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Hassan AF, Hussein O, Al-Barazenji T, Allouch A, Kamareddine L, Malki A, Moustafa AA, Khalil A. The effect of novel nitrogen-based chalcone analogs on colorectal cancer cells: Insight into the molecular pathways. Heliyon 2024; 10:e27002. [PMID: 38463818 PMCID: PMC10923686 DOI: 10.1016/j.heliyon.2024.e27002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 02/12/2024] [Accepted: 02/22/2024] [Indexed: 03/12/2024] Open
Abstract
In colorectal cancer (CRC), aberrations in KRAS are associated with aggressive tumorigenesis and an overall low survival rate because of chemoresistance and adverse effects. Ergo, complementary, and integrative medicines are being considered for CRC treatment. Among which is the use of natural chalcones that are known to exhibit anti-tumor activities in KRAS mutant CRC subtypes treatment regimens. Consequently, we examine the effect of two novel compounds (DK13 and DK14) having chalcones with nitrogen mustard moiety on CRC cell lines (HCT-116 and LoVo) with KRAS mutation. These compounds were synthesized in our lab and previously reported to exhibit potent activity against breast cancer cells. Our data revealed that DK13 and DK14 treatment suppress cell growth, disturb the progression of cell cycle, and trigger apoptosis in CRC cell lines. Besides, treatment with both compounds impedes cell invasion and colony formation in both cell lines as compared to 5-FU; this is accompanied by up and down regulations of E-cadherin and Vimentin, respectively. At the molecular level, both compounds deregulate the expression and phosphorylation of β-catenin, Akt and mTOR, which are the main likely molecular mechanisms underlying these biological occurrences. Our findings present DK13 and DK14 as novel chemotherapies against CRC, through β-catenin/Akt/mTOR signaling pathways.
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Affiliation(s)
- Arij Fouzat Hassan
- Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha, Qatar
| | - Ola Hussein
- Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha, Qatar
| | - Tara Al-Barazenji
- Department of Biomedical Science, College of Health Sciences, QU Health, Qatar University, Doha, Qatar
| | - Asma Allouch
- Department of Biomedical Science, College of Health Sciences, QU Health, Qatar University, Doha, Qatar
| | - Layla Kamareddine
- Department of Biomedical Science, College of Health Sciences, QU Health, Qatar University, Doha, Qatar
- Biomedical Research Centre, Qatar University, Doha, Qatar
| | - Ahmed Malki
- Department of Biomedical Science, College of Health Sciences, QU Health, Qatar University, Doha, Qatar
| | - Ala‐Eddin Al Moustafa
- Biomedical Research Centre, Qatar University, Doha, Qatar
- College of Medicine, QU Health, Qatar University, Doha, Qatar
- Oncology Department, McGill University, Montreal, QC, Canada
| | - Ashraf Khalil
- Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha, Qatar
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2
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Bruni S, Mercogliano MF, Mauro FL, Cordo Russo RI, Schillaci R. Cancer immune exclusion: breaking the barricade for a successful immunotherapy. Front Oncol 2023; 13:1135456. [PMID: 37284199 PMCID: PMC10239871 DOI: 10.3389/fonc.2023.1135456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Accepted: 05/10/2023] [Indexed: 06/08/2023] Open
Abstract
Immunotherapy has changed the course of cancer treatment. The initial steps were made through tumor-specific antibodies that guided the setup of an antitumor immune response. A new and successful generation of antibodies are designed to target immune checkpoint molecules aimed to reinvigorate the antitumor immune response. The cellular counterpart is the adoptive cell therapy, where specific immune cells are expanded or engineered to target cancer cells. In all cases, the key for achieving positive clinical resolutions rests upon the access of immune cells to the tumor. In this review, we focus on how the tumor microenvironment architecture, including stromal cells, immunosuppressive cells and extracellular matrix, protects tumor cells from an immune attack leading to immunotherapy resistance, and on the available strategies to tackle immune evasion.
