, second endoscopic biopsies were performed for determination of chemosensitivity and cytokine levels. The results demonstrated significant decreases in sensitivity to cisplatin (P=0.049) and oxaliplatin (P=0.014), meanwhile IL-8 protein expression levels were significantly increased by P=0.0423 in both drug treatments. There was no correlation of IL-6 and drug resistance when treatments of the primary gastric cultures involved each of the four chemotherapeutic drugs (P=0.0663). Conclusions Upregulation of IL-8 after drug intervention might be useful as predictive biomarker in monitoring drug resistance in GC patients; however, this needs to be confirmed among a larger number of patients and with control groups that are properly age-paired. The established primary gastric culture could serve as a valuable tool for chemotherapy screening, while the repeated usage of platinum drugs may result in drug resistance via upregulation of IL-8 levels.
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Affiliation(s)
- Sirikan Limpakan Yamada
- Division of Gastrointestinal Surgery and Endoscopy, Department of Surgery, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.,Gastric Cancer Research Cluster, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Pattama Wongsirisin
- Anticarcinogenesis and Apoptosis Research Cluster, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.,Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Supachai Yodkeeree
- Anticarcinogenesis and Apoptosis Research Cluster, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.,Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.,Center for Research and Development of Natural Products for Health, Chiang Mai University, Chiang Mai, Thailand
| | - Bandhuphat Chakrabandhu
- Division of Gastrointestinal Surgery and Endoscopy, Department of Surgery, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.,Gastric Cancer Research Cluster, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Wilaiwan Chongruksut
- Division of Gastrointestinal Surgery and Endoscopy, Department of Surgery, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.,Gastric Cancer Research Cluster, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Pornngarm Limtrakul Dejkriengkraikul
- Anticarcinogenesis and Apoptosis Research Cluster, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.,Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.,Center for Research and Development of Natural Products for Health, Chiang Mai University, Chiang Mai, Thailand
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25
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Gasiulė S, Dreize N, Kaupinis A, Ražanskas R, Čiupas L, Stankevičius V, Kapustina Ž, Laurinavičius A, Valius M, Vilkaitis G. Molecular Insights into miRNA-Driven Resistance to 5-Fluorouracil and Oxaliplatin Chemotherapy: miR-23b Modulates the Epithelial–Mesenchymal Transition of Colorectal Cancer Cells. J Clin Med 2019; 8:E2115. [PMID: 31810268 PMCID: PMC6947029 DOI: 10.3390/jcm8122115] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 11/27/2019] [Accepted: 11/29/2019] [Indexed: 02/07/2023] Open
Abstract
Although treatment of colorectal cancer with 5-florouracil and oxaliplatin is widely used, it is frequently followed by a relapse. Therefore, there is an urgent need for profound understanding of chemotherapy resistance mechanisms as well as the profiling of predictive markers for individualized treatment. In this study, we identified the changes in 14 miRNAs in 5-fluouracil and 40 miRNAs in oxaliplatin-resistant cell lines by miRNA sequencing. The decrease in miR-224-5p expression in the 5-fluorouracil-resistant cells correlated with drug insensitivity due to its overexpression-induced drug-dependent apoptosis. On the other hand, the miR-23b/27b/24-1 cluster was overexpressed in oxaliplatin-resistant cells. The knockout of miR-23b led to the partial restoration of oxaliplatin susceptibility, showing the essential role of miR-23b in the development of drug resistance by this cluster. Proteomic analysis identified target genes of miR-23b and showed that endothelial-mesenchymal transition (EMT) was implicated in oxaliplatin insensibility. Data revealed that EMT markers, such as vimentin and SNAI2, were expressed moderately higher in the oxaliplatin-resistant cells and their expression increased further in the less drug-resistant cells, which had miR-23b knockout. This establishes that the balance of EMT contributes to the drug resistance, showing the importance of the miR-23b-mediated fine-tuning of EMT in oxaliplatin-resistant cancer cells.
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Affiliation(s)
- Stasė Gasiulė
- Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius LT-10257, Lithuania; (S.G.); (R.R.); (L.Č.); (V.S.)
| | - Nadezda Dreize
- Institute of Biochemistry, Life Sciences Center, Vilnius University, Vilnius LT-10257, Lithuania; (N.D.); (A.K.)
| | - Algirdas Kaupinis
- Institute of Biochemistry, Life Sciences Center, Vilnius University, Vilnius LT-10257, Lithuania; (N.D.); (A.K.)
| | - Raimundas Ražanskas
- Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius LT-10257, Lithuania; (S.G.); (R.R.); (L.Č.); (V.S.)
| | - Laurynas Čiupas
- Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius LT-10257, Lithuania; (S.G.); (R.R.); (L.Č.); (V.S.)
| | - Vaidotas Stankevičius
- Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius LT-10257, Lithuania; (S.G.); (R.R.); (L.Č.); (V.S.)
| | - Žana Kapustina
- Thermo Fisher Scientific Baltics, Vilnius LT-02241, Lithuania;
| | - Arvydas Laurinavičius
- National Center of Pathology, Affiliate of Vilnius University Hospital Santaros Klinikos, Vilnius LT-08406, Lithuania;
- Faculty of Medicine, Vilnius University, Vilnius LT-03101, Lithuania
| | - Mindaugas Valius
- Institute of Biochemistry, Life Sciences Center, Vilnius University, Vilnius LT-10257, Lithuania; (N.D.); (A.K.)
| | - Giedrius Vilkaitis
- Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius LT-10257, Lithuania; (S.G.); (R.R.); (L.Č.); (V.S.)
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26
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The Crucial Role of CXCL8 and Its Receptors in Colorectal Liver Metastasis. DISEASE MARKERS 2019; 2019:8023460. [PMID: 31827643 PMCID: PMC6886345 DOI: 10.1155/2019/8023460] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Accepted: 10/25/2019] [Indexed: 12/18/2022]
Abstract
CXCL8 (also known as IL-8) can produce different biological effects by binding to its receptors: CXCR1, CXCR2, and the Duffy antigen receptor for chemokines (DARC). CXCL8 and its receptors are associated with the development of various tumor types, especially colorectal cancer and its liver metastases. In addition to promoting angiogenesis, proliferation, invasion, migration, and the survival of colorectal cancer (CRC) cells, CXCL8 and its receptors have also been known to induce the epithelial-mesenchymal transition (EMT) of CRC cells, to help them to escape host immunosurveillance as well as to enhance resistance to anoikis, which promotes the formation of circulating tumor cells (CTCs) and their colonization of distant organs. In this paper, we will review the established roles of CXCL8 signaling in CRC and discuss the possible strategies of targeting CXCL8 signaling for overcoming CRC drug resistance and cancer progression, including direct targeting of CXCL8/CXCR1/2 or indirect targeting through the inhibition of CXCL8-CXCR1/2 signaling.
