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Chiablaem K, Jinawath A, Nuanpirom J, Arora JK, Nasaree S, Thanomchard T, Singhto N, Chittavanich P, Suktitipat B, Charoensawan V, Chairoungdua A, Jinn-Chyuan Sheu J, Kiyotani K, Svasti J, Nakamura Y, Jinawath N. Identification of RNF213 as a Potential Suppressor of Local Invasion in Intrahepatic Cholangiocarcinoma. J Transl Med 2024; 104:102074. [PMID: 38723854 DOI: 10.1016/j.labinv.2024.102074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Revised: 04/08/2024] [Accepted: 04/30/2024] [Indexed: 06/14/2024] Open
Abstract
Intrahepatic cholangiocarcinoma (ICC) is a lethal cancer with poor survival especially when it spreads. The histopathology of its rare intraductal papillary neoplasm of the bile duct type (IPNB) characteristically shows cancer cells originating within the confined bile duct space. These cells eventually invade and infiltrate the nearby liver tissues, making it a good model to study the mechanism of local invasion, which is the earliest step of metastasis. To discover potential suppressor genes of local invasion in ICC, we analyzed the somatic mutation profiles and performed clonal evolution analyses of the 11 pairs of macrodissected locally invasive IPNB tissues (LI-IPNB) and IPNB tissues without local invasion from the same patients. We identified a protein-truncating variant in an E3 ubiquitin ligase, RNF213 (c.6967C>T; p.Gln2323X; chr17: 78,319,102 [hg19], exon 29), as the most common protein-truncating variant event in LI-IPNB samples (4/11 patients). Knockdown of RNF213 in HuCCT1 and YSCCC cells showed increased migration and invasion, and reduced vasculogenic mimicry but maintained normal proliferation. Transcriptomic analysis of the RNF213-knockdown vs control cells was then performed in the HuCCT1, YSCCC, and KKU-100 cells. Gene ontology enrichment analysis of the common differentially expressed genes revealed significantly altered cytokine and oxidoreductase-oxidizing metal ion activities, as confirmed by Western blotting. Gene Set Enrichment Analysis identified the most enriched pathways being oxidative phosphorylation, fatty acid metabolism, reactive oxygen species, adipogenesis, and angiogenesis. In sum, loss-of-function mutation of RNF213 is a common genetic alteration in LI-IPNB tissues. RNF213 knockdown leads to increased migration and invasion of ICC cells, potentially through malfunctions of the pathways related to inflammation and energy metabolisms.
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Affiliation(s)
- Khajeelak Chiablaem
- Program in Translational Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; Laboratory of Biochemistry, Chulabhorn Research Institute, Bangkok, Thailand
| | - Artit Jinawath
- Molecular Histopathology Laboratory, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Jiratchaya Nuanpirom
- Integrative Computational Bioscience (ICBS) Center, Mahidol University, Nakhon Pathom, Thailand
| | - Jantarika Kumar Arora
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Sirawit Nasaree
- Program in Translational Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Thanastha Thanomchard
- Ramathibodi Comprehensive Cancer Center, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Nilubon Singhto
- Ramathibodi Comprehensive Cancer Center, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Pamorn Chittavanich
- Program in Translational Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Bhoom Suktitipat
- Integrative Computational Bioscience (ICBS) Center, Mahidol University, Nakhon Pathom, Thailand; Department of Biochemistry, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Varodom Charoensawan
- Integrative Computational Bioscience (ICBS) Center, Mahidol University, Nakhon Pathom, Thailand; Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, Thailand; Department of Biochemistry, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; Siriraj Genomics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Arthit Chairoungdua
- Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Jim Jinn-Chyuan Sheu
- Institute of Biomedical Science, National Sun Yat-Sen University, Kaohsiung, Taiwan; School of Chinese Medicine, China Medical University, Taichung, Taiwan; Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Kazuma Kiyotani
- Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Jisnuson Svasti
- Laboratory of Biochemistry, Chulabhorn Research Institute, Bangkok, Thailand
| | - Yusuke Nakamura
- Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, Tokyo, Japan; National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
| | - Natini Jinawath
- Program in Translational Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; Integrative Computational Bioscience (ICBS) Center, Mahidol University, Nakhon Pathom, Thailand; Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bang Phli, Samut Prakan, Thailand.
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Trakoonsenathong R, Kunprom W, Aphivatanasiri C, Yueangchantuek P, Pimkeeree P, Sorin S, Khawkhiaw K, Chiu CF, Okada S, Wongkham S, Saengboonmee C. Liraglutide exhibits potential anti-tumor effects on the progression of intrahepatic cholangiocarcinoma, in vitro and in vivo. Sci Rep 2024; 14:13726. [PMID: 38877189 PMCID: PMC11178799 DOI: 10.1038/s41598-024-64774-2] [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: 02/12/2024] [Accepted: 06/12/2024] [Indexed: 06/16/2024] Open
Abstract
Glucagon-like peptide 1 receptor (GLP-1R) agonist is an emerging anti-diabetic medication whose effects on the risk and progression of cholangiocarcinoma (CCA) are controversial. This study aimed to elucidate the roles of GLP-1R and its agonists on intrahepatic CCA (iCCA) progression. Expressions of GLP-1R in iCCA tissues investigated by immunohistochemistry showed that GLP-1R expressions were significantly associated with poor histological grading (P = 0.027). iCCA cell lines, KKU-055 and KKU-213A, were treated with exendin-4 and liraglutide, GLP-1R agonists, and their effects on proliferation and migration were assessed. Exendin-4 and liraglutide did not affect CCA cell proliferation in vitro, but liraglutide significantly suppressed the migration of CCA cells, partly by inhibiting epithelial-mesenchymal transition. In contrast, liraglutide significantly reduced CCA tumor volumes and weights in xenografted mice (P = 0.046). GLP-1R appeared downregulated when CCA cells were treated with liraglutide in vitro and in vivo. In addition, liraglutide treatment significantly suppressed Akt and STAT3 signaling in CCA cells, by reducing their phosphorylation levels. These results suggested that liraglutide potentially slows down CCA progression, and further clinical investigation would benefit the treatment of CCA with diabetes mellitus.
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Affiliation(s)
- Ronnakrit Trakoonsenathong
- Cho-Kalaphruek Excellent Research Project for Medical Students, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Waritta Kunprom
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Chaiwat Aphivatanasiri
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
| | - Padcharee Yueangchantuek
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Paslada Pimkeeree
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Faculty of Medical Sciences, Naresuan University, Phitsanulok, Thailand
| | - Supannika Sorin
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
| | - Kullanat Khawkhiaw
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
| | - Ching-Feng Chiu
- Graduate Institute of Metabolism and Obesity Sciences, Taipei Medical University, Taipei, Taiwan
| | - Seiji Okada
- Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, Japan
| | - Sopit Wongkham
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
| | - Charupong Saengboonmee
- Cho-Kalaphruek Excellent Research Project for Medical Students, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand.
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand.
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Qian MB, Keiser J, Utzinger J, Zhou XN. Clonorchiasis and opisthorchiasis: epidemiology, transmission, clinical features, morbidity, diagnosis, treatment, and control. Clin Microbiol Rev 2024; 37:e0000923. [PMID: 38169283 PMCID: PMC10938900 DOI: 10.1128/cmr.00009-23] [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: 01/30/2023] [Accepted: 07/18/2023] [Indexed: 01/05/2024] Open
Abstract
Clonorchis sinensis, Opisthorchis viverrini, and Opisthorchis felineus are important liver flukes that cause a considerable public health burden in eastern Asia, southeastern Asia, and eastern Europe, respectively. The life cycles are complex, involving humans, animal reservoirs, and two kinds of intermediate hosts. An interplay of biological, cultural, ecological, economic, and social factors drives transmission. Chronic infections are associated with liver and biliary complications, most importantly cholangiocarcinoma. With regard to diagnosis, stool microscopy is widely used in epidemiologic surveys and for individual diagnosis. Immunologic techniques are employed for screening purposes, and molecular techniques facilitate species differentiation in reference laboratories. The mainstay of control is preventive chemotherapy with praziquantel, usually combined with behavioral change through information, education and communication, and environmental control. Tribendimidine, a drug registered in the People's Republic of China for soil-transmitted helminth infections, shows potential against both C. sinensis and O. viverrini and, hence, warrants further clinical development. Novel control approaches include fish vaccine and biological control. Considerable advances have been made using multi-omics which may trigger the development of new interventions. Pressing research needs include mapping the current distribution, disentangling the transmission, accurately estimating the disease burden, and developing new diagnostic and treatment tools, which would aid to optimize control and elimination measures.
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Affiliation(s)
- Men-Bao Qian
- National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention (Chinese Center for Tropical Diseases Research), Shanghai, People’s Republic of China
- NHC Key Laboratory of Parasite and Vector Biology, Shanghai, People’s Republic of China
- WHO Collaborating Centre for Tropical Diseases, Shanghai, People’s Republic of China
- School of Global Health, Chinese Center for Tropical Diseases Research, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
| | - Jennifer Keiser
- Swiss Tropical and Public Health Institute, Allschwil, Switzerland
- University of Basel, Basel, Switzerland
| | - Jürg Utzinger
- Swiss Tropical and Public Health Institute, Allschwil, Switzerland
- University of Basel, Basel, Switzerland
| | - Xiao-Nong Zhou
- National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention (Chinese Center for Tropical Diseases Research), Shanghai, People’s Republic of China
- NHC Key Laboratory of Parasite and Vector Biology, Shanghai, People’s Republic of China
- WHO Collaborating Centre for Tropical Diseases, Shanghai, People’s Republic of China
- School of Global Health, Chinese Center for Tropical Diseases Research, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
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Ferrell LD, Kakar S, Terracciano LM, Wee A. Tumours and Tumour-Like Lesions. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:842-946. [DOI: 10.1016/b978-0-7020-8228-3.00013-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Saengboonmee C, Sorin S, Sangkhamanon S, Chomphoo S, Indramanee S, Seubwai W, Thithuan K, Chiu CF, Okada S, Gingras MC, Wongkham S. γ-aminobutyric acid B2 receptor: A potential therapeutic target for cholangiocarcinoma in patients with diabetes mellitus. World J Gastroenterol 2023; 29:4416-4432. [PMID: 37576707 PMCID: PMC10415970 DOI: 10.3748/wjg.v29.i28.4416] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 06/05/2023] [Accepted: 07/05/2023] [Indexed: 07/26/2023] Open
Abstract
BACKGROUND The association between diabetes mellitus (DM) and the increased risk and progression of cholangiocarcinoma (CCA) has been reported with unclear underlying mechanisms. Previous studies showed that γ-aminobutyric acid (GABA) B2 receptor (GABBR2) was upregulated in CCA cells cultured in high glucose (HG) conditions. Roles of GABA receptors in CCA progression have also been studied, but their association with DM and hyperglycemia in CCA remains unclarified. AIM To investigate the effects of hyperglycemia on GABBR2 expression and the potential use of GABBR2 as a CCA therapeutic target. METHODS CCA cells, KKU-055 and KKU-213A, were cultured in Dulbecco Modified Eagle's Medium supplemented with 5.6 mmol/L (normal glucose, NG) or 25 mmol/L (HG) glucose and assigned as NG and HG cells, respectively. GABBR2 expression in NG and HG cells was investigated using real-time quantitative polymerase chain reaction and western blot. Expression and localization of GABBR2 in CCA cells were determined using immunocytofluorescence. GABBR2 expression in tumor tissues from CCA patients with and without DM was studied using immunohistochemistry, and the correlations of GABBR2 with the clinicopathological characteristics of patients were analyzed using univariate analysis. Effects of baclofen, a GABA-B receptor agonist, on CCA cell proliferation and clonogenicity were tested using the MTT and clonogenic assays. Phospho-kinases arrays were used to screen the affected signaling pathways after baclofen treatment, and the candidate signaling molecules were validated using the public transcriptomic data and western blot. RESULTS GABBR2 expression in CCA cells was induced by HG in a dose- and time-dependent manner. CCA tissues from patients with DM and hyperglycemia also showed a significantly higher GABBR2 expression compared with tumor tissues from those with euglycemia (P < 0.01). High GABBR2 expression was significantly associated with a poorer non-papillary histological subtype but with smaller sizes of CCA tumors (P < 0.05). HG cells of both tested CCA cell lines were more sensitive to baclofen treatment. Baclofen significantly suppressed the proliferation and clonogenicity of CCA cells in both NG and HG conditions (P < 0.05). Phospho-kinase arrays suggested glycogen synthase kinase 3 (GSK3), β-catenin, and the signal transducer and activator of transcription 3 (STAT3) as candidate signaling molecules under the regulation of GABBR2, which were verified in NG and HG cells of the individual CCA cell lines. Cyclin D1 and c-Myc, the common downstream targets of GSK3/β-catenin and STAT3 involving cell proliferation, were accordingly downregulated after baclofen treatment. CONCLUSION GABBR2 is upregulated by HG and holds a promising role as a therapeutic target for CCA regardless of the glucose condition.