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Hamabe‐Horiike T, Harada S, Yoshida K, Kinoshita J, Yamaguchi T, Fushida S. Adipocytes contribute to tumor progression and invasion of peritoneal metastasis by interacting with gastric cancer cells as cancer associated fibroblasts. Cancer Rep (Hoboken) 2022; 6:e1647. [PMID: 35691615 PMCID: PMC9875653 DOI: 10.1002/cnr2.1647] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Accepted: 04/17/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Peritoneal metastasis (PM) is one of the most common causes of noncurative surgery and the most frequent recurrence pattern in gastric cancer (GC). During the process of PM, GC cells detached from primary tumor interact with human peritoneal mesothelial cells (HPMC) overlapped with adipose tissues such as the omentum or mesentery. Although the interaction with HPMC promotes the malignancy of GC, the role of adipose tissues remains unclear. AIMS We aimed to clarify how adipose tissue are affected by adjacent primary tumors during the expression of adipokines and to elucidate whether GC cells transform adipocytes into CAFs in vitro. In addition, we investigated whether GC cells are affected by adipocytes in their ability to infiltrate. METHODS We investigated the phenotypic conversion of adipocytes during the malignant process of GC cells in vivo and in vitro. We evaluated the expression levels of adiponectin in the omental adipose tissue of gastric cancer patients by western blotting. Following adipocytes/gastric cancer cells coculture, adipocyte markers, adiponectin receptors, and inflammatory cytokine markers were detected by real-time PCR and/or western blotting in the single-cultured and co-cultured adipocytes; cancer-associated fibroblast (CAF) markers were detected by immunofluorescence and western blotting in the single-cultured and co-cultured adipocytes; invasion assays were performed in single cultured and co-cultured MKN45 and OCUM. RESULTS In omental adipose tissues that are situated close to the primary tumors, the expression of adiponectin tended to decrease in patients with subserosal or serosal invasion. By co-culturing with GC cells, adipocytes were dedifferentiated and the expression levels of CAF marker FSP1 and inflammatory cytokines, PAI-1 and IL-6, significantly increased (p < 0.05). Furthermore, GC cells co-cultured with adipocytes showed enhanced invasion ability. CONCLUSION Our findings suggest that the phenotypic conversion of adipocytes may promote the malignancy of GC in the construction of the cancer microenvironment of PM.
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Affiliation(s)
- Toshihide Hamabe‐Horiike
- Center for Biomedical Research and Education, School of MedicineKanazawa UniversityKanazawaJapan
| | - Shin‐ichi Harada
- Center for Biomedical Research and Education, School of MedicineKanazawa UniversityKanazawaJapan
| | - Kyoko Yoshida
- Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical ScienceKanazawa UniversityKanazawaJapan
| | - Jun Kinoshita
- Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical ScienceKanazawa UniversityKanazawaJapan
| | - Takahisa Yamaguchi
- Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical ScienceKanazawa UniversityKanazawaJapan
| | - Sachio Fushida
- Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical ScienceKanazawa UniversityKanazawaJapan
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Wan MC, Qin W, Lei C, Li QH, Meng M, Fang M, Song W, Chen JH, Tay F, Niu LN. Biomaterials from the sea: Future building blocks for biomedical applications. Bioact Mater 2021; 6:4255-4285. [PMID: 33997505 PMCID: PMC8102716 DOI: 10.1016/j.bioactmat.2021.04.028] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Revised: 04/15/2021] [Accepted: 04/17/2021] [Indexed: 02/08/2023] Open
Abstract
Marine resources have tremendous potential for developing high-value biomaterials. The last decade has seen an increasing number of biomaterials that originate from marine organisms. This field is rapidly evolving. Marine biomaterials experience several periods of discovery and development ranging from coralline bone graft to polysaccharide-based biomaterials. The latter are represented by chitin and chitosan, marine-derived collagen, and composites of different organisms of marine origin. The diversity of marine natural products, their properties and applications are discussed thoroughly in the present review. These materials are easily available and possess excellent biocompatibility, biodegradability and potent bioactive characteristics. Important applications of marine biomaterials include medical applications, antimicrobial agents, drug delivery agents, anticoagulants, rehabilitation of diseases such as cardiovascular diseases, bone diseases and diabetes, as well as comestible, cosmetic and industrial applications.