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27
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miR-361 enhances sensitivity to 5-fluorouracil by targeting the FOXM1-ABCC5/10 signaling pathway in colorectal cancer. Oncol Lett 2019; 18:4064-4073. [PMID: 31579069 PMCID: PMC6757261 DOI: 10.3892/ol.2019.10741] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2018] [Accepted: 06/28/2019] [Indexed: 12/18/2022] Open
Abstract
Colorectal cancer (CRC) is one of most common malignancies worldwide. 5-fluorouracil (5-FU) is a mainstay of CRC treatment, particularly in patients with advanced stages of the disease; however, 5-FU-based chemotherapy is not always effective and may result in progression of the disease. The present study investigated several candidate microRNAs (miRs) in parental and 5-FU-resistant HCT116 and HT29 cells, and identified miR-361 as a novel regulator of chemosensitivity. Overexpression of miR-361 enhanced the 5-FU susceptibility of parental and resistant HCT116 and HT29 cells in vitro. Impaired colony formation capacity and increased cell apoptosis (as determined via flow cytometry) was observed in resistant HCT116 and HT29 cells. Furthermore, forkhead box M1 (FOXM1) was identified as a target gene of miR-361 using a dual-luciferase reporter assay, western blotting and reverse transcription-quantitative PCR. Additionally, FOXM1 knockdown improved the cytotoxicity of 5-FU in resistant CRC. ATP binding cassette subfamily C members 5 and 10 (ABCC5/10) were found to be downstream effectors of miR-361. In conclusion, miR-361 increased chemosensitivity, at least in part, via modulation of FOXM1-ABCC5/10. miR-361 may serve as a potential therapeutic target for patients with CRC.
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28
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Cheng Y, Ma XL, Wei YQ, Wei XW. Potential roles and targeted therapy of the CXCLs/CXCR2 axis in cancer and inflammatory diseases. Biochim Biophys Acta Rev Cancer 2019; 1871:289-312. [DOI: 10.1016/j.bbcan.2019.01.005] [Citation(s) in RCA: 217] [Impact Index Per Article: 36.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2018] [Revised: 11/19/2018] [Accepted: 01/09/2019] [Indexed: 12/16/2022]
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29
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Verma V, Paek AR, Choi BK, Hong EK, You HJ. Loss of zinc-finger protein 143 contributes to tumour progression by interleukin-8-CXCR axis in colon cancer. J Cell Mol Med 2019; 23:4043-4053. [PMID: 30933430 PMCID: PMC6533486 DOI: 10.1111/jcmm.14290] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Revised: 03/03/2019] [Accepted: 03/07/2019] [Indexed: 12/11/2022] Open
Abstract
Several studies have shown that expression of zinc‐finger protein 143 (ZNF143) is closely related to tumour progression including colon cancer. However, it remains unclear how ZNF143 expression is related to tumour progression within the tumour microenvironment. Here, we investigated whether ZNF143 expression affects the tumour microenvironment and tumour progression by screening molecules secreted by colon cancer cells stably expressing short‐hairpin RNAs against ZNF143 or control RNAs. We observed that secretion of interleukin (IL)‐8 was increased when ZNF143 expression was reduced in two colon cancer cell lines. The mRNA and protein levels of IL‐8 were increased in cells following ZNF143 knockdown, and this effect was reversed when ZNF143 expression was restored. The Janus tyrosine kinase/signal transducer and activator of transcription (JAK/STAT) and extracellular signal‐regulated kinase pathways were also shown to contribute to IL‐8 expression in ZNF143‐knockdown cells. The expression levels of ZNF143 and IL‐8 were inversely correlated with three‐dimensionally grown spheroids and colon cancer tissues. THP‐1 cells were differentiated when cells were incubated with condition media from colon cancer cell with less ZNF143, drastically. Loss of ZNF143 may contribute to the development of colon cancer by regulating intracellular and intercellular signalling for cell plasticity and the tumour microenvironment respectively.
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Affiliation(s)
- Vikas Verma
- Translational Research Branch, Div. of Translational Science, Goyang, Gyeonggi, South Korea
| | - A Rome Paek
- Translational Research Branch, Div. of Translational Science, Goyang, Gyeonggi, South Korea
| | - Beom-Kyu Choi
- Biomedicine Production Branch, Research Institute, National Cancer Center, Goyang, Gyeonggi, South Korea
| | - Eun Kyung Hong
- Department of Pathology, National Cancer Center Hospital, Goyang, Gyeonggi, South Korea
| | - Hye Jin You
- Translational Research Branch, Div. of Translational Science, Goyang, Gyeonggi, South Korea.,Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Gyeonggi, South Korea
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30
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Bien SA, Su YR, Conti DV, Harrison TA, Qu C, Guo X, Lu Y, Albanes D, Auer PL, Banbury BL, Berndt SI, Bézieau S, Brenner H, Buchanan DD, Caan BJ, Campbell PT, Carlson CS, Chan AT, Chang-Claude J, Chen S, Connolly CM, Easton DF, Feskens EJM, Gallinger S, Giles GG, Gunter MJ, Hampe J, Huyghe JR, Hoffmeister M, Hudson TJ, Jacobs EJ, Jenkins MA, Kampman E, Kang HM, Kühn T, Küry S, Lejbkowicz F, Le Marchand L, Milne RL, Li L, Li CI, Lindblom A, Lindor NM, Martín V, McNeil CE, Melas M, Moreno V, Newcomb PA, Offit K, Pharaoh PDP, Potter JD, Qu C, Riboli E, Rennert G, Sala N, Schafmayer C, Scacheri PC, Schmit SL, Severi G, Slattery ML, Smith JD, Trichopoulou A, Tumino R, Ulrich CM, van Duijnhoven FJB, Van Guelpen B, Weinstein SJ, White E, Wolk A, Woods MO, Wu AH, Abecasis GR, Casey G, Nickerson DA, Gruber SB, Hsu L, Zheng W, Peters U. Genetic variant predictors of gene expression provide new insight into risk of colorectal cancer. Hum Genet 2019; 138:307-326. [PMID: 30820706 PMCID: PMC6483948 DOI: 10.1007/s00439-019-01989-8] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Accepted: 02/20/2019] [Indexed: 02/02/2023]
Abstract
Genome-wide association studies have reported 56 independently associated colorectal cancer (CRC) risk variants, most of which are non-coding and believed to exert their effects by modulating gene expression. The computational method PrediXcan uses cis-regulatory variant predictors to impute expression and perform gene-level association tests in GWAS without directly measured transcriptomes. In this study, we used reference datasets from colon (n = 169) and whole blood (n = 922) transcriptomes to test CRC association with genetically determined expression levels in a genome-wide analysis of 12,186 cases and 14,718 controls. Three novel associations were discovered from colon transverse models at FDR ≤ 0.2 and further evaluated in an independent replication including 32,825 cases and 39,933 controls. After adjusting for multiple comparisons, we found statistically significant associations using colon transcriptome models with TRIM4 (discovery P = 2.2 × 10- 4, replication P = 0.01), and PYGL (discovery P = 2.3 × 10- 4, replication P = 6.7 × 10- 4). Interestingly, both genes encode proteins that influence redox homeostasis and are related to cellular metabolic reprogramming in tumors, implicating a novel CRC pathway linked to cell growth and proliferation. Defining CRC risk regions as one megabase up- and downstream of one of the 56 independent risk variants, we defined 44 non-overlapping CRC-risk regions. Among these risk regions, we identified genes associated with CRC (P < 0.05) in 34/44 CRC-risk regions. Importantly, CRC association was found for two genes in the previously reported 2q25 locus, CXCR1 and CXCR2, which are potential cancer therapeutic targets. These findings provide strong candidate genes to prioritize for subsequent laboratory follow-up of GWAS loci. This study is the first to implement PrediXcan in a large colorectal cancer study and findings highlight the utility of integrating transcriptome data in GWAS for discovery of, and biological insight into, risk loci.