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Affiliation(s)
- Charupong Saengboonmee
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
- Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Supannika Sorin
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
- Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Sakkarn Sangkhamanon
- Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Surang Chomphoo
- Department of Anatomy, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Somsiri Indramanee
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
- Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Wunchana Seubwai
- Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand
- Department of Forensic Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Kanyarat Thithuan
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Ching-Feng Chiu
- Graduate Institute of Metabolism and Obesity Sciences, Taipei Medical University, Taipei 11031, Taiwan
| | - Seiji Okada
- Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto 860-0811, Japan
| | - Marie-Claude Gingras
- Human Genome Sequencing Center, Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, TX 77030, United States
- Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, United States
| | - Sopit Wongkham
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
- Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand
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Liu W, Li J, Zhao R, Lu Y, Huang P. The Uridine diphosphate (UDP)-glycosyltransferases (UGTs) superfamily: the role in tumor cell metabolism. Front Oncol 2023; 12:1088458. [PMID: 36741721 PMCID: PMC9892627 DOI: 10.3389/fonc.2022.1088458] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Accepted: 12/09/2022] [Indexed: 01/20/2023] Open
Abstract
UDP-glycosyltransferases (UGTs), important enzymes in biotransformation, control the levels and distribution of numerous endogenous signaling molecules and the metabolism of a wide range of endogenous and exogenous chemicals. The UGT superfamily in mammals consists of the UGT1, UGT2, UGT3, and UGT8 families. UGTs are rate-limiting enzymes in the glucuronate pathway, and in tumors, they are either overexpressed or underexpressed. Alterations in their metabolism can affect gluconeogenesis and lipid metabolism pathways, leading to alterations in tumor cell metabolism, which affect cancer development and prognosis. Glucuronidation is the most common mammalian conjugation pathway. Most of its reactions are mainly catalyzed by UGT1A, UGT2A and UGT2B. The body excretes UGT-bound small lipophilic molecules through the bile, urine, or feces. UGTs conjugate a variety of tiny lipophilic molecules to sugars, such as galactose, xylose, acetylglucosamine, glucuronic acid, and glucose, thereby inactivating and making water-soluble substrates, such as carcinogens, medicines, steroids, lipids, fatty acids, and bile acids. This review summarizes the roles of members of the four UGT enzyme families in tumor function, metabolism, and multiple regulatory mechanisms, and its Inhibitors and inducers. The function of UGTs in lipid metabolism, drug metabolism, and hormone metabolism in tumor cells are among the most important topics covered.
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Affiliation(s)
| | | | | | - Yao Lu
- *Correspondence: Yao Lu, ; Panpan Huang,
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Ji L, Piao L, Gu X, Xiao F, Hua Q, Wu J. Silencing PARP-1 binding protein Inhibits Cell Migration and Invasion via Suppressing UBE2C in Nasopharyngeal Cancer Cells. EAR, NOSE & THROAT JOURNAL 2022; 102:NP161-NP168. [PMID: 36576436 DOI: 10.1177/01455613221134408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Nasopharyngeal carcinoma (NPC) is a malignancy with a 2 per 100 000 incidence rate in the world. Overall survival (OS) of patients in stage I-II disease is around 80%, whereas OS of patients in stage III-IVB disease drops to 60%, implying the importance of diagnosis to reduce NPC mortality. However, more than 70% patients of NPC were diagnosed at advanced stages (stage III and IV) in clinics, and it definitely contributes to little substantial improvement in the 5-year survival rates although NPC is sensitive to radio-and chemotherapy. Hence, development of novel biomarkers and targetable genes in NPC is eagerly awaited. METHODS We had analyzed the dataset GSE12452 and found hundreds of genes trans-activated in NPC. Among them, this study focused on PARP-1 binding protein (PARPBP) whose overexpression was also validated in GSE13597 and GSE53819 datasets. RESULTS Knockdown of PARPBP significantly reduced cell viability in NPC and also identified hundreds of differentially expressed genes including 377 downregulated and 518 upregulated genes in HONE-1 cells with stably knockdown PARPBP. Furthermore, PARPBP might promote cell migration and invasion in NPC through positive regulation of ubiquitin-conjugating enzyme 2C (UBE2C). CONCLUSION The results demonstrate the aberrant expression of PARPBP in NPC, and imply its importance in nasopharyngeal carcinogenesis which further opens up the possibility of PARPBP as a novel diagnostic biomarker for NPC therapy.
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Affiliation(s)
- Li Ji
- Department of Otorhinolaryngology, 12461The Second People's Hospital of Changzhou affiliated to Nanjing Medical University, Changzhou, China
| | - Lianhua Piao
- Institute of Bioinformatics and Medical Engineering, 105810Jiangsu University of Technology, Changzhou, China
| | - Xiaofeng Gu
- Department of Otorhinolaryngology, 12461The Second People's Hospital of Changzhou affiliated to Nanjing Medical University, Changzhou, China
| | - Feng Xiao
- Department of Otorhinolaryngology, 12461The Second People's Hospital of Changzhou affiliated to Nanjing Medical University, Changzhou, China
| | - Qingquan Hua
- Department of Otolaryngology-Head and Neck Surgery, 117921Renmin Hospital of Wuhan University, Wuhan, China
| | - Jian Wu
- Department of Otorhinolaryngology, 12461The Second People's Hospital of Changzhou affiliated to Nanjing Medical University, Changzhou, China
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Li Y, Yuan SL, Yin JY, Yang K, Zhou XG, Xie W, Wang Q. Differences of core genes in liver fibrosis and hepatocellular carcinoma: Evidence from integrated bioinformatics and immunohistochemical analysis. World J Gastrointest Oncol 2022; 14:1265-1280. [PMID: 36051101 PMCID: PMC9305567 DOI: 10.4251/wjgo.v14.i7.1265] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 05/18/2022] [Accepted: 06/26/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Liver fibrosis and hepatocellular carcinoma (HCC) are common adverse consequences of chronic liver injury. The interaction of various risk factors may cause them to happen. Identification of specific biomarkers is of great significance for understanding the occurrence, development mechanisms, and determining the novel tools for diagnosis and treatment of both liver fibrosis and HCC.
AIM To identify liver fibrosis-related core genes, we analyzed the differential expression pattern of core genes in liver fibrosis and HCC.
METHODS Gene expression profiles of three datasets, GSE14323, GSE36411, and GSE89377, obtained from the Gene Expression Omnibus (GEO) database, were analyzed, and differentially expressed genes (DEGs) between patients with liver cirrhosis and healthy controls were identified by screening via R software packages and online tool for Venn diagrams. The WebGestalt online tool was used to identify DEGs enriched in biological processes, molecular functions, cellular components, and Kyoto Encyclopedia of Genes and Genomes pathways. The protein–protein interactions of DEGs were visualized using Cytoscape with STRING. Next, the expression pattern of core genes was analyzed using Western blot and immunohistochemistry in a carbon tetrachloride (CCl4)-induced liver cirrhosis mouse model and in patient liver samples. Finally, Kaplan-Meier curves were constructed using the Kaplan-Meier plotter online server.
RESULTS Forty-five DEGs (43 upregulated and 2 downregulated genes) associated with liver cirrhosis were identified from three GEO datasets. Ten hub genes were identified, which were upregulated in liver cirrhosis. Western blot and immunohistochemical analyses of the three core genes, decorin (DCN), dermatopontin (DPT), and SRY-box transcription factor 9 (SOX9), revealed that they were highly expressed in the CCl4-induced liver cirrhosis mouse model. The expression levels of DCN and SOX 9 were positively correlated with the degree of fibrosis, and SOX 9 level in HCC patients was significantly higher than that in fibrosis patients. However, high expression of DPT was observed only in patients with liver fibrosis, and its expression in HCC was low. The gene expression profiling interactive analysis server (GEPIA) showed that SOX9 was significantly upregulated whereas DCN and DPT were significantly downregulated in patients with HCC. In addition, the Kaplan-Meier curves showed that HCC patients with higher SOX9 expression had significantly lower 5-year survival rate, while patients with higher expression of DCN or DPT had significantly higher 5-year survival rates.
CONCLUSION The expression levels of DCN, DPT, and SOX9 were positively correlated with the degree of liver fibrosis but showed different correlations with the 5-year survival rates of HCC patients.
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Affiliation(s)
- Yue Li
- Department of Pathology, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
- Beijing Key Laboratory of Emerging Infectious Diseases, Beijing 100015, China
| | - Shou-Li Yuan
- Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Beijing 100101, China
| | - Jing-Ya Yin
- Center of Liver Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Kun Yang
- Department of Pathology, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Xin-Gang Zhou
- Department of Pathology, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Wen Xie
- Center of Liver Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Qi Wang
- Center of Liver Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
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Puthdee N, Sriswasdi S, Pisitkun T, Ratanasirintrawoot S, Israsena N, Tangkijvanich P. The LIN28B/TGF-β/TGFBI feedback loop promotes cell migration and tumour initiation potential in cholangiocarcinoma. Cancer Gene Ther 2022; 29:445-455. [PMID: 34548635 PMCID: PMC9113936 DOI: 10.1038/s41417-021-00387-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Revised: 07/25/2021] [Accepted: 09/03/2021] [Indexed: 02/02/2023]
Abstract
Cholangiocarcinoma (CCA), a lethal malignancy of the biliary epithelium, is the second most common primary liver cancer. The poor prognosis of CCA is due to the high rate of tumour invasion and distant metastasis. We found that the RNA-binding protein LIN28B, a known regulator of microRNA biogenesis, stem cell maintenance, and oncogenesis, is expressed in a subpopulation of CCA patients. To further investigate the potential role of LIN28B in CCA pathogenesis, we studied the effect of LIN28B overexpression in the cholangiocyte cell line MMNK-1 and cholangiocarcinoma cell lines HuCCT-1 and KKU-214. Here, we show that enhanced LIN28B expression promoted cancer stem cell-like properties in CCA, including enhanced cell migration, epithelial-to-mesenchymal transition (EMT), increased cell proliferation and spheroid formation. Proteomic analysis revealed TGF-β-induced protein (TGFBI) as a novel LIN28B target gene, and further analysis showed upregulation of other components of the TGF-β signalling pathway, including TGF-β receptor type I (TGFBRI) expression and cytokine TGFB-I, II and III secretion. Importantly, the small molecule TGF-β inhibitor SB431542 negated the effects of LIN28B on both cell migration and clonogenic potential. Overexpression of TGFBI alone promoted cholangiocarcinoma cell migration and EMT changes, but not spheroid formation, suggesting that TGFBI partially contributes to LIN28B-mediated aggressive cell behaviour. These observations are consistent with a model in which TGF-β and LIN28B work together to form a positive feedback loop during cholangiocarcinoma metastasis and provide a therapeutic intervention opportunity.
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Affiliation(s)
- Nattapong Puthdee
- Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Sira Sriswasdi
- Department of Research Affairs, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Trairak Pisitkun
- Department of Research Affairs, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | | | - Nipan Israsena
- Center of Excellence for Stem Cell and Cell Therapy, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
- Department of Pharmacology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
| | - Pisit Tangkijvanich
- Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
- Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
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10
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Zhang G, Liu X, Jian A, Zheng K, Wang H, Hao J, Zhi S, Zhang X. CHST4 might promote the malignancy of cholangiocarcinoma. PLoS One 2022; 17:e0265069. [PMID: 35294478 PMCID: PMC8926211 DOI: 10.1371/journal.pone.0265069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 02/22/2022] [Indexed: 11/19/2022] Open
Abstract
Background Cholangiocarcinoma (CCA) is reported as an aggressive cancer which leads to high mortality and no effective therapeutic target has yet been discovered. Surgical resection is the main method to treat patients with CCA. However, only one-third of CCA patients have the opportunity to accept the operation, leading to poor prognosis for CCA patients. Therefore, it is necessary to search for new therapeutic targets of CCA or core genes involved in the happening and growth of CCA. Aim In this study, we utilized bioinformatics technology and accessed to several medical databases trying to find the core genes of CCA for the purpose of intervening CCA through figuring out an effective curative target. Methods Firstly, three differentially expressed genes (DEGs) were discovered from GEPIA, and by further observing the distribution and gene expression, CHST4 was obtained as the core gene. Afterwards, correlated genes of CHST4 in CCA were identified using UALCAN to construct a gene expression profile. We obtained PPI network by Search Tool for the Retrieval of Interacting Networks Genes (STRING) and screened core genes using cytoscape software. Functional enrichment analyses were carried out and the expression of CHST in human tissues and tumors was observed. Finally, a CCA model was established for qPCR and staining validation. Results Three differentially expressed genes (DEGs), CHST4, MBOAT4 and RP11-525K10.3, were obtained. All were more over-expressed in CCA samples than the normal, among which the change multiple and the gene expression difference of CHST4 was the most obvious. Therefore, CHST4 was selected as the core gene. We can see in our established protein–protein interaction (PPI) network that CHST4 had the highest degree of connectivity, demonstrating its close association with CCA. We found that genes were mainly enriched in CCs in the PPI networks genes which shows functional enrichment analysis results, including golgi lumen, extracellular space and extracellular region. CHST4 was found very specifically expressed in the bile duct and was significantly different from that in normal tissues. The overexpression of CHST4 was further verified in the established animal model of TAA-induced CCA in rats. Quantitative PCR (qPCR) demonstrated that CHST4 was significantly overexpressed in tumor tissues, verifying the role of CHST4 as the core gene of CCA. Conclusion CHST4 was increasingly expressed in CCA and CHST4 is worth being studied much further in the intervention of CCA.