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Affiliation(s)
- Mei-chen Wan
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology, Department of Prosthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, PR China
| | - Wen Qin
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology, Department of Prosthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, PR China
| | - Chen Lei
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology, Department of Prosthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, PR China
| | - Qi-hong Li
- Department of Stomatology, The Fifth Medical Centre, Chinese PLA General Hospital (Former 307th Hospital of the PLA), Dongda Street, Beijing, 100071, PR China
| | - Meng Meng
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology, Department of Prosthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, PR China
| | - Ming Fang
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology, Department of Prosthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, PR China
| | - Wen Song
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology, Department of Prosthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, PR China
| | - Ji-hua Chen
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology, Department of Prosthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, PR China
| | - Franklin Tay
- College of Graduate Studies, Augusta University, Augusta, GA, 30912, USA
| | - Li-na Niu
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology, Department of Prosthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, PR China
- The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, 453000, PR China
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5
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Lv X, Xu G. Regulatory role of the transforming growth factor-β signaling pathway in the drug resistance of gastrointestinal cancers. World J Gastrointest Oncol 2021; 13:1648-1667. [PMID: 34853641 PMCID: PMC8603464 DOI: 10.4251/wjgo.v13.i11.1648] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 06/28/2021] [Accepted: 08/18/2021] [Indexed: 02/06/2023] Open
Abstract
Gastrointestinal (GI) cancer, including esophageal, gastric, and colorectal cancer, is one of the most prevalent types of malignant carcinoma and the leading cause of cancer-related deaths. Despite significant advances in therapeutic strategies for GI cancers in recent decades, drug resistance with various mechanisms remains the prevailing cause of therapy failure in GI cancers. Accumulating evidence has demonstrated that the transforming growth factor (TGF)-β signaling pathway has crucial, complex roles in many cellular functions related to drug resistance. This review summarizes current knowledge regarding the role of the TGF-β signaling pathway in the resistance of GI cancers to conventional chemotherapy, targeted therapy, immunotherapy, and traditional medicine. Various processes, including epithelial-mesenchymal transition, cancer stem cell development, tumor microenvironment alteration, and microRNA biogenesis, are proposed as the main mechanisms of TGF-β-mediated drug resistance in GI cancers. Several studies have already indicated the benefit of combining antitumor drugs with agents that suppress the TGF-β signaling pathway, but this approach needs to be verified in additional clinical studies. Moreover, the identification of potential biological markers that can be used to predict the response to TGF-β signaling pathway inhibitors during anticancer treatments will have important clinical implications in the future.
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Affiliation(s)
- Xiaoqun Lv
- Department of Pharmacy, Jinshan Hospital, Fudan University, Shanghai 201508, China
| | - Guoxiong Xu
- Research Center for Clinical Medicine, Jinshan Hospital, Fudan University, Shanghai 201508, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
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6
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Zhao H, Hu H, Chen B, Xu W, Zhao J, Huang C, Xing Y, Lv H, Nie C, Wang J, He Y, Wang SQ, Chen XB. Overview on the Role of E-Cadherin in Gastric Cancer: Dysregulation and Clinical Implications. Front Mol Biosci 2021; 8:689139. [PMID: 34422902 PMCID: PMC8371966 DOI: 10.3389/fmolb.2021.689139] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 07/19/2021] [Indexed: 01/04/2023] Open
Abstract
Gastric cancer is the fifth most common cancer and the third most common cause of cancer death all over the world. E-cadherin encoded by human CDH1 gene plays important roles in tumorigenesis as well as in tumor progression, invasion and metastasis. Full-length E-cadhrin tethered on the cell membrane mainly mediates adherens junctions between cells and is involved in maintaining the normal structure of epithelial tissues. After proteolysis, the extracellular fragment of the full-length E-cadhein is released into the extracellular environment and the blood, which is called soluble E-cadherin (sE-cadherin). sE-cadherin promots invasion and metastasis as a paracrine/autocrine signaling molecule in the progression of various types of cancer including gastric cancer. This review mainly summarizes the dysregulation of E-cadherin and the regulatory roles in the progression, invasion, metastasis, and drug-resistance, as well as its clinical applications in diagnosis, prognosis, and therapeutics of gastric cancer.