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Affiliation(s)
- Stephanie A Bien
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA.
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA.
| | - Yu-Ru Su
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - David V Conti
- USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90089, USA
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Tabitha A Harrison
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Conghui Qu
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Xingyi Guo
- Division of Epidemiology, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Yingchang Lu
- Division of Epidemiology, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Demetrius Albanes
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, 20892, USA
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Paul L Auer
- Joseph J. Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI, 53205, USA
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Barbara L Banbury
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Sonja I Berndt
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, 20892, USA
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Stéphane Bézieau
- Centre Hospitalier Universitaire Hotel-Dieu, 44093, Nantes, France
- Service de Génétique Médiczle, Centre Hospitalier Universitaire (CHU), 44093, Nantes, France
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), 69120, Heidelberg, Germany
- German Cancer Consortium (DKTK), 69120, Heidelberg, Germany
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Daniel D Buchanan
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC, 3010, Australia
- Colorectal Oncogenomics Group, Department of Pathology, University of Melbourne, Melbourne, VIC, 3010, Australia
- Genetic Medicine and Familial Cancer Centre, The Royal Melbourne Hospital, Parkville, VIC, 3010, Australia
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Bette J Caan
- Division of Research, Kaiser Permanente Medical Care Program of Northern California, Oakland, CA, 94612, USA
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Peter T Campbell
- Epidemiology Research Program, American Cancer Society, Atlanta, GA, 30329-4251, USA
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Christopher S Carlson
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Andrew T Chan
- Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
- Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Jenny Chang-Claude
- Unit of Genetic Epidemiology, Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany
- Genetic Tumour Epidemiology Group, University Medical Center Hamburg-Eppendorf, University Cancer Center Hamburg, 20246, Hamburg, Germany
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Sai Chen
- Department of Biostatistics, University of Michigan, Ann Arbor, MI, 48109, USA
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Charles M Connolly
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Douglas F Easton
- Department of Public Health and Primary Care School of Clinical Medicine, University of Cambridge, Cambridge, England, 01223, UK
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Edith J M Feskens
- Division of Human Nutrition, Wageningen University & Research, Wageningen, The Netherlands
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Steven Gallinger
- Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, 1X5, Canada
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Graham G Giles
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC, 3010, Australia
- Cancer Epidemiology & Intelligence Division, Cancer Council Victoria, Melbourne, 3004, Australia
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Marc J Gunter
- Section for Epidemiology, Department of Public Health, Aarhus University, Aarhus, Denmark
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Jochen Hampe
- Medical Department 1, University Hospital Dresden, TU Dresden, 01307, Dresden, Germany
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Jeroen R Huyghe
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Michael Hoffmeister
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Thomas J Hudson
- Ontario Institute for Cancer Research, Toronto, ON, Canada
- AbbVie Inc, 1500 Seaport Blvd, Redwood City, CA, 94063, USA
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Eric J Jacobs
- Epidemiology Research Program, American Cancer Society, Atlanta, GA, 30329-4251, USA
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Mark A Jenkins
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC, 3010, Australia
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Ellen Kampman
- Division of Human Nutrition, Wageningen University & Research, Wageningen, The Netherlands
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Hyun Min Kang
- Department of Biostatistics, University of Michigan, Ann Arbor, MI, 48109, USA
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Tilman Kühn
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Sébastien Küry
- Centre Hospitalier Universitaire Hotel-Dieu, 44093, Nantes, France
- Service de Génétique Médiczle, Centre Hospitalier Universitaire (CHU), 44093, Nantes, France
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Flavio Lejbkowicz
- Clalit Health Services National Israeli Cancer Control Center, 34361, Haifa, Israel
- Department of Community Medicine and Epidemiology, Carmel Medical Center, 34361, Haifa, Israel
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Loic Le Marchand
- University of Hawai'i Cancer Center, Honolulu, Hawaii, 96813, USA
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Roger L Milne
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC, 3010, Australia
- Cancer Epidemiology & Intelligence Division, Cancer Council Victoria, Melbourne, 3004, Australia
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Li Li
- Department of Family Medicine and Community Health, Case Western Reserve University, Cleveland, OH, 44106, USA
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Christopher I Li
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Annika Lindblom
- Department of Clinical Genetics, Karolinska University Hospital Solna, 171 77, Stockholm, Sweden
- Department of Molecular Medicine and Surgery, Karolinska Institutet Solna, 171 77, Stockholm, Sweden
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Noralane M Lindor
- Department of Health Science Research, Mayo Clinic Arizona, Scottsdale, AZ, 85259, USA
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Vicente Martín
- Biomedicine Institute (IBIOMED), University of León, León, Spain
- CIBER Epidemiología y Salud Pública (CIBERESP), 28029, Madrid, Spain
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Caroline E McNeil
- USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90089, USA
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Marilena Melas
- USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90089, USA