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Affiliation(s)
- Guanran Zhang
- Key Laboratory for Experimental Teratology of Ministry of Education, Department of Histology & Embryology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China
| | - Xuyue Liu
- Key Laboratory for Experimental Teratology of Ministry of Education, Department of Histology & Embryology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China
| | - Aiwen Jian
- Key Laboratory for Experimental Teratology of Ministry of Education, Department of Histology & Embryology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China
| | - Kexin Zheng
- Key Laboratory for Experimental Teratology of Ministry of Education, Department of Histology & Embryology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China
| | - Haiyan Wang
- Department of Radiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Jing Hao
- Key Laboratory for Experimental Teratology of Ministry of Education, Department of Histology & Embryology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China
| | - Sujuan Zhi
- Key Laboratory for Experimental Teratology of Ministry of Education, Department of Histology & Embryology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China
| | - Xiaoli Zhang
- Key Laboratory for Experimental Teratology of Ministry of Education, Department of Histology & Embryology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China
- * E-mail:
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11
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Kankeu Fonkoua LA, Serrano Uson Junior PL, Mody K, Mahipal A, Borad MJ, Roberts LR. Novel and emerging targets for cholangiocarcinoma progression: therapeutic implications. Expert Opin Ther Targets 2022; 26:79-92. [PMID: 35034558 DOI: 10.1080/14728222.2022.2029412] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
INTRODUCTION Cholangiocarcinoma (CCA) is a heterogeneous group of aggressive biliary malignancies. While surgery and liver transplantation are the only potentially curative modalities for early-stage disease, limited options are available for most patients with incurable-stage disease. Survival outcomes remain dismal. Recent molecular profiling efforts have led to improved understanding of the genomic landscape of CCA and to the identification of subgroups with distinct diagnostic, prognostic, and therapeutic implications. AREAS COVERED : We provide an updated review and future perspectives on features of cholangiocarcinogenesis that can be translated into therapeutic biomarkers and targets. We highlight the critical studies that have established current systemic chemotherapy and targeted therapeutics, while elaborating on novel targeted and immunotherapeutic approaches in development. Relevant literature and clinical studies were identified by searching PubMed and www.ClinicalTrials.gov. EXPERT OPINION : While therapies targeting the various molecular subgroups of CCA are rapidly emerging and changing treatment paradigms, their success has been limited by the genetic heterogeneity of CCA and the plasticity of the targets. Novel strategies aiming to combine immunotherapy, chemotherapy, and molecularly-targeted therapeutics will be required to offer durable clinical benefit and maximize survival.
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Affiliation(s)
| | | | - Kabir Mody
- Rochester, MN, and Oncology in Jacksonville, FL, Mayo Clinic, USA
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12
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Feng J, Wei T, Cui X, Wei R, Hong T. Identification of key genes and pathways in mild and severe nonalcoholic fatty liver disease by integrative analysis. Chronic Dis Transl Med 2021; 7:276-286. [PMID: 34786546 PMCID: PMC8579024 DOI: 10.1016/j.cdtm.2021.08.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Indexed: 12/13/2022] Open
Abstract
Background The global prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing. The pathogenesis of NAFLD is multifaceted, and the underlying mechanisms are elusive. We conducted data mining analysis to gain a better insight into the disease and to identify the hub genes associated with the progression of NAFLD. Methods The dataset GSE49541, containing the profile of 40 samples representing mild stages of NAFLD and 32 samples representing advanced stages of NAFLD, was acquired from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified using the R programming language. The Database for Annotation, Visualization and Integrated Discovery (DAVID) online tool and Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database were used to perform the enrichment analysis and construct protein–protein interaction (PPI) networks, respectively. Subsequently, transcription factor networks and key modules were identified. The hub genes were validated in a mice model of high fat diet (HFD)-induced NAFLD and in cultured HepG2 cells by real-time quantitative PCR. Results Based on the GSE49541 dataset, 57 DEGs were selected and enriched in chemokine activity and cellular component, including the extracellular region. Twelve transcription factors associated with DEGs were indicated from PPI analysis. Upregulated expression of five hub genes (SOX9, CCL20, CXCL1, CD24, and CHST4), which were identified from the dataset, was also observed in the livers of HFD-induced NAFLD mice and in HepG2 cells exposed to palmitic acid or advanced glycation end products. Conclusion The hub genes SOX9, CCL20, CXCL1, CD24, and CHST4 are involved in the aggravation of NAFLD. Our results offer new insights into the underlying mechanism of NAFLD progression.
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Affiliation(s)
- Jin Feng
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing 100191, China
| | - Tianjiao Wei
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing 100191, China
| | - Xiaona Cui
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing 100191, China
| | - Rui Wei
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing 100191, China
| | - Tianpei Hong
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing 100191, China
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13
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Mapping of population disparities in the cholangiocarcinoma urinary metabolome. Sci Rep 2021; 11:21286. [PMID: 34711878 PMCID: PMC8553759 DOI: 10.1038/s41598-021-00530-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Accepted: 10/11/2021] [Indexed: 11/21/2022] Open
Abstract
Phenotypic diversity in urinary metabolomes of different geographical populations has been recognized recently. In this study, urinary metabolic signatures from Western (United Kingdom) and South-East Asian (Thai) cholangiocarcinoma patients were characterized to understand spectral variability due to host carcinogenic processes and/or exogenous differences (nutritional, environmental and pharmaceutical). Urinary liquid chromatography mass spectroscopy (LC–MS) spectral profiles from Thai (healthy = 20 and cholangiocarcinoma = 14) and UK cohorts (healthy = 22 and cholangiocarcinoma = 10) were obtained and modelled using chemometric data analysis. Healthy metabolome disparities between the two distinct populations were primarily related to differences in dietary practices and body composition. Metabolites excreted due to drug treatment were dominant in urine specimens from cholangiocarcinoma patients, particularly in Western individuals. Urine from participants with sporadic (UK) cholangiocarcinoma contained greater levels of a nucleotide metabolite (uridine/pseudouridine). Higher relative concentrations of 7-methylguanine were observed in urine specimens from Thai cholangiocarcinoma patients. The urinary excretion of hippurate and methyladenine (gut microbial-host co-metabolites) showed a similar pattern of lower levels in patients with malignant biliary tumours from both countries. Intrinsic (body weight and body composition) and extrinsic (xenobiotic metabolism) factors were the main causes of disparities between the two populations. Regardless of the underlying aetiology, biological perturbations associated with cholangiocarcinoma urine metabolome signatures appeared to be influenced by gut microbial community metabolism. Dysregulation in nucleotide metabolism was associated with sporadic cholangiocarcinoma, possibly indicating differences in mitochondrial energy production pathways between cholangiocarcinoma tumour subtypes. Mapping population-specific metabolic disparities may aid in interpretation of disease processes and identification of candidate biomarkers.
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14
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Sinniah RS, Shapses MS, Ahmed MU, Babiker H, Chandana SR. Novel biomarkers for cholangiocarcinoma: how can it enhance diagnosis, prognostication, and investigational drugs? Part-1. Expert Opin Investig Drugs 2021; 30:1047-1056. [PMID: 34579607 DOI: 10.1080/13543784.2021.1985461] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
INTRODUCTION The development of novel biomarkers for cancer has exploded over the last decade with advances in novel technologies. Cholangiocarcinoma (CCA), a cancer of the bile ducts, has a dearth of strong disease and pathophysiology biomarkers, making early detection and prognostication a difficult task. AREAS COVERED In this comprehensive review, we discuss the spectrum of biomarkers for CCA diagnosis and prognostication. We elaborate on novel biomarker discovery through a comprehensive multi-omics approach. We also cover, how certain biomarkers may also serve as unique and potent targets for therapeutic development. EXPERT OPINION Despite the relatively poor diagnostic and prognostic performance of existing biomarkers for CCA, there is a vast range of novel biomarkers with exquisite diagnostic and prognostic performance for CCA in the pipeline. Moreover, these biomarkers may serve as potential targets for precision medicine. Existing strategies to target unique biomolecular classes are discussed, within the context of an overall 'omics' focused profiling strategy. Omics profiling will simultaneously allow for enhanced biomarker development and identification of unique subtypes of cholangiocarcinoma and how they are influenced by an individual's unique context. In this manner, patient management strategy and clinical trial design can be optimized to the individual.
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Affiliation(s)
- Ranu S Sinniah
- College of Human Medicine, Michigan State University, Grand Rapids, MI, USA
| | - Mark S Shapses
- Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA
| | | | - Hani Babiker
- Department of Medicine, Division of Hematology-Oncology, Mayo Clinic, Jacksonville, Florida, USA
| | - Sreenivasa R Chandana
- Phase I Program, Start Midwest, Grand Rapids, MI, USA.,Cancer and Hematology Centers of Western Michigan, Grand Rapids, MI, USA.,Department of Medicine, College of Human Medicine, Michigan State University, East Lansing, MI, USA
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15
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MXRA5 Is a Novel Immune-Related Biomarker That Predicts Poor Prognosis in Glioma. DISEASE MARKERS 2021; 2021:6680883. [PMID: 34211612 PMCID: PMC8211501 DOI: 10.1155/2021/6680883] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 03/15/2021] [Accepted: 05/25/2021] [Indexed: 11/17/2022]
Abstract
Background Glioma is the most common primary intracranial tumor and is associated with poor prognosis. Identifying effective biomarkers for glioma is particularly important. MXRA5, a secreted glycoprotein, is involved in cell adhesion and extracellular matrix remodeling and has been reported to be expressed in many cancers. However, the role and mechanism of action of MXRA5 in gliomas remain unclear. This study was aimed at investigating the role of MXRA5 at the transcriptome level and its clinical prognostic value. Methods In this study, RNA microarray data of 301 glioma patients from the Chinese Glioma Genome Atlas (CGGA) were collected as a training cohort and RNA-seq data of 702 glioma samples from The Cancer Genome Atlas (TCGA) were used for validation. We analyzed the clinical and molecular characteristics as well as the prognostic value of MXRA5 in glioma. In addition, the expression level of MXRA was evaluated in 28 glioma tissue samples. Results We found that MXRA5 expression was significantly upregulated in high-grade gliomas and IDH wild-type gliomas compared to controls. Receiver operating characteristic (ROC) analysis showed that MXRA5 is a potential marker of the mesenchymal subtype of glioblastoma multiforme (GBM). We found that MXRA5 expression is highly correlated with immune checkpoint molecule expression levels and tumor-associated macrophage infiltration. High MXRA5 expression could be used as an independent indicator of poor prognosis in glioma patients. Conclusion Our study suggests that MXRA5 expression is associated with the clinicopathologic features and poor prognosis of gliomas. MXRA5 may play an important role in the immunosuppressive microenvironment of glioma. As a secreted glycoprotein, MXRA5 is a potential circulating biomarker for glioma, deserving further investigation.
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16
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Osataphan S, Mahankasuwan T, Saengboonmee C. Obesity and cholangiocarcinoma: A review of epidemiological and molecular associations. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2021; 28:1047-1059. [PMID: 34053180 DOI: 10.1002/jhbp.1001] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 05/02/2021] [Accepted: 05/19/2021] [Indexed: 11/10/2022]
Abstract
Cholangiocarcinoma (CCA) is a malignancy of bile duct epithelium, and its incidence is increasing globally. Numerous factors are reported associated with an increased risk of CCA and vary among populations across different areas. Obesity is a major, worldwide public health problem that leads to several complications and is associated with increased cancer risk. Although several epidemiological studies have shown that obesity is likely associated with the increased risk of CCA, this association might be limited to Western countries. Multiple hormones, cytokines, and metabolite perturbations in obese states have been shown to enhance tumorigenicity and metastasis potentials. Understanding the biological linkage of obesity to CCA might lead to novel prevention and therapeutic approaches to CCA treatment. This review summarizes the current evidence and highlights the knowledge gaps regarding the relationship between obesity and CCA from epidemiological and molecular perspectives.
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Affiliation(s)
| | | | - Charupong Saengboonmee
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.,Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
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17
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Klinhom-On N, Seubwai W, Sawanyawisuth K, Lert-Itthiporn W, Waraasawapati S, Detarya M, Wongkham S. FOXM1c is the predominant FOXM1 isoform expressed in cholangiocarcinoma that associated with metastatic potential and poor prognosis of patients. Heliyon 2021; 7:e06846. [PMID: 33997388 PMCID: PMC8093466 DOI: 10.1016/j.heliyon.2021.e06846] [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: 12/18/2020] [Revised: 03/16/2021] [Accepted: 04/14/2021] [Indexed: 12/22/2022] Open
Abstract
Forkhead box M1 (FOXM1) is a transcriptional factor which plays an important role in oncogenesis. Four FOXM1 isoforms, FOXM1a, FOXM1b, FOXM1c and FOXM1d, are known so far. Different FOXM1 isoforms influence progression of cancer in different cancer types. In this study, the FOXM1c isoform and its impact in cholangiocarcinoma (CCA) was identified. FOXM1c was found to be the predominant isoform in patient-CCA tissues and cell lines. Detection of FOXM1c expression in CCA tissues reflected the worse prognosis of the patients, namely the advanced stage and shorter survival. Suppression of FOXM1 expression using siRNA considerably reduced migration and invasion abilities of CCA cell lines. RNA sequencing analysis revealed claudin-1 as a target of FOXM1. FOXM1 exhibited a negative correlation with claudin-1 expression which was demonstrated in patient CCA tissues and cell lines. FOXM1 may be a potential target for therapeutic treatment of the metastatic CCA.