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Affiliation(s)
- Huichen Zhao
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Huihui Hu
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Beibei Chen
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China.,State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, China
| | - Weifeng Xu
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Jing Zhao
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Chen Huang
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Yishu Xing
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Huifang Lv
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Caiyun Nie
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Jianzheng Wang
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Yunduan He
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Sai-Qi Wang
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China.,State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, China
| | - Xiao-Bing Chen
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China.,State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, China
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7
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Garrone O, Michelotti A, Paccagnella M, Montemurro F, Vandone AM, Abbona A, Geuna E, Vanella P, De Angelis C, Lo Nigro C, Falletta A, Crosetto N, Di Maio M, Merlano M. Exploratory analysis of circulating cytokines in patients with metastatic breast cancer treated with eribulin: the TRANSERI-GONO (Gruppo Oncologico del Nord Ovest) study. ESMO Open 2021; 5:e000876. [PMID: 33051191 PMCID: PMC7555105 DOI: 10.1136/esmoopen-2020-000876] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Revised: 08/01/2020] [Accepted: 08/08/2020] [Indexed: 01/16/2023] Open
Abstract
Background Anticancer drugs can interact with the tumour microenvironment and their effects could be exploited to favour anticancer immune response. Eribulin contributes to tumour vasculature remodelling and transforming growth factor β (TGF-β) modulation in experimental models and in humans. We performed a prospective, translational, exploratory analysis of the levels of circulating cytokines at different time points in patients with metastatic breast cancer treated with eribulin. Methods TGF-β, tumour necrosis factor α, vascular endothelial growth factor, IL-6, IL-8, IL-10, IL-21 and C-C motif chemokine ligand-2 levels were assessed in peripheral blood samples obtained from seven healthy volunteers and 41 patients at baseline (T0), after four cycles of eribulin (T1) and at disease progression (TPD). Baseline values and longitudinal changes in cytokine levels were then related to clinical outcome. Results In the 41 patients, high IL-6 and IL-8 (above the median) at T0 significantly correlated with worse survival. At T1, IL-21 significantly decreased in patients with TPD within the fourth course of treatment, compared with patients without progression. TGF-β and IL-8 above the median and IL-21 below the median at T1 significantly correlates with worse progression free survival (PFS). Patients exhibiting an increase of TGF-β or a decline of IL-21 between T0 and T1 showed a significantly worse PFS. Multivariate Cox regression analysis showed that only plasma TGF-β changes at T1 correlated with survival. At TPD, TGF-β significantly increased in all patients. Conclusions We observed a significant correlation between TGF-β decline during eribulin treatment and outcome in patients with metastatic breast cancer. Altogether, our data suggest that eribulin treatment might interfere with the tumour microenvironment.
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Affiliation(s)
- Ornella Garrone
- Department of Medical Oncology, Azienda Ospedaliera S. Croce e Carle, Cuneo, Italy.
| | | | - Matteo Paccagnella
- Department of Medical Oncology, Azienda Ospedaliera S. Croce e Carle, Cuneo, Italy
| | - Filippo Montemurro
- Multidisciplinary Oncologic Day Hospital Department of Medical Oncology, Candiolo Cancer Institute, Candiolo, Italy
| | - Anna Maria Vandone
- Department of Medical Oncology, Azienda Ospedaliera S. Croce e Carle, Cuneo, Italy
| | - Andrea Abbona
- Department of Medical Oncology, Azienda Ospedaliera S. Croce e Carle, Cuneo, Italy
| | - Elena Geuna
- Multidisciplinary Oncologic Day Hospital Department of Medical Oncology, Candiolo Cancer Institute, Candiolo, Italy
| | - Paola Vanella
- Department of Medical Oncology, Azienda Ospedaliera S. Croce e Carle, Cuneo, Italy
| | | | - Cristiana Lo Nigro
- Department of Medical Oncology, Azienda Ospedaliera S. Croce e Carle, Cuneo, Italy
| | - Antonella Falletta
- Department of Medical Oncology, Azienda Ospedaliera S. Croce e Carle, Cuneo, Italy
| | - Nicola Crosetto
- Science for Life Laboratory Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden
| | - Massimo Di Maio
- Department of Oncology, Universita' degli Studi di Torino, Torino, Italy
| | - Marco Merlano
- Department of Medical Oncology, Candiolo Cancer Institute, Candiolo, Italy
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8
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Na D, Chae J, Cho SY, Kang W, Lee A, Min S, Kang J, Kim MJ, Choi J, Lee W, Shin D, Min A, Kim YJ, Lee KH, Kim TY, Suh YS, Kong SH, Lee HJ, Kim WH, Park H, Im SA, Yang HK, Lee C, Kim JI. Predictive biomarkers for 5-fluorouracil and oxaliplatin-based chemotherapy in gastric cancers via profiling of patient-derived xenografts. Nat Commun 2021; 12:4840. [PMID: 34376661 PMCID: PMC8355375 DOI: 10.1038/s41467-021-25122-4] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 07/16/2021] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer (GC) is commonly treated by chemotherapy using 5-fluorouracil (5-FU) derivatives and platinum combination, but predictive biomarker remains lacking. We develop patient-derived xenografts (PDXs) from 31 GC patients and treat with a combination of 5-FU and oxaliplatin, to determine biomarkers associated with responsiveness. When the PDXs are defined as either responders or non-responders according to tumor volume change after treatment, the responsiveness of PDXs is significantly consistent with the respective clinical outcomes of the patients. An integrative genomic and transcriptomic analysis of PDXs reveals that pathways associated with cell-to-cell and cell-to-extracellular matrix interactions enriched among the non-responders in both cancer cells and the tumor microenvironment (TME). We develop a 30-gene prediction model to determine the responsiveness to 5-FU and oxaliplatin-based chemotherapy and confirm the significant poor survival outcomes among cases classified as non-responder-like in three independent GC cohorts. Our study may inform clinical decision-making when designing treatment strategies.