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Victor Moreno
- CIBER Epidemiología y Salud Pública (CIBERESP), 28029, Madrid, Spain
- Catalan Institute of Oncology, Bellvitge Biomedical Research Institute (IDIBELL), 08028, Barcelona, Spain
- University of Barcelona, 08007, Barcelona, Spain
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Polly A Newcomb
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Kenneth Offit
- Department of Medicine, Clinical Genetics Service, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Paul D P Pharaoh
- Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, CB2 1TN, UK
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - John D Potter
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Chenxu Qu
- USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90089, USA
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Elio Riboli
- School of Public Health, Imperial College London, London, UK
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Gad Rennert
- Clalit Health Services National Israeli Cancer Control Center, 34361, Haifa, Israel
- Department of Community Medicine and Epidemiology, Carmel Medical Center, 34361, Haifa, Israel
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Núria Sala
- Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, 08908, Barcelona, Spain
- Molecular Epidemiology Group, Translational Research Laboratory, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, 08908, Barcelona, Spain
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Clemens Schafmayer
- Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein, Campus Kiel, 24118, Kiel, Germany
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Peter C Scacheri
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, 44106, USA
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Stephanie L Schmit
- Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Inc, Tampa, FL, 33612, USA
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Inc, Tampa, FL, 33612, USA
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Gianluca Severi
- Centre for Research in Epidemiology and Population Health, Institut de Cancérologie Gustave Roussy, Villejuif, France
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Martha L Slattery
- Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Joshua D Smith
- Department Genome Sciences, University of Washington, 98195, Seattle, WA, USA
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Antonia Trichopoulou
- Hellenic Health Foundation, 13 Kaisareias & Alexandroupoleos, 115 27, Athens, Greece
- WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology and Nutrition in Public Health, Department of Hygiene, Epidemiology and Medical Statistics, Medical School, National and Kapodistrian University of Athens, Mikras Asias 75, 115 27, Athens, Greece
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Rosario Tumino
- Affiliation Cancer Registry, Department of Prevention, Azienda Sanitaria Provinciale di Ragusa, Ragusa, Italy
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Cornelia M Ulrich
- Population Sciences, Huntsman Cancer Institute, Salt Lake City, UT, 84112, USA
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Fränzel J B van Duijnhoven
- Division of Human Nutrition, Wageningen University & Research, Wageningen, The Netherlands
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Bethany Van Guelpen
- Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Stephanie J Weinstein
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, 20892, USA
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Emily White
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Alicja Wolk
- Institute of Environmental Medicine, Karolinska Institutet Solna, 17177, Stockholm, Sweden
- Department of Surgical Sciences, Uppsala University, 75121, Uppsala, Sweden
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Michael O Woods
- Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, Saint John's, NL, A1B 3V6, Canada
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Anna H Wu
- USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90089, USA
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Goncalo R Abecasis
- Department of Biostatistics, University of Michigan, Ann Arbor, MI, 48109, USA
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Graham Casey
- Centre for Research in Epidemiology and Population Health, Institut de Cancérologie Gustave Roussy, Villejuif, France
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Deborah A Nickerson
- Department Genome Sciences, University of Washington, 98195, Seattle, WA, USA
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Stephen B Gruber
- USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90089, USA
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Li Hsu
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Wei Zheng
- Division of Epidemiology, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
- Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN, 37232, USA
| | - Ulrike Peters
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
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31
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Li X, Chen W, Jin Y, Xue R, Su J, Mu Z, Li J, Jiang S. miR-142-5p enhances cisplatin-induced apoptosis in ovarian cancer cells by targeting multiple anti-apoptotic genes. Biochem Pharmacol 2019; 161:98-112. [DOI: 10.1016/j.bcp.2019.01.009] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2018] [Accepted: 01/09/2019] [Indexed: 01/02/2023]
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Grigaitis P, Jonusiene V, Zitkute V, Dapkunas J, Dabkeviciene D, Sasnauskiene A. Exogenous interleukin-1α signaling negatively impacts acquired chemoresistance and alters cell adhesion molecule expression pattern in colorectal carcinoma cells HCT116. Cytokine 2018; 114:38-46. [PMID: 30583087 DOI: 10.1016/j.cyto.2018.11.031] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2018] [Revised: 11/19/2018] [Accepted: 11/25/2018] [Indexed: 02/05/2023]
Abstract
Proinflammatory cytokine and chemokine signaling from the tumor microenvironment is thought to be crucial for developing and sustaining colorectal cancer by regulating a multitude of pathways associated with a variety of cellular mechanisms. Among these pathways there is acquired chemoresistance, which is usually a major obstacle in the way towards successful chemotherapeutic treatment of advanced colorectal cancer cases. Despite of an emerging body of data published on the role of cytokine signaling network in cancer, little is known about the effects of the upstream cytokine interleukin-1α (IL-1α) signaling to the cancer cells. In this study we have shown that the increase in exogenous IL-1α signaling increases chemosensitivity of both chemosensitive and chemoresistant colorectal cancer cell lines, treated with a widely used cytotoxic antimetabolite 5-fluorouracil (5-FU). This was a result of increased cell death but not of the changes in 5-FU-induced cell cycle arrest. Noticeably, combined exogenous IL-1α and 5-FU treatment had significant effects on the expression of cell adhesion molecules, suggesting a decrease in adhesion-dependent chemoresistance and, on the other hand, an increase in metastatic potential of the cells. These results lead to a conclusion that modulation of IL-1 receptor activity could have applications as a part of combination therapy for advanced and highly metastatic colorectal cancers.