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Affiliation(s)
- Nathakan Klinhom-On
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, 40002, Thailand
| | - Wunchana Seubwai
- Department of Forensic Medicine, Faculty of Medicine, Khon Kaen University, 40002, Thailand.,Cholangiocarcinoma Research Institute, Khon Kaen University, 40002, Thailand
| | - Kanlayanee Sawanyawisuth
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, 40002, Thailand.,Cholangiocarcinoma Research Institute, Khon Kaen University, 40002, Thailand
| | - Worachart Lert-Itthiporn
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, 40002, Thailand.,Cholangiocarcinoma Research Institute, Khon Kaen University, 40002, Thailand
| | - Sakda Waraasawapati
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.,Cholangiocarcinoma Research Institute, Khon Kaen University, 40002, Thailand
| | - Marutpong Detarya
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, 40002, Thailand
| | - Sopit Wongkham
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, 40002, Thailand.,Cholangiocarcinoma Research Institute, Khon Kaen University, 40002, Thailand
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18
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Mordvinov VA, Minkova GA, Kovner AV, Ponomarev DV, Lvova MN, Zaparina O, Romanenko SA, Shilov AG, Pakharukova MY. A tumorigenic cell line derived from a hamster cholangiocarcinoma associated with Opisthorchis felineus liver fluke infection. Life Sci 2021; 277:119494. [PMID: 33862109 DOI: 10.1016/j.lfs.2021.119494] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 03/19/2021] [Accepted: 04/01/2021] [Indexed: 01/23/2023]
Abstract
AIMS The food-born trematode Opisthorchis felineus colonizes bile ducts of the liver of fish-eating mammals including humans. There is growing evidence that this liver fluke is a risk factor for cholangiocarcinoma (CCA). Cancer cell lines are necessary for drug screening and for identifying protein markers of CCA. The aim was to establish a cell line derived from cholangiocarcinoma associated with opisthorchiasis felinea. MAIN METHODS Allotransplantation, immunohistochemistry, karyotype analysis, cell culture techniques, immunocytochemistry and real-time PCR. KEY FINDINGS Here we repot the establishment of first CCA cell line, CCA-OF, from a primary tumor of an experimental CCA in Syrian hamsters treated with low doses of dimethyl nitrosamine and associated with O. felineus infection. The cell line was found to be allotransplantable. Expression of epithelial and mesenchymal markers (cytokeratin 7, glycosyltransferase exostosin 1, Ca2+-dependent phospholipid-binding protein annexin A1 and vimentin) was demonstrated by immunostaining of the primary tumors, CCA-OF cells, and allotransplants. CCA-OF cells were found to express presumed CCA biomarkers previously detected in both human and experimental tumors associated with the liver fluke infection. The cells were diploid-like (2n = 42-46) with complex chromosomal rearrangements and have morphological features of epithelial-like cells. The usefulness of the CCA-OF cell model for antitumor activity testing was demonstrated by an analysis of effects of resveratrol treatment. It was shown that resveratrol treatment inhibited the proliferation and the migration ability of CCA-OF cells. SIGNIFICANCE Thus, the allotransplantable CCA-OF cell line can be used in studies on helminth-associated cholangiocarcinogenesis and for the testing of antitumor drugs.
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Affiliation(s)
- Viatcheslav A Mordvinov
- Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (ICG SB RAS), 10 Lavrentiev Ave., Novosibirsk 630090, Russia.
| | - Galina A Minkova
- Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (ICG SB RAS), 10 Lavrentiev Ave., Novosibirsk 630090, Russia
| | - Anna V Kovner
- Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (ICG SB RAS), 10 Lavrentiev Ave., Novosibirsk 630090, Russia
| | - Dmitriy V Ponomarev
- Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (ICG SB RAS), 10 Lavrentiev Ave., Novosibirsk 630090, Russia
| | - Maria N Lvova
- Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (ICG SB RAS), 10 Lavrentiev Ave., Novosibirsk 630090, Russia.
| | - Oxana Zaparina
- Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (ICG SB RAS), 10 Lavrentiev Ave., Novosibirsk 630090, Russia
| | - Svetlana A Romanenko
- Institute of Molecular and Cellular Biology, Siberian Branch of Russian Academy of Sciences, 8/2 Lavrentiev Ave., Novosibirsk 630090, Russia.
| | - Alexander G Shilov
- Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (ICG SB RAS), 10 Lavrentiev Ave., Novosibirsk 630090, Russia.
| | - Maria Y Pakharukova
- Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (ICG SB RAS), 10 Lavrentiev Ave., Novosibirsk 630090, Russia; Department of Natural Sciences, Novosibirsk State University, 2 Pirogova Str., Novosibirsk 630090, Russia
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19
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Hu B, Ma X, Fu P, Sun Q, Tang W, Sun H, Yang Z, Yu M, Zhou J, Fan J, Xu Y. miRNA-mRNA Regulatory Network and Factors Associated with Prediction of Prognosis in Hepatocellular Carcinoma. GENOMICS PROTEOMICS & BIOINFORMATICS 2021; 19:913-925. [PMID: 33741523 PMCID: PMC9402792 DOI: 10.1016/j.gpb.2021.03.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/28/2018] [Revised: 01/02/2019] [Accepted: 02/15/2019] [Indexed: 12/22/2022]
Abstract
The aim of this study was to identify novel gene and miRNA biomarkers of risk and prognostic factors for hepatocarcinogenesis using methods in systems biology. Differentially expressed genes (DEGs), microRNAs (miRNAs), and long non-coding RNA (lncRNAs) were compared between hepatocellular carcinoma (HCC) tumour tissue and normal liver tissues in the Cancer Genome Atlas (TCGA) database. Subsequently, the prognosis-associated gene co-expression network, mRNA-miRNA, and mRNA-miRNA-lncRNA regulatory networks were constructed to identify biomarkers of risk for HCC through Cox survival analysis. Seven prognosis-associated gene co-expression modules were obtained by analyzing these DEGs. An expression module including 120 genes significantly correlated with HCC patient survival. Combined with patient survival data, several mRNAs and miRNAs, including CHST4, SLC22A8, STC2, hsa-miR-326, and hsa-miR-21 were identified from the network to predict HCC patient prognosis. Clinical significance was investigated using tissue microarray analysis of samples from 258 patients with HCC. Functional annotation of hsa-miR-326 and hsa-miR-21-5p indicated specific associations with several cancer-related pathways. The present study provides a bioinformatics method for biomarker screening, which led to the identification of an integrated mRNA-miRNA-lncRNA regulatory network and their co-expression in relation to predicting HCC patient survival.
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Affiliation(s)
- Bo Hu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, China
| | - Xiaolu Ma
- Laboratory Medicine Department, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, China
| | - Peiyao Fu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, China
| | - Qiman Sun
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, China
| | - Weiguo Tang
- Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai 201199, China
| | - Haixiang Sun
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, China
| | - Zhangfu Yang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, China
| | - Mincheng Yu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, China
| | - Jian Zhou
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, China; State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200032, China; Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Jia Fan
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, China; State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200032, China; Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Yang Xu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, China.
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20
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Valle JW, Kelley RK, Nervi B, Oh DY, Zhu AX. Biliary tract cancer. Lancet 2021; 397:428-444. [PMID: 33516341 DOI: 10.1016/s0140-6736(21)00153-7] [Citation(s) in RCA: 538] [Impact Index Per Article: 134.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Revised: 07/14/2020] [Accepted: 07/23/2020] [Indexed: 02/06/2023]
Abstract
Biliary tract cancers, including intrahepatic, perihilar, and distal cholangiocarcinoma as well as gallbladder cancer, are low-incidence malignancies in most high-income countries, but represent a major health problem in endemic areas; moreover, the incidence of intrahepatic cholangiocarcinoma is rising globally. Surgery is the cornerstone of cure; the optimal approach depends on the anatomical site of the primary tumour and the best outcomes are achieved through management by specialist multidisciplinary teams. Unfortunately, most patients present with locally advanced or metastatic disease. Most studies in advanced disease have pooled the various subtypes of biliary tract cancer by necessity to achieve adequate sample sizes; however, differences in epidemiology, clinical presentation, natural history, surgical therapy, response to treatment, and prognosis have long been recognised. Additionally, the identification of distinct patient subgroups harbouring unique molecular alterations with corresponding targeted therapies (such as isocitrate dehydrogenase-1 mutations and fibroblast growth factor receptor-2 fusions in intrahepatic cholangiocarcinoma, among others) is changing the treatment paradigm. In this Seminar we present an update of the causes, diagnosis, molecular classification, and treatment of biliary tract cancer.
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Affiliation(s)
- Juan W Valle
- Division of Cancer Sciences, University of Manchester, Manchester, UK; Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK.
| | - R Katie Kelley
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA
| | - Bruno Nervi
- Department of Hematology Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Do-Youn Oh
- Division of Medical Oncology, Department of Internal Medicine, Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Andrew X Zhu
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA; Jiahui International Cancer Center, Jiahui Health, Shanghai, China
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21
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Prajumwongs P, Waenphimai O, Vaeteewoottacharn K, Wongkham S, Sawanyawisuth K. Reversine, a selective MPS1 inhibitor, induced autophagic cell death via diminished glucose uptake and ATP production in cholangiocarcinoma cells. PeerJ 2021; 9:e10637. [PMID: 33505802 PMCID: PMC7797171 DOI: 10.7717/peerj.10637] [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: 06/08/2020] [Accepted: 12/02/2020] [Indexed: 12/18/2022] Open
Abstract
Reversine is a selective inhibitor of mitotic kinase monopolar spindle 1 (MPS1) and has been reported as an anticancer agent in various cancers. The effects of reversine on bile duct cancer, cholangiocarcinoma (CCA), a lethal cancer in Northeastern Thailand, were investigated. This study reports that reversine inhibited cell proliferation of CCA cell lines in dose- and time-dependent manners but had less inhibitory effect on an immortalized cholangiocyte cell line. Reversine also triggered apoptotic cell death by decreasing anti-apoptotic proteins, Bcl-XL and Mcl-1, increasing Bax pro-apoptotic protein and activating caspase-3 activity. Moreover, reversine induced autophagic cell death by increasing LC3-II and Beclin 1 while decreasing p62. Reversine activated autophagy via the AKT signaling pathway. Additionally, this study demonstrated for the first time that reversine could diminish the expression of Hypoxia-Inducible Factor 1- alpha (HIF-1α) and glucose transporter 1 (GLUT1), resulting in a reduction of glucose uptake and energy production in CCA cell lines. These findings suggest that reversine could be a good candidate as an alternative or supplementary drug for CCA treatment.
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Affiliation(s)
- Piya Prajumwongs
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.,Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Orawan Waenphimai
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.,Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Kulthida Vaeteewoottacharn
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.,Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Sopit Wongkham
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.,Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Kanlayanee Sawanyawisuth
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.,Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
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22
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Prajumwongs P, Phumphu R, Waenphimai O, Lert-itthiporn W, Vaeteewoottacharn K, Wongkham S, Chamgramol Y, Pairojkul C, Sawanyawisuth K. High Monopolar Spindle 1 Is Associated with Short Survival of Cholangiocarcinoma Patients and Enhances the Progression Via AKT and STAT3 Signaling Pathways. Biomedicines 2021; 9:68. [PMID: 33450849 PMCID: PMC7828338 DOI: 10.3390/biomedicines9010068] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Revised: 01/08/2021] [Accepted: 01/09/2021] [Indexed: 12/31/2022] Open
Abstract
Cholangiocarcinoma (CCA) is a malignancy of the bile duct epithelium. The major problems of this cancer are late diagnosis and a high rate of metastasis. CCA patients in advanced stages have poor survival and cannot be cured with surgery. Therefore, targeting molecules involved in the metastatic process may be an effective CCA treatment. Monopolar spindle 1 (MPS1) is a kinase protein that controls the spindle assemble checkpoint in mitosis. It is overexpressed in proliferating cells and various cancers. The functional roles of MPS1 in CCA progression have not been investigated. The aims of this study were to examine the roles and molecular mechanisms of MPS1 in CCA progression. Immunohistochemistry results showed that MPS1 was up-regulated in carcinogenesis of CCA in a hamster model, and positive expression of MPS1 in human CCA tissues was correlated to short survival of CCA patients (n = 185). Small interfering RNA (siRNA)-induced knockdown of MPS1 expression reduced cell proliferation via G2/M arrest, colony formation, migration, and invasion. Moreover, MPS1 controlled epithelial to mesenchymal transition (EMT)-mediated migration via AKT and STAT3 signaling transductions. MPS1 was also involved in MMPs-dependent invasion of CCA cell lines. The current research highlights for the first time that MPS1 has an essential role in promoting the progression of CCA via AKT and STAT3 signaling pathways and could be an attractive target for metastatic CCA treatment.
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Affiliation(s)
- Piya Prajumwongs
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; (P.P.); (R.P.); (O.W.); (W.L.-i.); (K.V.); (S.W.)
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand; (Y.C.); (C.P.)
| | - Ratthaphong Phumphu
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; (P.P.); (R.P.); (O.W.); (W.L.-i.); (K.V.); (S.W.)
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand; (Y.C.); (C.P.)
| | - Orawan Waenphimai
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; (P.P.); (R.P.); (O.W.); (W.L.-i.); (K.V.); (S.W.)
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand; (Y.C.); (C.P.)
| | - Worachart Lert-itthiporn
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; (P.P.); (R.P.); (O.W.); (W.L.-i.); (K.V.); (S.W.)
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand; (Y.C.); (C.P.)
| | - Kulthida Vaeteewoottacharn
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; (P.P.); (R.P.); (O.W.); (W.L.-i.); (K.V.); (S.W.)
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand; (Y.C.); (C.P.)
| | - Sopit Wongkham
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; (P.P.); (R.P.); (O.W.); (W.L.-i.); (K.V.); (S.W.)
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand; (Y.C.); (C.P.)
| | - Yaovalux Chamgramol
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand; (Y.C.); (C.P.)
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Chawalit Pairojkul
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand; (Y.C.); (C.P.)
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Kanlayanee Sawanyawisuth
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; (P.P.); (R.P.); (O.W.); (W.L.-i.); (K.V.); (S.W.)
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand; (Y.C.); (C.P.)
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23
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Kasemsuk T, Saehlim N, Arsakhant P, Sittithumcharee G, Okada S, Saeeng R. A novel synthetic acanthoic acid analogues and their cytotoxic activity in cholangiocarcinoma cells. Bioorg Med Chem 2020; 29:115886. [PMID: 33290909 DOI: 10.1016/j.bmc.2020.115886] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Revised: 11/01/2020] [Accepted: 11/07/2020] [Indexed: 12/15/2022]
Abstract
A novel series of acanthoic acid analogues containing triazole moiety were synthesized through esterification and CuAAC reaction. Evaluation of their biological activities against four cell lines of cholangiocarcinoma cells showed that 3d exhibited the strongest activity with an IC50 value of 18 µM against KKU-213 cell line, which was 8 fold more potent than acanthoic acid. Interestingly, the triazole ring and nitro group on benzyl ring play very significant role in cytotoxic activity. The computational studies revealed that 3d occupies the binding energy of -12.7 and -10.8 kcal/mol with CDK-2 and EGFR protein kinases, respectively. This result might provide a beginning for the development of acanthoic acid analogues as an anticancer agent.