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Affiliation(s)
- Deukchae Na
- Ewha Institute of Convergence Medicine, Ewha Womans University Mokdong Hospital, Seoul, Korea
| | - Jeesoo Chae
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
- Cancer Evolution Research Center, The Catholic University of Korea, Seoul, Korea
| | - Sung-Yup Cho
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
- Cancer Research Institute, Seoul National University, Seoul, Korea
- Medical Research Center, Genomic Medicine Institute (GMI), Seoul National University, Seoul, Korea
| | - Wonyoung Kang
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
| | - Ahra Lee
- Department of Life Science, Ewha Womans University, Seoul, Korea
| | - Seoyeon Min
- Department of Life Science, Ewha Womans University, Seoul, Korea
| | - Jinjoo Kang
- Department of Life Science, Ewha Womans University, Seoul, Korea
| | - Min Jung Kim
- Medical Research Center, Genomic Medicine Institute (GMI), Seoul National University, Seoul, Korea
| | - Jaeyong Choi
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
| | - Woochan Lee
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
| | - Dongjin Shin
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
| | - Ahrum Min
- Cancer Research Institute, Seoul National University, Seoul, Korea
- Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
| | - Yu-Jin Kim
- Cancer Research Institute, Seoul National University, Seoul, Korea
| | - Kyung-Hun Lee
- Cancer Research Institute, Seoul National University, Seoul, Korea
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Tae-Yong Kim
- Cancer Research Institute, Seoul National University, Seoul, Korea
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Yun-Suhk Suh
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
- Department of Surgery, Seoul National University Bundang Hospital, Seoul, Korea
| | - Seong-Ho Kong
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Hyuk-Joon Lee
- Cancer Research Institute, Seoul National University, Seoul, Korea
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Woo-Ho Kim
- Cancer Research Institute, Seoul National University, Seoul, Korea
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
| | - Hansoo Park
- Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology (GIST), Gwangju, Korea
| | - Seock-Ah Im
- Cancer Research Institute, Seoul National University, Seoul, Korea.
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.
| | - Han-Kwang Yang
- Cancer Research Institute, Seoul National University, Seoul, Korea.
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea.
| | - Charles Lee
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
- Department of Life Science, Ewha Womans University, Seoul, Korea.
- Precision Medicine Center, The First Affiliated Hospital of Xiu'an Jiaotong University, Shaanxi, People's Republic of China.
| | - Jong-Il Kim
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
- Cancer Research Institute, Seoul National University, Seoul, Korea.
- Medical Research Center, Genomic Medicine Institute (GMI), Seoul National University, Seoul, Korea.
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9
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Lai X, Lin P, Ye J, Liu W, Lin S, Lin Z. Reference Module-Based Analysis of Ovarian Cancer Transcriptome Identifies Important Modules and Potential Drugs. Biochem Genet 2021; 60:433-451. [PMID: 34173117 DOI: 10.1007/s10528-021-10101-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Accepted: 06/16/2021] [Indexed: 12/18/2022]
Abstract
Ovarian cancer (OVC) is often diagnosed at the advanced stage resulting in a poor overall outcome for the patient. The disease mechanisms, prognosis, and treatment require imperative elucidation. A rank-based module-centric framework was proposed to analyze the key modules related to the development, prognosis, and treatment of OVC. The ovarian cancer cell line microarray dataset GSE43765 from the Gene Expression Omnibus database was used to construct the reference modules by weighted gene correlation network analysis. Twenty-three reference modules were tested for stability and functionally annotated. Furthermore, to demonstrate the utility of reference modules, two more OVC datasets were collected, and their gene expression profiles were projected to the reference modules to generate a module-level expression. An epithelial-mesenchymal transition module was activated in OVC compared to the normal epithelium, and a pluripotency module was activated in ovarian cancer stroma compared to ovarian cancer epithelium. Seven differentially expressed modules were identified in OVC compared to the normal ovarian epithelium, with five up-regulated, and two down-regulated. One module was identified to be predictive of patient overall survival. Four modules were enriched with SNP signals. Based on differentially expressed modules and hub genes, five candidate drugs were screened. The hub genes of those modules merit further investigation. We firstly propose the reference module-based analysis of OVC. The utility of the analysis framework can be extended to transcriptome data of other kinds of diseases.