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Affiliation(s)
- Pranas Grigaitis
- Institute of Biosciences, Life Sciences Center, Vilnius University, Sauletekio al. 7, Vilnius 10227, Lithuania.
| | - Violeta Jonusiene
- Institute of Biosciences, Life Sciences Center, Vilnius University, Sauletekio al. 7, Vilnius 10227, Lithuania.
| | - Vilmante Zitkute
- Institute of Biosciences, Life Sciences Center, Vilnius University, Sauletekio al. 7, Vilnius 10227, Lithuania.
| | - Justas Dapkunas
- Institute of Biotechnology, Life Sciences Center, Vilnius University, Sauletekio al. 7, Vilnius 10227, Lithuania.
| | - Daiva Dabkeviciene
- Institute of Biosciences, Life Sciences Center, Vilnius University, Sauletekio al. 7, Vilnius 10227, Lithuania.
| | - Ausra Sasnauskiene
- Institute of Biosciences, Life Sciences Center, Vilnius University, Sauletekio al. 7, Vilnius 10227, Lithuania.
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Antrodia cinnamomea induces autophagic cell death via the CHOP/TRB3/Akt/mTOR pathway in colorectal cancer cells. Sci Rep 2018; 8:17424. [PMID: 30479369 PMCID: PMC6258711 DOI: 10.1038/s41598-018-35780-y] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Accepted: 11/09/2018] [Indexed: 01/19/2023] Open
Abstract
Antrodia cinnamomea, a well-known traditional medicine used in Taiwan, is a potent anticancer drug for colorectal cancer, but the upstream molecular mechanism of its anticancer effects remains unclear. In this study, A. cinnamomea extracts showed cytotoxicity in HCT116, HT29, SW480, Caco-2 and, Colo205 colorectal cancer cells. Whole-genome expression profiling of A. cinnamomea extracts in HCT116 cells was performed. A. cinnamomea extracts upregulated the expression of the endoplasmic reticulum stress marker CHOP and its downstream gene TRB3. Moreover, dephosphorylation of Akt and mTOR as well as autophagic cell death were observed. Gene expression and autophagic cell death were reversed by the knockdown of CHOP and TRB3. Autophagy inhibition but not apoptosis inhibition reversed A. cinnamomea-induced cell death. Finally, we demonstrated that A. cinnamomea extracts significantly suppressed HCT116 tumour growth in nude mice. Our findings suggest that autophagic cell death via the CHOP/TRB3/Akt/mTOR pathway may represent a new mechanism of anti-colorectal cancer action by A. cinnamomea. A. cinnamomea is a new CHOP activator and potential drug that can be used in colorectal cancer treatment.
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34
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Lee NH, Nikfarjam M, He H. Functions of the CXC ligand family in the pancreatic tumor microenvironment. Pancreatology 2018; 18:705-716. [PMID: 30078614 DOI: 10.1016/j.pan.2018.07.011] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Revised: 07/06/2018] [Accepted: 07/30/2018] [Indexed: 02/06/2023]
Abstract
Therapeutic resistance is the major contributor to the poor prognosis of and low survival from pancreatic cancer (PC). Cancer progression is a complex process reliant on interactions between the tumor and the tumor microenvironment (TME). Members of the CXCL family of chemokines are present in the pancreatic TME and seem to play a vital role in regulating PC progression. As pancreatic tumors interact with the TME and with PC stem cells (CSCs), determining the roles of specific members of the CXCL family is vital to the development of improved therapies. This review highlights the roles of selected CXCLs in the interactions between pancreatic tumor and its stroma, and in CSC phenotypes, which can be used to identify potential treatment targets.
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Affiliation(s)
- Nien-Hung Lee
- Department of Surgery, University of Melbourne, Austin Health, Melbourne, Victoria, Australia
| | - Mehrdad Nikfarjam
- Department of Surgery, University of Melbourne, Austin Health, Melbourne, Victoria, Australia
| | - Hong He
- Department of Surgery, University of Melbourne, Austin Health, Melbourne, Victoria, Australia.
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35
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Kukcinaviciute E, Jonusiene V, Sasnauskiene A, Dabkeviciene D, Eidenaite E, Laurinavicius A. Significance of Notch and Wnt signaling for chemoresistance of colorectal cancer cells HCT116. J Cell Biochem 2018; 119:5913-5920. [PMID: 29637602 DOI: 10.1002/jcb.26783] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2017] [Accepted: 02/02/2018] [Indexed: 12/21/2022]
Abstract
5-fluorouracil (5-FU) and oxaliplatin (OxaPt) are the main chemotherapeutics for colorectal cancer (CRC). Chemotherapy response rates for advanced CRC remain low, primarily due to intrinsic or acquired chemoresistance. The importance of Notch and Wnt signaling for carcinogenesis of CRC as well as crosstalk of Notch and Wnt signaling with many oncogenic signaling pathways suggest that Notch and Wnt pathways could be responsible for chemoresistance. In this study, we compared changes in Notch and Wnt signaling after 5-FU and OxaPt treatment in CRC cells HCT116 and its chemoresistant sublines HCT116/FU and HCT116/OXA. The levels of Notch1 receptor intracellular domain NICD1 and non-phosphorylated β-catenin, the reporters of Notch and Wnt signaling, were upregulated in untreated chemoresistant HCT116/FU and HCT116/OXA cells. Our data suggest that Notch inhibitor RO4929097 (RO) and Wnt inhibitor XAV939 (XAV) enhance the survival potential of OxaPt-treated cells. The protein level of Notch target gene HES1 was significantly upregulated in chemoresistant HCT116/FU and HCT116/OXA cells, compared to HCT116. HES1 silencing increased viability of HCT116 and its chemoresistant sublines after 5-FU or OxaPt treatment. The results of HES1 downregulation coincide with RO and XAV effects on cell viability of OxaPt-treated cells.