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Affiliation(s)
- Teerapich Kasemsuk
- Department of Chemistry, Faculty of Science and Technology, Rambhai Barni Rajabhat University, Chanthaburi 22000, Thailand
| | - Natthiya Saehlim
- Department of Chemistry and Center for Innovation in Chemistry, Faculty of Science, Burapha University, Chonburi 20131, Thailand
| | - Patcharee Arsakhant
- Department of Chemistry and Center for Innovation in Chemistry, Faculty of Science, Burapha University, Chonburi 20131, Thailand
| | - Gunya Sittithumcharee
- Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection & Graduate School of Medical Sciences, Kumamoto University, Japan
| | - Seiji Okada
- Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection & Graduate School of Medical Sciences, Kumamoto University, Japan
| | - Rungnapha Saeeng
- Department of Chemistry and Center for Innovation in Chemistry, Faculty of Science, Burapha University, Chonburi 20131, Thailand; The Research Unit in Synthetic Compounds and Synthetic Analogues from Natural Product for Drug Discovery (RSND), Burapha University, Chonburi 20131, Thailand.
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24
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Carbohydrate Antigen 50: Values for Diagnosis and Prognostic Prediction of Intrahepatic Cholangiocarcinoma. ACTA ACUST UNITED AC 2020; 56:medicina56110616. [PMID: 33207685 PMCID: PMC7696328 DOI: 10.3390/medicina56110616] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 11/06/2020] [Accepted: 11/10/2020] [Indexed: 02/06/2023]
Abstract
Background and objectives: Cancer-associated carbohydrate antigen 50 (CA50) is a marker for detection of gastrointestinal cancers, especially of pancreatic and colon cancer. In this study, the power of CA50 as a diagnostic and prognostic marker was evaluated in intrahepatic cholangiocarcinoma (iCCA). Materials and Methods: Serum CA50 levels of iCCA patients and non-cholangiocarcinoma controls (non-CCA, including healthy persons and patients with benign biliary diseases and other gastrointestinal cancers) were measured using MAGLUMI®800 CLIA analyzer. Diagnostic and prognostic values of serum CA50 levels were evaluated. Results: CA50 levels in the sera of iCCA patients were significantly higher than those of non-CCA controls (p < 0.001, Mann–Whitney U test). Using cut-off value of 25 U/mL, CA50 provided 65.9% sensitivity, 87.3% specificity, and 80.1% accuracy for diagnosis of iCCA. Serum CA50 levels were increased and associated with the severity of bile duct pathology. In addition, a higher level of CA50 was associated with poor clinical outcome and shorter survival in iCCA patients. Multivariate survival analysis by Cox regression model revealed the potential of CA50 as an independent poor prognostic indicator for iCCA, regardless of the age, sex, histological types, or tumor stages. Conclusions: CA50 can be a diagnostic and poor prognostic marker candidate for iCCA.
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25
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Zhang L, Fan Y, Wang X, Yang M, Wu X, Huang W, Lan J, Liao L, Huang W, Yuan L, Pan H, Wu Y, Chen L, Guan J. Carbohydrate Sulfotransferase 4 Inhibits the Progression of Hepatitis B Virus-Related Hepatocellular Carcinoma and Is a Potential Prognostic Marker in Several Tumors. Front Oncol 2020; 10:554331. [PMID: 33178582 PMCID: PMC7593664 DOI: 10.3389/fonc.2020.554331] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Accepted: 09/15/2020] [Indexed: 12/11/2022] Open
Abstract
Carbohydrate sulfotransferase 4 (CHST4) plays an important role in lymphocyte homing and is abnormally expressed in several cancer types; however, its precise function in tumor development and progression is unknown. Here we confirm that CHST4 is aberrantly expressed in various tumor subtypes. In particular, we found that CHST4 expression was downregulated in hepatitis B virus-related hepatocellular carcinoma (HBV-HCC) tumors compared to paired normal tissue. We also showed that CHST4 overexpression inhibited the proliferation and metastasis of HCC cells in vitro. Clinically, CHST4 was identified as an independent prognostic factor for HBV-HCC patients. We further illuminated the anti-tumor role and mechanism of CHST4 in HBV-HCC by constructing a FENDRR–miR-10b-5p–CHST4 competing endogenous RNA network. We found that downregulation of CHST4 expression may promote HBV expression and regulate ribonucleoprotein complex biogenesis to promote malignant behaviors in HBV-HCC. CHST4 may also recruit CD4+ T cells, macrophages, dendritic cells, and neutrophils into the tumor microenvironment to inhibit the progression of HBV-HCC. Overall, our findings suggest that CHST4 acts as a tumor suppressor in HCC-HBV and represents a potential diagnostic and therapeutic target.
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Affiliation(s)
- Longshan Zhang
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yao Fan
- Department of Oncology, The First Hospital of Hebei Medical University, Shijiazhuang, China
| | - Xiaoqing Wang
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Mi Yang
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - XiXi Wu
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Weiqiang Huang
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jin Lan
- Department of General Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
| | - Liwei Liao
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Wenqi Huang
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Lu Yuan
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Hua Pan
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yuting Wu
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Longhua Chen
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jian Guan
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
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26
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NF-κB and STAT3 co-operation enhances high glucose induced aggressiveness of cholangiocarcinoma cells. Life Sci 2020; 262:118548. [PMID: 33038372 DOI: 10.1016/j.lfs.2020.118548] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Revised: 09/17/2020] [Accepted: 09/28/2020] [Indexed: 12/15/2022]
Abstract
AIMS The present report aimed to investigate the underlying genes and pathways of high glucose driving cholangiocarcinoma (CCA) aggressiveness. MAIN METHODS We screened and compared the gene expression profiles obtained by RNA sequencing, of CCA cells cultured in high and normal glucose. Results from the transcriptomic analysis were confirmed in additional cell lines using in vitro migration-invasion assay, Western blotting and immunocytofluorescence. KEY FINDINGS Data indicated that high glucose increased the expression of interleukin-1β (IL-1β), an upstream regulator of nuclear factor-κB (NF-κB) pathway, through the nuclear localization of NF-κB. High glucose-induced NF-κB increased the migration and invasion of CCA cells and the expression of downstream NF-κB targeted genes associated with aggressiveness, including interleukin-6, a potent triggering signal of the signal transducer and activator of transcription 3 (STAT3) pathway. Such effects were reversed by inhibiting NF-κB nuclear translocation which additionally reduced the phosphorylation of STAT3 at Y705. SIGNIFICANCE These results indicate that NF-κB is activated by high glucose and they suggest that NF-κB interaction with STAT3 enhances CCA aggressiveness. Therefore, targeting multiple pathways such as STAT3 and NF-κB might improve CCA treatment outcome especially in condition such as hyperglycemia.
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27
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Saengboonmee C, Seubwai W, Lert-Itthiporn W, Sanlung T, Wongkham S. Association of Diabetes Mellitus and Cholangiocarcinoma: Update of Evidence and the Effects of Antidiabetic Medication. Can J Diabetes 2020; 45:282-290. [PMID: 33218924 DOI: 10.1016/j.jcjd.2020.09.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 09/03/2020] [Accepted: 09/11/2020] [Indexed: 12/13/2022]
Abstract
Diabetes mellitus (DM) is a risk factor for cancer in many organs and associated with an increased risk of cholangiocarcinoma (CCA). The molecular linkage between these diseases has been demonstrated in preclinical studies, which have highlighted the role of hyperinsulinemia and hyperglycemia in the carcinogenesis and progression of CCA. Recent studies on the emerging role of antidiabetic medication in the development and progression of CCA showed a subclass of antidiabetic drug with a therapeutic effect on CCA. Although associations between CCA, insulin analogues and sulfonylureas are unclear, incretin-based therapy is likely associated with an increased risk for CCA, and may lead to CCA progression, as demonstrated by in vitro and in vivo experiments. In contrast, biguanides, especially metformin, exert an opposite effect, associated with a reduced risk of CCA and inhibited in vitro and in vivo CCA progression. The association between incretin-based therapy and the risk of CCA needs further clarification, as metformin is being studied in an ongoing clinical trial. Understanding the association between DM and CCA is critical for preventing the development of CCA in patients with DM, and for establishing the appropriateness of antidiabetic medication to treat CCA. Determining how metformin affects CCA can lead to repurposing this safe and well-known drug for improving CCA treatment, regardless of the diabetes status of patients.
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Affiliation(s)
- Charupong Saengboonmee
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand; Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States; Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States.
| | - Wunchana Seubwai
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand; Department of Forensic Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand; Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Worachart Lert-Itthiporn
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand; Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand; Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Thanachai Sanlung
- Division of Medical Oncology, Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Sopit Wongkham
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand; Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand; Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
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28
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Silsirivanit A, Matsuda A, Kuno A, Tsuruno C, Uenoyama Y, Seubwai W, Angata K, Teeravirote K, Wongkham C, Araki N, Takahama Y, Wongkham S, Narimatsu H. Multi-serum glycobiomarkers improves the diagnosis and prognostic prediction of cholangiocarcinoma. Clin Chim Acta 2020; 510:142-149. [PMID: 32659223 DOI: 10.1016/j.cca.2020.07.017] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 06/12/2020] [Accepted: 07/08/2020] [Indexed: 01/20/2023]
Abstract
BACKGROUND Aberrant glycosylation has been reported to play important roles in progression of cholangiocarcinoma (CCA) and hence the aberrant expressed glycans are beneficial markers for diagnosis and prognostic prediction of CCA. METHODS Five CCA-associated glycobiomarkers-carbohydrate antigen 19-9 (CA19-9), carbohydrate antigen-S27 (CA-S27), CCA-associated carbohydrate antigen (CCA-CA), WFA-positive MUC1 (WFA+-MUC1), and WFA-positive M2BP (WFA+-M2BP), in the sera from CCA patients (N = 138) were determined in comparison with non-CCA control subjects (N = 246). RESULTS Receiver operating characteristic analysis suggested the significance of each glycobiomarker in discriminating CCA from non-CCA with area under curve of 0.580-0.777. High levels of CA19-9, CCA-CA, CA-S27, or WFA+-MUC1 were associated with poor prognosis and poor survival of CCA patients. Combination of these glycobiomarkers and graded as a GlycoBiomarker (GB)-score could increase the power of the tests in diagnosis than an individual marker with 81% of sensitivity, specificity and accuracy. CONCLUSIONS According to the GB-score, these glycobiomarkers not only increased diagnostic power but also discriminated survival of patients indicating the diagnostic and prognostic values of GB-score.
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Affiliation(s)
- Atit Silsirivanit
- Department of Biochemistry, and Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand.
| | - Atsushi Matsuda
- Department of Biochemistry, School of Medicine, Keio University, Tokyo 160-8582, Japan
| | - Atsushi Kuno
- Molecular and Cellular Glycoproteomics Research Group, Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology, Ibaraki 305-8565, Japan
| | | | | | - Wunchana Seubwai
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand; Department of Forensic Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Kiyohiko Angata
- Molecular and Cellular Glycoproteomics Research Group, Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology, Ibaraki 305-8565, Japan
| | - Karuntarat Teeravirote
- Department of Biochemistry, and Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Chaisiri Wongkham
- Department of Biochemistry, and Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Norie Araki
- Department of Tumor Genetics and Biology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | | | - Sopit Wongkham
- Department of Biochemistry, and Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Hisashi Narimatsu
- Molecular and Cellular Glycoproteomics Research Group, Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology, Ibaraki 305-8565, Japan.
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29
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Sripa B, Seubwai W, Vaeteewoottacharn K, Sawanyawisuth K, Silsirivanit A, Kaewkong W, Muisuk K, Dana P, Phoomak C, Lert-Itthiporn W, Luvira V, Pairojkul C, Teh BT, Wongkham S, Okada S, Chamgramol Y. Functional and genetic characterization of three cell lines derived from a single tumor of an Opisthorchis viverrini-associated cholangiocarcinoma patient. Hum Cell 2020; 33:695-708. [PMID: 32207095 DOI: 10.1007/s13577-020-00334-w] [Citation(s) in RCA: 76] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Accepted: 02/14/2020] [Indexed: 12/21/2022]
Abstract
Three cholangiocarcinoma (CCA) cell line-formerly named, M156, M213 and M214 have been intensively used with discrepancy of their tumor origins. They were assumed to be originated from three different donors without authentication. To verify the origins of these cell lines, the short tandem repeat (STR) analysis of the currently used cell lines, the cell stocks from the establisher and the primary tumor of a CCA patient were performed. Their phenotypic and genotypic originality were compared. The currently used 3 CCA cell lines exhibited similar STR as CCA patient ID-M213 indicating the same origin of these cells. The cell stocks from the establisher, however, revealed the same STR of M213 and M214 cells, but not M156. The misidentification of M214 and M156 is probably due to the mislabeling and cross-contamination of M213 cells during culture. These currently used cell lines were renamed as KKU-213A, -213B and -213C, for the formerly M213, M214 and M156 cells, respectively. These cell lines were established from a male with an intrahepatic mass-forming CCA stage-4B. The tumor was an adenosquamous carcinoma with the liver fluke ova granuloma in evidence. All cell lines had positive CK19 with differential CA19-9 expression. They exhibited aneuploidy karyotypes, distinct cell morphology, cell growth, cytogenetic characteristic and progressive phenotypes. KKU-213C formed a adenosquamous carcinoma, whereas KKU-213A and KKU-213B formed poorly- and well-differentiated squamous cell carcinomas in xenografted mice. mRNA microarray revealed different expression profiles among these three cell lines. The three cell lines have unique characteristics and may resemble the heterogeneity of tumor origin.