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Affiliation(s)
- Xuedan Lai
- Department of Gynaecology and Obstetrics, Fuzhou First Hospital Affiliated to Fujian Medical University, Fuzhou, 350009, People's Republic of China
| | - Peihong Lin
- Department of Gynaecology and Obstetrics, Fuzhou First Hospital Affiliated to Fujian Medical University, Fuzhou, 350009, People's Republic of China
| | - Jianwen Ye
- Department of Gynaecology and Obstetrics, Fuzhou First Hospital Affiliated to Fujian Medical University, Fuzhou, 350009, People's Republic of China
| | - Wei Liu
- Department of Bioinformatics, College of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou, 350002, People's Republic of China
| | - Shiqiang Lin
- Department of Bioinformatics, College of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou, 350002, People's Republic of China
| | - Zhou Lin
- Department of Gynaecology and Obstetrics, Fuzhou First Hospital Affiliated to Fujian Medical University, Fuzhou, 350009, People's Republic of China.
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Pietrobon V, Cesano A, Marincola F, Kather JN. Next Generation Imaging Techniques to Define Immune Topographies in Solid Tumors. Front Immunol 2021; 11:604967. [PMID: 33584676 PMCID: PMC7873485 DOI: 10.3389/fimmu.2020.604967] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 12/03/2020] [Indexed: 12/12/2022] Open
Abstract
In recent years, cancer immunotherapy experienced remarkable developments and it is nowadays considered a promising therapeutic frontier against many types of cancer, especially hematological malignancies. However, in most types of solid tumors, immunotherapy efficacy is modest, partly because of the limited accessibility of lymphocytes to the tumor core. This immune exclusion is mediated by a variety of physical, functional and dynamic barriers, which play a role in shaping the immune infiltrate in the tumor microenvironment. At present there is no unified and integrated understanding about the role played by different postulated models of immune exclusion in human solid tumors. Systematically mapping immune landscapes or "topographies" in cancers of different histology is of pivotal importance to characterize spatial and temporal distribution of lymphocytes in the tumor microenvironment, providing insights into mechanisms of immune exclusion. Spatially mapping immune cells also provides quantitative information, which could be informative in clinical settings, for example for the discovery of new biomarkers that could guide the design of patient-specific immunotherapies. In this review, we aim to summarize current standard and next generation approaches to define Cancer Immune Topographies based on published studies and propose future perspectives.
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Affiliation(s)
| | | | | | - Jakob Nikolas Kather
- Medical Oncology, National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
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11
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Abstract
Over the last few years, cancer immunotherapy experienced tremendous developments and it is nowadays considered a promising strategy against many types of cancer. However, the exclusion of lymphocytes from the tumor nest is a common phenomenon that limits the efficiency of immunotherapy in solid tumors. Despite several mechanisms proposed during the years to explain the immune excluded phenotype, at present, there is no integrated understanding about the role played by different models of immune exclusion in human cancers. Hypoxia is a hallmark of most solid tumors and, being a multifaceted and complex condition, shapes in a unique way the tumor microenvironment, affecting gene transcription and chromatin remodeling. In this review, we speculate about an upstream role for hypoxia as a common biological determinant of immune exclusion in solid tumors. We also discuss the current state of ex vivo and in vivo imaging of hypoxic determinants in relation to T cell distribution that could mechanisms of immune exclusion and discover functional-morphological tumor features that could support clinical monitoring.