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Affiliation(s)
- Egle Kukcinaviciute
- Institute of Biosciences, Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Violeta Jonusiene
- Institute of Biosciences, Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Ausra Sasnauskiene
- Institute of Biosciences, Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Daiva Dabkeviciene
- Institute of Biosciences, Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Eigile Eidenaite
- Institute of Biosciences, Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Arvydas Laurinavicius
- Faculty of Medicine, Vilnius University, Vilnius, Lithuania.,National Center of Pathology, Affiliate of Vilnius University Hospital Santara Clinics, Vilnius, Lithuania
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36
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Chan LP, Wang LF, Chiang FY, Lee KW, Kuo PL, Liang CH. IL-8 promotes HNSCC progression on CXCR1/2-meidated NOD1/RIP2 signaling pathway. Oncotarget 2018; 7:61820-61831. [PMID: 27557518 PMCID: PMC5308693 DOI: 10.18632/oncotarget.11445] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2016] [Accepted: 08/13/2016] [Indexed: 01/05/2023] Open
Abstract
NOD1 (nucleotide-binding oligomerization domain 1) is overexpressed in head and neck squamous cell carcinoma (HNSCC) cells, as is IL-8 in cancer cells. However, the mechanism of the IL-8-mediated overexpression of NOD in HNSCC not been identified. This study determines whether IL-8 promotes tumor progression via the NOD signaling pathway in HNSCC. Higher IL-8, NOD1 and receptor-interacting protein kinase (RIP2) expressions were observed in HNSCC tissue than in non-cancerous matched tissue (NCMT), whereas NOD2 was weakly expressed. Furthermore, IL-8 stimulated the proliferation of HNSCC cells (SCC4, SCC9 and SCC25) but not dysplastic oral mucosa DOK cells. Exposure to IL-8 increased the clonogenicity of HNSCC cells. IL-8 siRNA inhibited cell proliferation and cell colony formation, suggesting that IL-8 is involved in HNSCC cancer progression. The expressions of CXCR1 and CXCR2 were higher in HNSCC tissue than in NCMT. HNSCC cells that were exposed to IL-8 exhibited higher expression of CXCR1/2 than did controls. The blocking of IL-8 by siRNA reduced CXCR1/2 expression in HNSCC cells, suggesting that the cancer progression of HNSCC cells that is induced by IL-8 depends on CXCR1/2. Additionally, IL-8 is associated with increased NOD1 and RIP2 expression and reduced NOD2 expression in three types of HNSCC cells. The blocking of IL-8 by siRNA reduces IL-8, NOD1 and RIP2 expressions in HNSCC cells, but not the level of NOD2. These results suggest that IL-8 has an important role in HNSCC progression via a CXCR1/2-meidated NOD1/RIP2 signaling pathway.
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Affiliation(s)
- Leong-Perng Chan
- Graduate Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Department of Otolaryngology-Head and Neck Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ling-Feng Wang
- Department of Otolaryngology-Head and Neck Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Feng-Yu Chiang
- Department of Otolaryngology-Head and Neck Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ka-Wo Lee
- Department of Otolaryngology-Head and Neck Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Po-Lin Kuo
- Graduate Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Institute of Medical Science and Technology, National Sun Yat-Sen University, Kaohsiung, Taiwan
| | - Chia-Hua Liang
- Department of Cosmetic Science and Institute of Cosmetic Science, Chia Nan University of Pharmacy and Science, Tainan, Taiwan
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Bhavsar C, Momin M, Khan T, Omri A. Targeting tumor microenvironment to curb chemoresistance via novel drug delivery strategies. Expert Opin Drug Deliv 2018; 15:641-663. [PMID: 29301448 DOI: 10.1080/17425247.2018.1424825] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Tumor is a heterogeneous mass of malignant cells co-existing with non-malignant cells. This co-existence evolves from the initial developmental stages of the tumor and is one of the hallmarks of cancer providing a protumorigenic niche known as tumor microenvironment (TME). Proliferation, invasiveness, metastatic potential and maintenance of stemness through cross-talk between tumors and its stroma forms the basis of TME. AREAS COVERED The article highlights the developmental phases of a tumor from dysplasia to the formation of clinically detectable tumors. The authors discuss the mechanistic stages involved in the formation of TME and its contribution in tumor outgrowth and chemoresistance. The authors have reviewed various approaches for targeting TME and its hallmarks along with their advantages and pitfalls. The authors also highlight cancer stem cells (CSCs) that are resistant to chemotherapeutics and thus a primary reason for tumor recurrence thereby, posing a challenge for the oncologists. EXPERT OPINION Recent understanding of the cellular and molecular mechanisms involved in acquired chemoresistance has enabled scientists to target the tumor niche and TME and modulate and/or disrupt this communication leading to the transformation from a tumor-supportive niche environment to a tumor-non-supporting environment and give synergistic results towards an effective management of cancer.
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Affiliation(s)
- Chintan Bhavsar
- a Department of Pharmaceutics, SVKMs Dr. Bhanuben Nanavati College of Pharmacy , University of Mumbai , Mumbai , India
| | - Munira Momin
- a Department of Pharmaceutics, SVKMs Dr. Bhanuben Nanavati College of Pharmacy , University of Mumbai , Mumbai , India
| | - Tabassum Khan
- b Department of Quality Assurance and Pharmaceutical Chemistry, SVKMs Dr. Bhanuben Nanavati College of Pharmacy , University of Mumbai , Mumbai , India
| | - Abdelwahab Omri
- c The Novel Drug & Vaccine Delivery Systems Facility, Department of Chemistry and Biochemistry , Laurentian University , Sudbury , ON , Canada
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38
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Chowdhury R, Gales D, Valenzuela P, Miller S, Yehualaeshet T, Manne U, Francia G, Samuel T. Bromoethylindole (BEI-9) redirects NF-κB signaling induced by camptothecin and TNFα to promote cell death in colon cancer cells. Apoptosis 2017; 22:1553-1563. [PMID: 29116428 PMCID: PMC6005376 DOI: 10.1007/s10495-017-1427-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Chemotherapeutic regimens containing camptothecin (CPT), 5-fluorouracil, and oxaliplatin are used to treat advanced colorectal cancer. We previously reported that an indole derivative, 3-(2-bromoethyl)indole (BEI-9), inhibited the proliferation of colon cancer cells and suppressed NF-κB activation. Here, we show that a combination of BEI-9 with either CPT or tumor necrosis factor alpha (TNFα) enhances cell death. Using colorectal cancer cells, we examined the activation of NF-κB by drugs, the potential of BEI-9 for inhibiting drug-induced NF-κB activation, and the enhancement of cell death by combination treatments. Cells were treated with the chemotherapeutic drugs alone or in combination with BEI-9. NF-κB activation, cell cycle profiles, DNA-damage response, markers of cell death signaling and targets of NF-κB were evaluated to determine the effects of single and co-treatments. The combination of BEI-9 with CPT or TNFα inhibited NF-κB activation and reduced the expression of NF-κB-responsive genes, Bcl-xL and COX2. Compared to CPT or BEI-9 alone, sequential treatment of the cells with CPT and BEI-9 significantly enhanced caspase activation and cell death. Co-treatment with TNFα and BEI-9 also caused more cytotoxicity than TNFα or BEI-9 alone. Combined BEI-9 and TNFα enhanced cell death through caspase activation and cleavage of the switch-protein, RIP1 kinase. BEI-9 reduced the expression of COX2 both alone and in combination with CPT or TNF. We postulate that BEI-9 enhances the effects of these drugs on cancer cells by turning off or redirecting NF-κB signaling. Therefore, the combination of BEI-9 with drugs that activate NF-κB needs to be evaluated for clinical applications.