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Affiliation(s)
- Banchob Sripa
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand.,Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Wunchana Seubwai
- Department of Forensic Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand.,Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Kulthida Vaeteewoottacharn
- Department of Biochemistry, and Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand.,Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Kanlayanee Sawanyawisuth
- Department of Biochemistry, and Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand.,Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Atit Silsirivanit
- Department of Biochemistry, and Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand.,Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Worasak Kaewkong
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand.,Department of Biochemistry, Faculty of Medical Sciences, Naresuan University, Phitsanulok, 65000, Thailand
| | - Kanha Muisuk
- Department of Forensic Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand.,Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Paweena Dana
- Department of Biochemistry, and Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand.,Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Chatchai Phoomak
- Department of Biochemistry, and Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand.,Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Worachart Lert-Itthiporn
- Department of Biochemistry, and Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand.,Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Vor Luvira
- Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Chawalit Pairojkul
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand.,Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Bin T Teh
- Duke-NUS Medical School, Singapore, 169857, Singapore
| | - Sopit Wongkham
- Department of Biochemistry, and Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand.,Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Seiji Okada
- Division of Hematopoeisis, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, 860-0811, Japan.
| | - Yaovalux Chamgramol
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand. .,Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand.
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Li H, Wei N, Ma Y, Wang X, Zhang Z, Zheng S, Yu X, Liu S, He L. Integrative module analysis of HCC gene expression landscapes. Exp Ther Med 2020; 19:1779-1788. [PMID: 32104233 PMCID: PMC7027144 DOI: 10.3892/etm.2020.8437] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Accepted: 11/22/2019] [Indexed: 12/13/2022] Open
Abstract
Despite hepatocellular carcinoma (HCC) being a common cancer globally, its initiation and progression are not well understood. The present study was designed to investigate the hub genes and biological processes of HCC, which change substantially during its progression. Three gene expression profiles of 480 patients with HCC were obtained from the Gene Expression Omnibus database. Subsequent to performing functional annotations and constructing protein-protein interaction (PPI) networks, 657 differentially expressed genes were identified, which were subsequently used to screen candidate hub genes. PPI networks were modularized using the weighted gene correlation network analysis algorithm, the topological overlapping matrix and the hierarchical cluster tree, which were utilized via STRING. Clinical data obtained from The Cancer Genome Atlas were then analyzed to validate the experiments performed using six hub genes. Additionally, a transcription factor and microRNA-mRNA network were constructed to determine the potential regulatory mechanisms of six hub genes. The results revealed that the oxidation-reduction process and cell cycle associated processes were markedly involved in HCC progression. Six highly expressed genes, including cyclin B2, cell division cycle 20, mitotic arrest deficient 2 like 1, minichromosome maintenance complex component 2, centromere protein F and BUB mitotic checkpoint serine/threonine kinase B, were confirmed as hub genes and validated via experiments associated with cell division. These hub genes are necessary for confirmatory experiments and may be used in clinical gene therapy as biomarkers or drug targets.
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Affiliation(s)
- Hongshi Li
- Department of Medical Oncology, People's Hospital of Liaoning Province, Shenyang, Liaoning 110016, P.R. China
| | - Ning Wei
- Department of Medical Oncology, People's Hospital of Liaoning Province, Shenyang, Liaoning 110016, P.R. China
| | - Yi Ma
- Department of Medical Oncology, People's Hospital of Liaoning Province, Shenyang, Liaoning 110016, P.R. China
| | - Xiaozhou Wang
- Department of Medical Oncology, People's Hospital of Liaoning Province, Shenyang, Liaoning 110016, P.R. China
| | - Zhiqiang Zhang
- Department of Medical Oncology, People's Hospital of Liaoning Province, Shenyang, Liaoning 110016, P.R. China
| | - Shuang Zheng
- Department of Medical Oncology, People's Hospital of Liaoning Province, Shenyang, Liaoning 110016, P.R. China
| | - Xi Yu
- Department of Medical Oncology, People's Hospital of Liaoning Province, Shenyang, Liaoning 110016, P.R. China
| | - Shuang Liu
- Department of Medical Oncology, People's Hospital of Liaoning Province, Shenyang, Liaoning 110016, P.R. China
| | - Lijie He
- Department of Medical Oncology, People's Hospital of Liaoning Province, Shenyang, Liaoning 110016, P.R. China
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Yu B, Ding Y, Liao X, Wang C, Wang B, Chen X. Overexpression of PARPBP Correlates with Tumor Progression and Poor Prognosis in Hepatocellular Carcinoma. Dig Dis Sci 2019; 64:2878-2892. [PMID: 30949905 DOI: 10.1007/s10620-019-05608-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2018] [Accepted: 03/27/2019] [Indexed: 12/24/2022]
Abstract
BACKGROUND PARP1-binding protein (PARPBP/PARI/C12orf48), a negative regulator of homologous recombination (HR), has been suggested to function as an oncogene in cervical, lung, and pancreatic cancer. OBJECTIVE To investigate the expression profile of PARPBP and its role in hepatocellular carcinoma (HCC). METHODS Using data from the Cancer Genome Atlas and Human Protein Atlas databases, PARPBP expression level and its clinical implication in HCC were identified by t test and Chi-square test. The prognostic value of PARPBP in HCC was evaluated by Kaplan-Meier method, Cox regression analysis, and nomogram. Gene set enrichment analysis (GSEA) was used to screen biological pathways correlated with PARPBP expression in HCC. RESULTS PARPBP was significantly upregulated in HCC tissues compared with normal liver tissues (P < 0.05). High PARPBP expression was significantly associated with elevated serum AFP level, vascular invasion, poor tumor differentiation, and advanced TNM stage (all P < 0.05). Kaplan-Meier analyses suggested that upregulation of PARPBP was correlated with worse overall survival (OS) and recurrence-free survival (RFS) in HCC. Multivariate analyses further confirmed that PARPBP upregulation was an independent indicator of poor OS and RFS (all P < 0.05). The prognostic nomograms based on PARPBP mRNA expression and TNM stage were superior to those based on the TNM staging system alone (all P < 0.05). Besides, PARPBP DNA copy gain and miR-139-5p downregulation were associated with PARPBP upregulation in HCC. GSEA revealed that "cell cycle," "HR," "DNA replication," and "p53 signaling" pathways were enriched in high PARPBP expression group. CONCLUSION PARPBP may be a promising prognostic biomarker and candidate therapeutic target in HCC.
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Affiliation(s)
- Bin Yu
- Department of Hepatobiliary and Laparoscopic Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, People's Republic of China
| | - Youming Ding
- Department of Hepatobiliary and Laparoscopic Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, People's Republic of China.
| | - Xiaofeng Liao
- Department of General Surgery, Xiangyang Central Hospital, Xiangyang, 441021, Hubei Province, People's Republic of China
| | - Changhua Wang
- Department of Pathology and Pathophysiology, Wuhan University School of Basic Medical Sciences, Wuhan, 430071, Hubei Province, People's Republic of China
| | - Bin Wang
- Department of Hepatobiliary and Laparoscopic Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, People's Republic of China
| | - Xiaoyan Chen
- Department of Hepatobiliary and Laparoscopic Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, People's Republic of China
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Intuyod K, Armartmuntree N, Jusakul A, Sakonsinsiri C, Thanan R, Pinlaor S. Current omics-based biomarkers for cholangiocarcinoma. Expert Rev Mol Diagn 2019; 19:997-1005. [PMID: 31566016 DOI: 10.1080/14737159.2019.1673162] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Introduction: Cholangiocarcinoma (CCA) is a malignancy of the biliary tract. CCA generally has a low incidence worldwide but incidence is typically high in Southeast Asian countries, particularly in northeastern Thailand, where small liver-fluke (Opisthorchis viverrini) infection is endemic. CCA has a poor prognosis as most CCA patients present with advanced stages. Poor prognosis and worse outcomes are due to the lack of specific and early-stage CCA biomarkers. Areas covered: In this review, we discuss the use of CCA tissues, serum and bile samples as sources of diagnostic and prognostic markers by using -omics approaches, including genomics, epigenomics, transcriptomics and proteomics. The current state of the discovery of molecular candidates and their potential to be used as diagnostic and prognostic biomarkers for CCA are summarized and discussed. Expert opinion: Various potential molecules have been discovered, some of which have been verified as diagnostic biomarkers for CCA. However, most identified molecules require much further evaluation to help us find markers with high specificity, low cost and ease-of-use in routine diagnostic laboratories.
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Affiliation(s)
- Kitti Intuyod
- Department of Parasitology, Faculty of Medicine, Khon Kaen University , Khon Kaen , Thailand.,Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University , Khon Kaen , Thailand
| | - Napat Armartmuntree
- Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University , Khon Kaen , Thailand.,Department of Biochemistry, Faculty of Medicine, Khon Kaen University , Khon Kaen , Thailand
| | - Apinya Jusakul
- Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University , Khon Kaen , Thailand.,Faculty of Associated Medical Sciences, Khon Kaen University , Khon Kaen , Thailand
| | - Chadamas Sakonsinsiri
- Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University , Khon Kaen , Thailand.,Department of Biochemistry, Faculty of Medicine, Khon Kaen University , Khon Kaen , Thailand
| | - Raynoo Thanan
- Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University , Khon Kaen , Thailand.,Department of Biochemistry, Faculty of Medicine, Khon Kaen University , Khon Kaen , Thailand
| | - Somchai Pinlaor
- Department of Parasitology, Faculty of Medicine, Khon Kaen University , Khon Kaen , Thailand.,Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University , Khon Kaen , Thailand
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Huang XB, He YG, Zheng L, Feng H, Li YM, Li HY, Yang FX, Li J. Identification of hepatitis B virus and liver cancer bridge molecules based on functional module network. World J Gastroenterol 2019; 25:4921-4932. [PMID: 31543683 PMCID: PMC6737318 DOI: 10.3748/wjg.v25.i33.4921] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Revised: 06/29/2019] [Accepted: 07/19/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The potential role of chronic inflammation in the development of cancer has been widely recognized. However, there has been little research fully and thoroughly exploring the molecular link between hepatitis B virus (HBV) and hepatocellular carcinoma (HCC). AIM To elucidate the molecular links between HBV and HCC through analyzing the molecular processes of HBV-HCC using a multidimensional approach. METHODS First, maladjusted genes shared between HBV and HCC were identified by disease-related differentially expressed genes. Second, the protein-protein interaction network based on dysfunctional genes identified a series of dysfunctional modules and significant crosstalk between modules based on the hypergeometric test. In addition, key regulators were detected by pivot analysis. Finally, targeted drugs that have regulatory effects on diseases were predicted by modular methods and drug target information. RESULTS The study found that 67 genes continued to increase in the HBV-HCC process. Moreover, 366 overlapping genes in the module network participated in multiple functional blocks. It could be presumed that these genes and their interactions play an important role in the relationship between inflammation and cancer. Correspondingly, significant crosstalk constructed a module level bridge for HBV-HCC molecular processes. On the other hand, a series of non-coding RNAs and transcription factors that have potential pivot regulatory effects on HBV and HCC were identified. Among them, some of the regulators also had persistent disorders in the process of HBV-HCC including microRNA-192, microRNA-215, and microRNA-874, and early growth response 2, FOS, and Kruppel-like factor 4. Therefore, the study concluded that these pivots are the key bridge molecules outside the module. Last but not least, a variety of drugs that may have some potential pharmacological or toxic side effects on HBV-induced HCC were predicted, but their mechanisms still need to be further explored. CONCLUSION The results suggest that the persistent inflammatory environment of HBV can be utilized as an important risk factor to induce the occurrence of HCC, which is supported by molecular evidence.
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Affiliation(s)
- Xiao-Bing Huang
- Department of Hepatobiliary Surgery, Second Hospital Affiliated to Third Military Medical University of Xinqiao Hospital, Chongqing 400037, China
| | - Yong-Gang He
- Department of Hepatobiliary Surgery, Second Hospital Affiliated to Third Military Medical University of Xinqiao Hospital, Chongqing 400037, China
| | - Lu Zheng
- Department of Hepatobiliary Surgery, Second Hospital Affiliated to Third Military Medical University of Xinqiao Hospital, Chongqing 400037, China
| | - Huan Feng
- Division of Nursing, Second Hospital Affiliated to Third Military Medical University, Xinqiao Hospital, Chongqing 400037, China
| | - Yu-Ming Li
- Department of Hepatobiliary Surgery, Second Hospital Affiliated to Third Military Medical University of Xinqiao Hospital, Chongqing 400037, China
| | - Hong-Yan Li
- Department of Hepatobiliary Surgery, Second Hospital Affiliated to Third Military Medical University of Xinqiao Hospital, Chongqing 400037, China
| | - Feng-Xia Yang
- Department of Hepatobiliary Surgery, Second Hospital Affiliated to Third Military Medical University of Xinqiao Hospital, Chongqing 400037, China
| | - Jing Li
- Department of Hepatobiliary Surgery, Second Hospital Affiliated to Third Military Medical University of Xinqiao Hospital, Chongqing 400037, China
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Vaeteewoottacharn K, Pairojkul C, Kariya R, Muisuk K, Imtawil K, Chamgramol Y, Bhudhisawasdi V, Khuntikeo N, Pugkhem A, Saeseow OT, Silsirivanit A, Wongkham C, Wongkham S, Okada S. Establishment of Highly Transplantable Cholangiocarcinoma Cell Lines from a Patient-Derived Xenograft Mouse Model. Cells 2019; 8:496. [PMID: 31126020 PMCID: PMC6562875 DOI: 10.3390/cells8050496] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2019] [Revised: 05/13/2019] [Accepted: 05/21/2019] [Indexed: 12/11/2022] Open
Abstract
Cholangiocarcinoma (CCA) is a deadly malignant tumor of the liver. It is a significant health problem in Thailand. The critical obstacles of CCA diagnosis and treatment are the high heterogeneity of disease and considerable resistance to treatment. Recent multi-omics studies revealed the promising targets for CCA treatment; however, limited models for drug discovery are available. This study aimed to develop a patient-derived xenograft (PDX) model as well as PDX-derived cell lines of CCA for future drug screening. From a total of 16 CCA frozen tissues, 75% (eight intrahepatic and four extrahepatic subtypes) were successfully grown and subpassaged in Balb/c Rag-2-/-/Jak3-/- mice. A shorter duration of PDX growth was observed during F0 to F2 transplantation; concomitantly, increased Oct-3/4 and Sox2 were evidenced in 50% and 33%, respectively, of serial PDXs. Only four cell lines were established. The cell lines exhibited either bile duct (KKK-D049 and KKK-D068) or combined hepatobiliary origin (KKK-D131 and KKK-D138). These cell lines acquired high transplantation efficiency in both subcutaneous (100%) and intrasplenic (88%) transplantation models. The subcutaneously transplanted xenograft retained the histological architecture as in the patient tissues. Our models of CCA PDX and PDX-derived cell lines would be a useful platform for CCA precision medicine.