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12
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Kozak J, Forma A, Czeczelewski M, Kozyra P, Sitarz E, Radzikowska-Büchner E, Sitarz M, Baj J. Inhibition or Reversal of the Epithelial-Mesenchymal Transition in Gastric Cancer: Pharmacological Approaches. Int J Mol Sci 2020; 22:ijms22010277. [PMID: 33383973 PMCID: PMC7795012 DOI: 10.3390/ijms22010277] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 12/22/2020] [Accepted: 12/24/2020] [Indexed: 12/12/2022] Open
Abstract
Epithelial-mesenchymal transition (EMT) constitutes one of the hallmarks of carcinogenesis consisting in the re-differentiation of the epithelial cells into mesenchymal ones changing the cellular phenotype into a malignant one. EMT has been shown to play a role in the malignant transformation and while occurring in the tumor microenvironment, it significantly affects the aggressiveness of gastric cancer, among others. Importantly, after EMT occurs, gastric cancer patients are more susceptible to the induction of resistance to various therapeutic agents, worsening the clinical outcome of patients. Therefore, there is an urgent need to search for the newest pharmacological agents targeting EMT to prevent further progression of gastric carcinogenesis and potential metastases. Therapies targeted at EMT might be combined with other currently available treatment modalities, which seems to be an effective strategy to treat gastric cancer patients. In this review, we have summarized recent advances in gastric cancer treatment in terms of targeting EMT specifically, such as the administration of polyphenols, resveratrol, tangeretin, luteolin, genistein, proton pump inhibitors, terpenes, other plant extracts, or inorganic compounds.
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Affiliation(s)
- Joanna Kozak
- Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland;
| | - Alicja Forma
- Department of Forensic Medicine, Medical University of Lublin, 20-090 Lublin, Poland; (A.F.); (M.C.)
| | - Marcin Czeczelewski
- Department of Forensic Medicine, Medical University of Lublin, 20-090 Lublin, Poland; (A.F.); (M.C.)
| | - Paweł Kozyra
- Student Research Group, Independent Radiopharmacy Unit, Faculty of Pharmacy, Medical University of Lublin, PL-20093 Lublin, Poland;
| | - Elżbieta Sitarz
- 1st Department of Psychiatry, Psychotherapy and Early Intervention, Medical University of Lublin, Gluska Street 1, 20-439 Lublin, Poland;
| | - Elżbieta Radzikowska-Büchner
- Department of Plastic Surgery, Central Clinical Hospital of the Ministry of the Interior in Warsaw, 01-211 Warsaw, Poland;
| | - Monika Sitarz
- Department of Conservative Dentistry with Endodontics, Medical University of Lublin, 20-090 Lublin, Poland;
| | - Jacek Baj
- Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland;
- Correspondence:
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13
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Abstract
Checkpoint inhibitor therapy (CIT) has revolutionized cancer treatment but it has also reached a standstill when an absent dialog between cancer and immune cells makes it irrelevant. This occurs with high prevalence in the context of "immune silent" and, even perhaps, "immune-excluded" tumors. The latter are characterized by T cells restricted to the periphery of cancer nests. Since in either case T cells do not come in direct contact with most cancer cells, CIT rests immaterial. Adoptive cell therapy (ACT), may also be affected by limited access to antigen-bearing cancer cells. While lack of immunogenicity intuitively explains the immune silent phenotype, immune exclusion is perplexing. The presence of T cells at the periphery suggests that chemo-attraction recruits them and an immunogenic stimulus promotes their persistence. However, what stops the T cells from infiltrating the tumors' nests and reaching the germinal center (GC)? Possibly, a concentric gradient of increased chemo-repulsion or decreased chemo-attraction demarcates an abrupt "do not trespass" warning. Various hypotheses suggest physical or functional barriers but no definitive consensus exists over the weight that each plays in human cancers. On one hand, it could be hypothesized that the intrinsic biology of cancer cells may degenerate from a "cancer stem cell" (CSC)-like phenotype in the GC toward a progressively more immunogenic phenotype prone to immunogenic cell death (ICD) at the periphery. On the other hand, the intrinsic biology of the cancer cells may not change but it is the disorderly architecture of the tumor microenvironment (TME) that alters in a centripetal direction cancer cell metabolism, both directly and indirectly, the function of surrounding stromal cells. In this chapter, we examine whether the paradoxical exclusion of T cells from tumors may serve as a model to understand the requirements for tumor immune infiltration and, correspondingly, we put forth strategies to restore the dialog between immune cells and cancer to enhance the effectiveness of immune oncology (IO) approaches.
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Affiliation(s)
- Sara I Pai
- Massachusetts General Hospital, Harvard University, Boston, MA, USA.