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Affiliation(s)
- Rupak Chowdhury
- College of Veterinary Medicine, Tuskegee University, 1200 W. Montgomery Road, Tuskegee, AL, 36088, USA
| | - Dominique Gales
- College of Veterinary Medicine, Tuskegee University, 1200 W. Montgomery Road, Tuskegee, AL, 36088, USA
| | - Paloma Valenzuela
- University of Texas El Paso, 500 W. University Ave., El Paso, TX, 79968, USA
| | - Sonni Miller
- College of Veterinary Medicine, Tuskegee University, 1200 W. Montgomery Road, Tuskegee, AL, 36088, USA
| | - Teshome Yehualaeshet
- College of Veterinary Medicine, Tuskegee University, 1200 W. Montgomery Road, Tuskegee, AL, 36088, USA
| | - Upender Manne
- Wallace Tumor Institute, University of Alabama Birmingham, 1802, 6th Avenue South, Birmingham, AL, 35294, USA
| | - Giulio Francia
- University of Texas El Paso, 500 W. University Ave., El Paso, TX, 79968, USA
| | - Temesgen Samuel
- College of Veterinary Medicine, Tuskegee University, 1200 W. Montgomery Road, Tuskegee, AL, 36088, USA.
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39
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Zhou X, An D, Liu X, Jiang M, Yuan C, Hu J. TNFα induces tolerant production of CXC chemokines in colorectal cancer HCT116 cells via A20 inhibition of ERK signaling. Int Immunopharmacol 2017; 54:296-302. [PMID: 29175508 DOI: 10.1016/j.intimp.2017.11.027] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2017] [Revised: 11/21/2017] [Accepted: 11/21/2017] [Indexed: 12/16/2022]
Abstract
Ubiquitin editing enzyme A20 functions as a tumor suppressor in various cancer. However, the mechanism for A20 regulation of cancer progress is not fully understood. In this study, we found that in human colorectal cancer HCT116 cells, TNFα induced a tolerant production of CXC chemokines, including CXCL1, 2, and 8 in a dose and time dependent manner. TNFα pre-treatment of HCT116 cells down-regulated the chemokine production induced by TNFα re-treatment. TNFα induced the phosphorylation of MAPKs ERK, JNK, P38 and NF-κB P65, but only ERK inhibition decreased TNFα-induced chemokine production. Both RT-PCR and FACS results showed that TNFα treatment did not regulate the expression of TNF receptors. However, TNFα up-regulated the expression of A20 at both mRNA and protein levels significantly. TNFα pre-treatment inhibited the signal transduction of MAPKs induced by TNFα re-stimulation, and A20 over-expression decreased the signal transduction of ERK and P38. Meanwhile, A20 inhibition by RNA interference reversed chemokine down-regulation induced by TNFα re-stimulation after TNFα pre-treatment. Taken together, these results suggested that in human colorectal cancer cells, A20 may function to inhibit cancer progression via down-regulation of TNFα-induced chemokine production by suppression of ERK signaling.
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Affiliation(s)
- Xin Zhou
- Changsha Cancer Institute, Changsha Central Hospital, Changsha, Hunan 410004, China; Graduate School, University of South China, Hengyang, Hunan 421001, China
| | - Dongjian An
- Changsha Cancer Institute, Changsha Central Hospital, Changsha, Hunan 410004, China.
| | - Xueting Liu
- Medical Research Center, Changsha Central Hospital, Changsha, Hunan 410004, China
| | - Manli Jiang
- Medical Research Center, Changsha Central Hospital, Changsha, Hunan 410004, China
| | - Chuang Yuan
- Medical Research Center, Changsha Central Hospital, Changsha, Hunan 410004, China
| | - Jinyue Hu
- Medical Research Center, Changsha Central Hospital, Changsha, Hunan 410004, China.
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Ma JC, Sun XW, Su H, Chen Q, Guo TK, Li Y, Chen XC, Guo J, Gong ZQ, Zhao XD, Qi JB. Fibroblast-derived CXCL12/SDF-1α promotes CXCL6 secretion and co-operatively enhances metastatic potential through the PI3K/Akt/mTOR pathway in colon cancer. World J Gastroenterol 2017; 23:5167-5178. [PMID: 28811711 PMCID: PMC5537183 DOI: 10.3748/wjg.v23.i28.5167] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Revised: 04/13/2017] [Accepted: 05/09/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the underlying mechanism by which CXCL12 and CXCL6 influences the metastatic potential of colon cancer and internal relation of colon cancer and stromal cells.
METHODS Western blotting was used to detect the expression of CXCL12 and CXCL6 in colon cancer cells and stromal cells. The co-operative effects of CXCL12 and CXCL6 on proliferation and invasion of colon cancer cells and human umbilical vein endothelial cells (HUVECs) were determined by enzyme-linked immunosorbent assay, and proliferation and invasion assays. The angiogenesis of HUVECs through interaction with cancer cells and stromal cells was examined by angiogenesis assay. We eventually investigated activation of PI3K/Akt/mTOR signaling by CXCL12 involved in the metastatic process of colon cancer.
RESULTS CXCL12 was expressed in DLD-1 cancer cells and fibroblasts. The secretion level of CXCL6 by colon cancer cells and HUVECs were significantly promoted by fibroblasts derived from CXCL12. CXCL6 and CXCL2 could significantly enhance HUVEC proliferation and migration (P < 0.01). CXCL6 and CXCL2 enhanced angiogenesis by HUVECs when cultured with fibroblast cells and colon cancer cells (P < 0.01). CXCL12 also enhanced the invasion of colon cancer cells. Stromal cell-derived CXCL12 promoted the secretion level of CXCL6 and co-operatively promoted metastasis of colon carcinoma through activation of the PI3K/Akt/mTOR pathway.
CONCLUSION Fibroblast-derived CXCL12 enhanced the CXCL6 secretion of colon cancer cells, and both CXCL12 and CXCL6 co-operatively regulated the metastasis via the PI3K/Akt/mTOR signaling pathway. Blocking this pathway may be a potential anti-metastatic therapeutic target for patients with colon cancer.