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Affiliation(s)
- Kulthida Vaeteewoottacharn
- Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection and Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-0811, Japan.
- Department of Biochemistry, Khon Kaen University, Khon Kaen 40002, Thailand.
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand.
| | - Chawalit Pairojkul
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand.
- Department of Pathology, Khon Kaen University, Khon Kaen 40002, Thailand.
| | - Ryusho Kariya
- Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection and Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-0811, Japan.
| | - Kanha Muisuk
- Department of Forensic Sciences, Khon Kaen University, Khon Kaen 40002, Thailand.
| | - Kanokwan Imtawil
- Department of Biochemistry, Khon Kaen University, Khon Kaen 40002, Thailand.
| | - Yaovalux Chamgramol
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand.
- Department of Pathology, Khon Kaen University, Khon Kaen 40002, Thailand.
| | - Vajarabhongsa Bhudhisawasdi
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand.
- Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
| | - Narong Khuntikeo
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand.
- Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
| | - Ake Pugkhem
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand.
- Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
| | - O-Tur Saeseow
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand.
- Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
| | - Atit Silsirivanit
- Department of Biochemistry, Khon Kaen University, Khon Kaen 40002, Thailand.
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand.
| | - Chaisiri Wongkham
- Department of Biochemistry, Khon Kaen University, Khon Kaen 40002, Thailand.
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand.
| | - Sopit Wongkham
- Department of Biochemistry, Khon Kaen University, Khon Kaen 40002, Thailand.
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand.
| | - Seiji Okada
- Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection and Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-0811, Japan.
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Intuyod K, Saavedra-García P, Zona S, Lai CF, Jiramongkol Y, Vaeteewoottacharn K, Pairojkul C, Yao S, Yong JS, Trakansuebkul S, Waraasawapati S, Luvira V, Wongkham S, Pinlaor S, Lam EWF. FOXM1 modulates 5-fluorouracil sensitivity in cholangiocarcinoma through thymidylate synthase (TYMS): implications of FOXM1-TYMS axis uncoupling in 5-FU resistance. Cell Death Dis 2018; 9:1185. [PMID: 30538221 PMCID: PMC6290025 DOI: 10.1038/s41419-018-1235-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2018] [Revised: 11/01/2018] [Accepted: 11/23/2018] [Indexed: 12/21/2022]
Abstract
Fluorouracil (5-FU) is the first-line chemotherapeutic drug for cholangiocarcinoma (CCA), but its efficacy has been compromised by the development of resistance. Development of 5-FU resistance is associated with elevated expression of its cellular target, thymidylate synthase (TYMS). E2F1 transcription factor has previously been shown to modulate the expression of FOXM1 and TYMS. Immunohistochemical (IHC) analysis revealed a strong correlated upregulation of FOXM1 (78%) and TYMS (48%) expression at the protein levels in CCA tissues. In agreement, RT-qPCR and western blot analyses of four human CCA cell lines at the baseline level and in response to high doses of 5-FU revealed good correlations between FOXM1 and TYMS expression in the CCA cell lines tested, except for the highly 5-FU-resistant HuCCA cells. Consistently, siRNA-mediated knockdown of FOXM1 reduced the clonogenicity and TYMS expression in the relatively sensitive KKU-D131 but not in the highly resistant HuCCA cells. Interestingly, silencing of TYMS sensitized both KKU-D131 and HuCCA to 5-FU treatment, suggesting that resistance to very high levels of 5-FU is due to the inability of the genotoxic sensor FOXM1 to modulate TYMS expression. Consistently, ChIP analysis revealed that FOXM1 binds efficiently to the TYMS promoter and modulates TYMS expression at the promoter level upon 5-FU treatment in KKU-D131 but not in HuCCA cells. In addition, E2F1 expression did not correlate with either FOXM1 or TYMS expression and E2F1 depletion has no effects on the clonogenicity and TYMS expression in the CCA cells. In conclusion, our data show that FOXM1 regulates TYMS expression to modulate 5-FU resistance in CCA and that severe 5-FU resistance can be caused by the uncoupling of the regulation of TYMS by FOXM1. Our findings suggest that the FOXM1–TYMS axis can be a novel diagnostic, predictive and prognostic marker as well as a therapeutic target for CCA.
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Affiliation(s)
- Kitti Intuyod
- Department of Surgery and Cancer, Imperial College London, Imperial College London, Hammersmith Hospital Campus, London, W12 0NN, UK.,Biomedical Science Program, Graduate School, Khon Kaen University, Khon Kaen, 40002, Thailand.,Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Paula Saavedra-García
- Department of Surgery and Cancer, Imperial College London, Imperial College London, Hammersmith Hospital Campus, London, W12 0NN, UK
| | - Stefania Zona
- Department of Surgery and Cancer, Imperial College London, Imperial College London, Hammersmith Hospital Campus, London, W12 0NN, UK
| | - Chun-Fui Lai
- Department of Surgery and Cancer, Imperial College London, Imperial College London, Hammersmith Hospital Campus, London, W12 0NN, UK
| | - Yannasittha Jiramongkol
- Department of Surgery and Cancer, Imperial College London, Imperial College London, Hammersmith Hospital Campus, London, W12 0NN, UK
| | - Kulthida Vaeteewoottacharn
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand.,Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Chawalit Pairojkul
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand.,Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Shang Yao
- Department of Surgery and Cancer, Imperial College London, Imperial College London, Hammersmith Hospital Campus, London, W12 0NN, UK
| | - Jay-Sze Yong
- Department of Surgery and Cancer, Imperial College London, Imperial College London, Hammersmith Hospital Campus, London, W12 0NN, UK
| | - Sasanan Trakansuebkul
- Department of Surgery and Cancer, Imperial College London, Imperial College London, Hammersmith Hospital Campus, London, W12 0NN, UK
| | - Sakda Waraasawapati
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand.,Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Vor Luvira
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand.,Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Sopit Wongkham
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand.,Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Somchai Pinlaor
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand. .,Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
| | - Eric W-F Lam
- Department of Surgery and Cancer, Imperial College London, Imperial College London, Hammersmith Hospital Campus, London, W12 0NN, UK.
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Harrington D, Lamberton PHL, McGregor A. Human liver flukes. Lancet Gastroenterol Hepatol 2018; 2:680-689. [PMID: 28786389 DOI: 10.1016/s2468-1253(17)30111-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2016] [Revised: 03/26/2017] [Accepted: 04/03/2017] [Indexed: 12/12/2022]
Abstract
Liver fluke infections occur in people worldwide. In some low-income regions, a combination of ecological, agricultural, and culinary factors leads to a very high prevalence of infection but, in higher-income regions, infections are uncommon. Infection is associated with substantial morbidity and several liver fluke species are recognised as biological carcinogens. Here, we review the epidemiology, clinical significance, and diagnostic and treatment strategies of human infection with these pathogens.
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Affiliation(s)
- David Harrington
- Department of Infectious Diseases and Tropical Medicine, Northwick Park Hospital, London, UK.
| | - Poppy H L Lamberton
- Institute of Biodiversity, Animal Health, and Comparative Medicine, and Wellcome Centre for Molecular Parasitology, University of Glasgow, Glasgow, UK; Faculty of Medicine, Imperial College London, London, UK
| | - Alastair McGregor
- Department of Infectious Diseases and Tropical Medicine, Northwick Park Hospital, London, UK; Faculty of Medicine, Imperial College London, London, UK
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Thinking beyond Opisthorchis viverrini for risk of cholangiocarcinoma in the lower Mekong region: a systematic review and meta-analysis. Infect Dis Poverty 2018; 7:44. [PMID: 29769113 PMCID: PMC5956617 DOI: 10.1186/s40249-018-0434-3] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Accepted: 04/25/2018] [Indexed: 12/11/2022] Open
Abstract
Background Cholangiocarcinoma (CCA) is a fatal bile duct cancer associated with infection by the liver fluke, Opisthorchis viverrini, in the lower Mekong region. Numerous public health interventions have focused on reducing exposure to O. viverrini, but incidence of CCA in the region remains high. While this may indicate the inefficacy of public health interventions due to complex social and cultural factors, it may further indicate other risk factors or interactions with the parasite are important in pathogenesis of CCA. This systematic review aims to provide a comprehensive analysis of described risk factors for CCA in addition to O. viverrini to guide future integrative interventions. Main body We searched five international and seven Thai research databases to identify studies relevant to risk factors for CCA in the lower Mekong region. Selected studies were assessed for risk of bias and quality in terms of study design, population, CCA diagnostic methods, and statistical methods. The final 18 included studies reported numerous risk factors which were grouped into behaviors, socioeconomics, diet, genetics, gender, immune response, other infections, and treatment for O. viverrini. Seventeen risk factors were reported by two or more studies and were assessed with random effects models during meta-analysis. This meta-analysis indicates that the combination of alcohol and smoking (OR = 11.1, 95% CI: 5.63–21.92, P < 0.0001) is most significantly associated with increased risk for CCA and is an even greater risk factor than O. viverrini exposure. This analysis also suggests that family history of cancer, consumption of raw cyprinoid fish, consumption of high nitrate foods, and praziquantel treatment are associated with significantly increased risk. These risk factors may have complex relationships with the host, parasite, or pathogenesis of CCA, and many of these risk factors were found to interact with each other in one or more studies. Conclusions Our findings suggest that a complex variety of risk factors in addition to O. viverrini infection should be addressed in future public health interventions to reduce CCA in affected regions. In particular, smoking and alcohol use, dietary patterns, and socioeconomic factors should be considered when developing intervention programs to reduce CCA. Electronic supplementary material The online version of this article (10.1186/s40249-018-0434-3) contains supplementary material, which is available to authorized users.
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Saengboonmee C, Sawanyawisuth K, Chamgramol Y, Wongkham S. Prognostic biomarkers for cholangiocarcinoma and their clinical implications. Expert Rev Anticancer Ther 2018; 18:579-592. [PMID: 29676221 DOI: 10.1080/14737140.2018.1467760] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
INTRODUCTION Cholangiocarcinoma (CCA) is a poorly prognostic cancer with limited treatment options. Most patients have unresectable tumors when they are diagnosed and the chemotherapies provided are of limited benefit. Prognostic markers are therefore necessary to predict the disease outcome, risk of relapse, or to suggest the best treatment option. Areas covered: This article provides an up-to-date review of biomarkers with promising characteristics to be prognostic markers for CCA reported in the past 5 years. The biomarkers are sub-classified into tissue and serum markers. Proteins, RNAs, peripheral blood cells etc., that are associated with aggressive phenotypes, signal pathways, chemo-drug resistance, and those that reflect the survival time of CCA patients are evaluated for their prognostic prediction values. Expert commentary: CCAs are heterogeneous tumors of different histo-pathological subtypes and genetic influences and, therefore, potential markers should be validated in larger collectives with varied epidemiological backgrounds. A systematic review and meta-analysis should be done to clarify the impact of the reported biomolecules for their potential prognostic values. Non- or low-invasive sample collections, as well as the simple and affordable determination methods, should be constructed to make the prognostic biomarkers available in clinical practice.