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14
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Zhang H, Zhang Z, Wang D. Epigenetic regulation of IncRNA KCNKI5-ASI in gastric cancer. Cancer Manag Res 2019; 11:8589-8602. [PMID: 31572012 PMCID: PMC6759217 DOI: 10.2147/cmar.s186002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Accepted: 11/21/2018] [Indexed: 12/14/2022] Open
Abstract
Background Long noncoding RNAs (lncRNAs) play an important role in gastric cancer. In this study, we aimed to uncover the epigenetic regulatory mechanism of lncRNA KCNK15-AS1 in gastric cancer progression. Patients and methods Forty patients were included in the study. The expression of KCNK15-AS1 was detected by real-time PCR (RT-PCR), the promoter of KCNK15-AS1 was detected by methylation-specific PCR, and the luciferase assay was performed to detect the relationship between KCNK15-AS1 and miR-21. The relationship of the proteins was explored by an RNA pull-down assay and RNA immunoprecipitation. Chromatin immunoprecipitation was performed to detect the relationship between the promoter and the protein. Results The expression of KCNK15-AS1 was lower in the tumor tissue compared to the normal tissue. KCNK15-AS1 interacted with miR-21. Both the overexpression of KCNK15-AS1 and the knockdown of the expression of miR-21 inhibited proliferation and promoted apoptosis and decreased the level of MMP-9, bcl-2, and MMP-2 but increased the level of Bax. In addition, the methylation of KCNK15-AS1 was detected in the tumor tissue but was not detected in the normal tissue. Treatment with 5-azacytidine and chidamide decreased the level of DNMT1 and HDAC1 and increased the level of KCNK15-AS1. The RNA pull-down and RNA immunoprecipitation results showed that KCNK15-AS1 interacted with DNMT1 and HDAC1. The ChIP-seq result showed that the promoter of MAPK interacted with DNMT1, and the promoter of AKT and STAT5 interacted with HDAC1. Conclusion In this study, we identified two regulatory axes, namely KCNK15-AS1-DNMT1-MAPK and KCNK15-AS1-HDAC1-AKT, which were associated with gastric cancer progression. Chidamide and 5-azacytidine might provide new modes for treating gastric cancer.
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Affiliation(s)
- Haiyan Zhang
- Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China
| | - Zhuo Zhang
- Department of Urology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China
| | - Dayu Wang
- Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China
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Zhu L, Liu Z, Dong R, Wang X, Zhang M, Guo X, Yu N, Zeng A. MicroRNA-3662 targets ZEB1 and attenuates the invasion of the highly aggressive melanoma cell line A375. Cancer Manag Res 2019; 11:5845-5856. [PMID: 31388313 PMCID: PMC6607987 DOI: 10.2147/cmar.s200540] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2019] [Accepted: 05/29/2019] [Indexed: 12/16/2022] Open
Abstract
Background Cutaneous melanoma is the most aggressive form of skin cancer. It accounts for approximately 5% of all cutaneous malignancies and is currently responsible for the majority of skin cancer-related deaths. However, the exact mechanisms responsible for the occurrence of melanoma, in particular the invasive growth in normal skin or muscle tissue, remain unknown. Materials and methods miR-3662, a microRNA is a potential tumor suppressor targeting zinc finger E-box binding homeobox 1 (ZEB1), which functions as a key regulator of the epithelial-mesenchymal transition (EMT) process. This microRNA was identified using an online database (miRDB) and expression was confirmed by Western blot analysis. Quantitative polymerase chain reaction (qPCR) was used to examine whether miR-3662 inhibits the EMT process in the aggressive melanoma cell line, A375, through the modification of the expression of invasion-related genes in A375 cells. The effects of miR-3662 on the in vivo growth of A375 cells were examined in a nude mouse model. Results Using virtual screening of the miRDB database, miR-3662 was shown to target the 3ʹ untranslated region (UTR) of the ZEB1 gene. Expression of miR-3662 via a lentivirus vector significantly decreased protein levels of ZEB1 and inhibited the growth of A375 cells in vitro and in vivo. The reduction in ZEB1 expression induced by miR-3662 resulted in EMT inhibition in A375 cells and decreased the relative expression of metastasis genes. Conclusion Down-regulation of ZEB1’s expression via miR-3662 lentivirus vectors significantly decreased the in vitro and in vivo growth of the highly aggressive melanoma cell line A375.
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Affiliation(s)
- Lin Zhu
- Department of Plastic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, People's Republic of China
| | - Zhifei Liu
- Department of Plastic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, People's Republic of China
| | - Ruijia Dong
- Department of Plastic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, People's Republic of China
| | - Xiaojun Wang
- Department of Plastic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, People's Republic of China
| | - Mingzi Zhang
- Department of Plastic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, People's Republic of China
| | - Xiao Guo
- Department of Plastic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, People's Republic of China
| | - Nanze Yu
- Department of Plastic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, People's Republic of China
| | - Ang Zeng
- Department of Plastic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, People's Republic of China
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