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Chen JLY, Tsai YC, Tsai MH, Lee SY, Wei MF, Kuo SH, Shieh MJ. Prominin-1-Specific Binding Peptide-Modified Apoferritin Nanoparticle Carrying Irinotecan as a Novel Radiosensitizer for Colorectal Cancer Stem-Like Cells. PARTICLE & PARTICLE SYSTEMS CHARACTERIZATION 2017; 34:1600424. [DOI: 10.1002/ppsc.201600424] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/17/2025]
Affiliation(s)
- Jenny Ling-Yu Chen
- Institute of Biomedical Engineering; College of Medicine and College of Engineering; National Taiwan University; 100 Taipei Taiwan
- Department of Oncology; National Taiwan University Hospital; 100 Taipei Taiwan
- Department of Oncology; National Taiwan University Yun-Lin Branch; Yun-Lin 640 Taiwan
| | - Yuan-Chun Tsai
- Institute of Biomedical Engineering; College of Medicine and College of Engineering; National Taiwan University; 100 Taipei Taiwan
| | - Ming-Hsien Tsai
- Institute of Biomedical Engineering; College of Medicine and College of Engineering; National Taiwan University; 100 Taipei Taiwan
| | - Shin-Yu Lee
- Institute of Biomedical Engineering; College of Medicine and College of Engineering; National Taiwan University; 100 Taipei Taiwan
| | - Ming-Feng Wei
- Institute of Biomedical Engineering; College of Medicine and College of Engineering; National Taiwan University; 100 Taipei Taiwan
| | - Sung-Hsin Kuo
- Department of Oncology; National Taiwan University Hospital; 100 Taipei Taiwan
| | - Ming-Jium Shieh
- Institute of Biomedical Engineering; College of Medicine and College of Engineering; National Taiwan University; 100 Taipei Taiwan
- Department of Oncology; National Taiwan University Hospital; 100 Taipei Taiwan
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Amoroso MR, Matassa DS, Agliarulo I, Avolio R, Maddalena F, Condelli V, Landriscina M, Esposito F. Stress-Adaptive Response in Ovarian Cancer Drug Resistance: Role of TRAP1 in Oxidative Metabolism-Driven Inflammation. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2017; 108:163-198. [PMID: 28427560 DOI: 10.1016/bs.apcsb.2017.01.004] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Metabolic reprogramming is one of the most frequent stress-adaptive response of cancer cells to survive environmental changes and meet increasing nutrient requirements during their growth. These modifications involve cellular bioenergetics and cross talk with surrounding microenvironment, in a dynamic network that connect different molecular processes, such as energy production, inflammatory response, and drug resistance. Even though the Warburg effect has long been considered the main metabolic feature of cancer cells, recent reports identify mitochondrial oxidative metabolism as a driving force for tumor growth in an increasing number of cellular contexts. In recent years, oxidative phosphorylation has been linked to a remodeling of inflammatory response due to autocrine or paracrine secretion of interleukines that, in turn, induces a regulation of gene expression involving, among others, molecules responsible for the onset of drug resistance. This process is especially relevant in ovarian cancer, characterized by low survival, high frequency of disease relapse and chemoresistance. Recently, the molecular chaperone TRAP1 (tumor necrosis factor-associated protein 1) has been identified as a key junction molecule in these processes in ovarian cancer: in fact, TRAP1 mediates a metabolic switch toward oxidative phosphorylation that, in turn, triggers cytokines secretion, with consequent gene expression remodeling, finally leading to cisplatin resistance and epithelial-to-mesenchymal transition in ovarian cancer models. This review summarizes how metabolism, chemoresistance, inflammation, and epithelial-to-mesenchymal transition are strictly interconnected, and how TRAP1 stays at the crossroads of these processes, thus shedding new lights on molecular networks at the basis of ovarian cancer.
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Affiliation(s)
| | | | | | | | - Francesca Maddalena
- Laboratorio di ricerca preclinica e traslazionale, IRCCS-CROB, Centro di Riferimento Oncologico della Basilicata, Rionero in Vulture, Italy
| | - Valentina Condelli
- Laboratorio di ricerca preclinica e traslazionale, IRCCS-CROB, Centro di Riferimento Oncologico della Basilicata, Rionero in Vulture, Italy
| | - Matteo Landriscina
- Laboratorio di ricerca preclinica e traslazionale, IRCCS-CROB, Centro di Riferimento Oncologico della Basilicata, Rionero in Vulture, Italy; Università degli Studi di Foggia, Foggia, Italy.
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Liu Q, Li A, Tian Y, Wu JD, Liu Y, Li T, Chen Y, Han X, Wu K. The CXCL8-CXCR1/2 pathways in cancer. Cytokine Growth Factor Rev 2016; 31:61-71. [PMID: 27578214 PMCID: PMC6142815 DOI: 10.1016/j.cytogfr.2016.08.002] [Citation(s) in RCA: 465] [Impact Index Per Article: 51.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2016] [Revised: 08/13/2016] [Accepted: 08/23/2016] [Indexed: 02/07/2023]
Abstract
Persistent infection or chronic inflammation contributes significantly to tumourigenesis and tumour progression. C-X-C motif ligand 8 (CXCL8) is a chemokine that acts as an important multifunctional cytokine to modulate tumour proliferation, invasion and migration in an autocrine or paracrine manner. Studies have suggested that CXCL8 and its cognate receptors, C-X-C chemokine receptor 1 (CXCR1) and CX-C chemokine receptor 2 (CXCR2), mediate the initiation and development of various cancers including breast cancer, prostate cancer, lung cancer, colorectal carcinoma and melanoma. CXCL8 also integrates with multiple intracellular signalling pathways to produce coordinated effects. Neovascularisation, which provides a basis for fostering tumour growth and metastasis, is now recognised as a critical function of CXCL8 in the tumour microenvironment. In this review, we summarize the biological functions and ficlinical significance of the CXCL8 signalling axis in cancer. We also propose that CXCL8 may be a potential therapeutic target for cancer treatment
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Affiliation(s)
- Qian Liu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Anping Li
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Yijun Tian
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Jennifer D Wu
- Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA
| | - Yu Liu
- Department of Geriatric, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Tengfei Li
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Yuan Chen
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Xinwei Han
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
| | - Kongming Wu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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