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Affiliation(s)
- Charupong Saengboonmee
- a Department of Biochemistry, Faculty of Medicine , Khon Kaen University , Khon Kaen , Thailand.,b Cholangiocarcinoma Research Institute , Khon Kaen University , Khon Kaen , Thailand
| | - Kanlayanee Sawanyawisuth
- a Department of Biochemistry, Faculty of Medicine , Khon Kaen University , Khon Kaen , Thailand.,b Cholangiocarcinoma Research Institute , Khon Kaen University , Khon Kaen , Thailand
| | - Yaovalux Chamgramol
- b Cholangiocarcinoma Research Institute , Khon Kaen University , Khon Kaen , Thailand.,c Department of Pathology, Faculty of Medicine , Khon Kaen University , Khon Kaen , Thailand
| | - Sopit Wongkham
- a Department of Biochemistry, Faculty of Medicine , Khon Kaen University , Khon Kaen , Thailand.,b Cholangiocarcinoma Research Institute , Khon Kaen University , Khon Kaen , Thailand
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Intuyod K, Priprem A, Pairojkul C, Hahnvajanawong C, Vaeteewoottacharn K, Pinlaor P, Pinlaor S. Anthocyanin complex exerts anti-cholangiocarcinoma activities and improves the efficacy of drug treatment in a gemcitabine-resistant cell line. Int J Oncol 2018; 52:1715-1726. [PMID: 29512768 DOI: 10.3892/ijo.2018.4306] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Accepted: 03/01/2018] [Indexed: 11/05/2022] Open
Abstract
Cholangiocarcinoma (CCA) is a deleterious bile duct tumor with poor prognosis and is relatively resistant to chemotherapy. Therefore, alternative or supplementary agents with anticancer and chemosensitizing activities may be useful for the treatment of CCA. A novel anthocyanin complex (AC) nanoparticle, developed from extracts of cobs of purple waxy corn and petals of blue butterfly pea, has exhibited chemopreventive potential in vivo. In the present study, the anti-CCA activities of AC and their underlying molecular mechanisms were investigated further in vitro using a CCA cell line (KKU213). The potential use of AC as a chemosensitizer was also evaluated in a gemcitabine-resistant CCA cell line (KKU214GemR). It was demonstrated that AC treatment suppressed proliferation of KKU213 CCA cells in dose- and time-dependent manners. AC treatment also induced apoptosis and mitochondrial superoxide production, decreased clonogenicity of CCA cells, and downregulated forkhead box protein M1 (FOXM1), nuclear factor-κB (NF-κB) and pro-survival protein B-cell lymphoma-2 (Bcl-2). The expression of endoplasmic reticulum (ER) stress-response proteins, including protein kinase RNA-like ER kinase, phosphorylated eIF2α, eukaryotic initiation factor 2α and activating transcription factor 4, also decreased following AC treatment. It was also identified that AC treatment inhibited KKU214GemR cell proliferation in dose- and time-dependent manners. Co-treatment of KKU214GemR cells with low doses of AC together with gemcitabine significantly enhanced efficacy of the latter against this cell line. Therefore, it is suggested that AC treatment is cytotoxic to KKU213 cells, possibly via downregulation of FOXM1, NF-κB, Bcl-2 and the ER stress response, and by induction of mitochondrial superoxide production. AC also sensitizes KKU214GemR to gemcitabine treatment, which may have potential for overcoming drug resistance of CCA.
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Affiliation(s)
- Kitti Intuyod
- Biomedical Science Program, Graduate School, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Aroonsri Priprem
- Department of Pharmaceutical Technology, Faculty of Pharmaceutical Science, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Chawalit Pairojkul
- Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Chariya Hahnvajanawong
- Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Kulthida Vaeteewoottacharn
- Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Porntip Pinlaor
- Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Somchai Pinlaor
- Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
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40
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Circulating oncometabolite D-2-hydroxyglutarate enantiomer is a surrogate marker of isocitrate dehydrogenase-mutated intrahepatic cholangiocarcinomas. Eur J Cancer 2018; 90:83-91. [PMID: 29274619 DOI: 10.1016/j.ejca.2017.11.024] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2017] [Accepted: 11/22/2017] [Indexed: 01/04/2023]
Abstract
Therapeutic resources are limited for advanced biliary tract cancers and prognosis remains poor. Somatic mutations in isocitrate dehydrogenase (IDH)1/2 gene are found in 5-36% of patients with intrahepatic cholangiocarcinoma (ICC). The mutant forms of IDH1/2 catalyse the non-reversible accumulation of 2-hydroxyglutarate (2HG). Increasing numbers of indirect or direct-targeted therapies are developed to IDH1/2 mutations and could be assisted by a routinely feasible, rapid and inexpensive serum 2HG measurement by liquid chromatography coupled to tandem mass spectrometry. By comparing eight patients with an IDH1/2-mutated ICC to nine patients with wild-type IDH1/2 ICC, we found significantly higher levels of 2HG in patients with IDH1/2 mutations versus the wild-type group (median, 10.9 vs. 0.8 μmol/L, p = 0.0037). D and L-2HG enantiomer levels significantly differed between the two groups with a higher level of D-2HG (p < 0.0001) in patients with IDH1/2 mutations. Accordingly, the D/L ratio was markedly higher in the patients with IDH1/2 mutations compared with the wild-type group (38.0 vs. 0.9 μmol/L, p < 0.0001). D-2HG measurement ensured 100% sensitivity and specificity at a cut-off of 0.6 μmol/L. D-2HG levels were correlated with tumour burden and tumour response to treatment with IDH-targeted therapies or indirect therapies. D-2HG serum level measurement by liquid chromatography coupled to tandem mass spectrometry is a sensitive, specific, precise (a coefficient of variation <10% and an accuracy >95%), fast (9 min run per sample) and inexpensive surrogate marker of IDH1/2 somatic mutation in ICC. Systematic measurement in patients with ICC may facilitate access to, and monitoring of, IDH-driven therapies.
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41
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Ferrell LD, Kakar S, Terracciano LM, Wee A. Tumours and Tumour-like Lesions of the Liver. MACSWEEN'S PATHOLOGY OF THE LIVER 2018:780-879. [DOI: 10.1016/b978-0-7020-6697-9.00013-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Shiao MS, Chiablaem K, Charoensawan V, Ngamphaiboon N, Jinawath N. Emergence of Intrahepatic Cholangiocarcinoma: How High-Throughput Technologies Expedite the Solutions for a Rare Cancer Type. Front Genet 2018; 9:309. [PMID: 30158952 PMCID: PMC6104394 DOI: 10.3389/fgene.2018.00309] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Accepted: 07/23/2018] [Indexed: 12/16/2022] Open
Abstract
Intrahepatic cholangiocarcinoma (ICC) is the cancer of the intrahepatic bile ducts, and together with hepatocellular carcinoma (HCC), constitute the majority of primary liver cancers. ICC is a rare disorder as its overall incidence is < 1/100,000 in the United States and Europe. However, it shows much higher incidence in particular geographical regions, such as northeastern Thailand, where liver fluke infection is the most common risk factor of ICC. Since the early stages of ICC are often asymptomatic, the patients are usually diagnosed at advanced stages with no effective treatments available, leading to the high mortality rate. In addition, unclear genetic mechanisms, heterogeneous nature, and various etiologies complicate the development of new efficient treatments. Recently, a number of studies have employed high-throughput approaches, including next-generation sequencing and mass spectrometry, in order to understand ICC in different biological aspects. In general, the majority of recurrent genetic alterations identified in ICC are enriched in known tumor suppressor genes and oncogenes, such as mutations in TP53, KRAS, BAP1, ARID1A, IDH1, IDH2, and novel FGFR2 fusion genes. Yet, there are no major driver genes with immediate clinical solutions characterized. Interestingly, recent studies utilized multi-omics data to classify ICC into two main subgroups, one with immune response genes as the main driving factor, while another is enriched with driver mutations in the genes associated with epigenetic regulations, such as IDH1 and IDH2. The two subgroups also show different hypermethylation patterns in the promoter regions. Additionally, the immune response induced by host-pathogen interactions, i.e., liver fluke infection, may further stimulate tumor growth through alterations of the tumor microenvironment. For in-depth functional studies, although many ICC cell lines have been globally established, these homogeneous cell lines may not fully explain the highly heterogeneous genetic contents of this disorder. Therefore, the advent of patient-derived xenograft and 3D patient-derived organoids as new disease models together with the understanding of evolution and genetic alterations of tumor cells at the single-cell resolution will likely become the main focus to fill the current translational research gaps of ICC in the future.
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Affiliation(s)
- Meng-Shin Shiao
- Research Center, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Khajeelak Chiablaem
- Program in Translational Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Varodom Charoensawan
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, Thailand
- Integrative Computational BioScience (ICBS) Center, Mahidol University, Nakhon Pathom, Thailand
- Systems Biology of Diseases Research Unit, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Nuttapong Ngamphaiboon
- Medical Oncology Unit, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Natini Jinawath
- Program in Translational Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
- Integrative Computational BioScience (ICBS) Center, Mahidol University, Nakhon Pathom, Thailand
- *Correspondence: Natini Jinawath ;
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Bragazzi MC, Ridola L, Safarikia S, Matteo SD, Costantini D, Nevi L, Cardinale V. New insights into cholangiocarcinoma: multiple stems and related cell lineages of origin. Ann Gastroenterol 2017; 31:42-55. [PMID: 29333066 PMCID: PMC5759612 DOI: 10.20524/aog.2017.0209] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2017] [Accepted: 09/14/2017] [Indexed: 12/12/2022] Open
Abstract
Cholangiocarcinoma (CCA) is a heterogeneous group of malignancies that may develop at any level of the biliary tree. CCA is currently classified into intrahepatic (iCCA), perihilar (pCCA) and distal (dCCA) on the basis of its anatomical location. Notably, although these three CCA subtypes have common features, they also have important inter- and intra-tumor differences that can affect their pathogenesis and outcome. A unique feature of CCA is that it manifests in the hepatic parenchyma or large intrahepatic and extrahepatic bile ducts, furnished by two distinct stem cell niches: the canals of Hering and the peribiliary glands, respectively. The complexity of CCA pathogenesis highlights the need for a multidisciplinary, translational, and systemic approach to this malignancy. This review focuses on advances in the knowledge of CCA histomorphology, risk factors, molecular pathogenesis, and subsets of CCA.
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Affiliation(s)
- Maria Consiglia Bragazzi
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Lorenzo Ridola
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Samira Safarikia
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Sabina Di Matteo
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Daniele Costantini
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Lorenzo Nevi
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Vincenzo Cardinale
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
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44
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The construction of intrahepatic cholangiocarcinoma model in zebrafish. Sci Rep 2017; 7:13419. [PMID: 29042681 PMCID: PMC5645375 DOI: 10.1038/s41598-017-13815-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Accepted: 10/02/2017] [Indexed: 02/07/2023] Open
Abstract
Intrahepatic cholangiocarcinoma (ICC) is a highly malignant tumor, difficult to diagnose even at an early stage. In this study, we successfully constructed an nras61K-induced ICC model in zebrafish. Transcriptome analysis and gene set enrichment analysis (GSEA) of liver samples of the ICC and WT (wild-type) zebrafish revealed that the genes differentially expressed between the two groups were mainly involved in focal adhesion, chemokine signaling and metabolic pathways. Analysis of DNA methylomes revealed that compared with WT samples, methylated genes in ICC samples were enriched in functions associated with cellular, single-organism and metabolic processes. In particular, our result discovered eleven potential biomarker genes of ICC which were conserved between zebrafish and humans. Moreover, three potential biomarker genes were hypomethylated in the tumorigenesis of ICC: ehf, epha4 and itgb6. In summary, our study provides a comprehensive analysis of molecular mechanisms accompanying the progressive nras61K-induced ICC. This work indicates that our transgenic zebrafish could be a valuable model, not only for studying liver cancer, but also for exploring new therapeutic targets.
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45
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Verlingue L, Hollebecque A, Boige V, Ducreux M, Malka D, Ferté C. Matching genomic molecular aberrations with molecular targeted agents: Are biliary tract cancers an ideal playground? Eur J Cancer 2017. [PMID: 28628842 DOI: 10.1016/j.ejca.2017.05.006] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Yokobori T, Nishiyama M. TGF-β Signaling in Gastrointestinal Cancers: Progress in Basic and Clinical Research. J Clin Med 2017; 6:jcm6010011. [PMID: 28106769 PMCID: PMC5294964 DOI: 10.3390/jcm6010011] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Revised: 12/31/2016] [Accepted: 01/16/2017] [Indexed: 12/18/2022] Open
Abstract
Transforming growth factor (TGF)-β superfamily proteins have many important biological functions, including regulation of tissue differentiation, cell proliferation, and migration in both normal and cancer cells. Many studies have reported that TGF-β signaling is associated with disease progression and therapeutic resistance in several cancers. Similarly, TGF-β-induced protein (TGFBI)—a downstream component of the TGF-β signaling pathway—has been shown to promote and/or inhibit cancer. Here, we review the state of basic and clinical research on the roles of TGF-β and TGFBI in gastrointestinal cancers.
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Affiliation(s)
- Takehiko Yokobori
- Research Program for Omics-based Medical Science, Division of Integrated Oncology Research, Gunma University Initiative for Advanced Research, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan.
| | - Masahiko Nishiyama
- Research Program for Omics-based Medical Science, Division of Integrated Oncology Research, Gunma University Initiative for Advanced Research, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan.
- Department of Molecular Pharmacology and Oncology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan.
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47
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Goeppert B, Ernst C, Baer C, Roessler S, Renner M, Mehrabi A, Hafezi M, Pathil A, Warth A, Stenzinger A, Weichert W, Bähr M, Will R, Schirmacher P, Plass C, Weichenhan D. Cadherin-6 is a putative tumor suppressor and target of epigenetically dysregulated miR-429 in cholangiocarcinoma. Epigenetics 2016; 11:780-790. [PMID: 27593557 DOI: 10.1080/15592294.2016.1227899] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Cholangiocarcinoma (CC) is a rare malignancy of the extrahepatic or intrahepatic biliary tract with an outstanding poor prognosis. Non-surgical therapeutic regimens result in minimally improved survival of CC patients. Global genomic analyses identified a few recurrently mutated genes, some of them in genes involved in epigenetic patterning. In a previous study, we demonstrated global DNA methylation changes in CC, indicating major contribution of epigenetic alterations to cholangiocarcinogenesis. Here, we aimed at the identification and characterization of CC-related, differentially methylated regions (DMRs) in potential microRNA promoters and of genes targeted by identified microRNAs. Twenty-seven hypermethylated and 13 hypomethylated potential promoter regions of microRNAs, known to be associated with cancer-related pathways like Wnt, ErbB, and PI3K-Akt signaling, were identified. Selected DMRs were confirmed in 2 independent patient cohorts. Inverse correlation between promoter methylation and expression suggested miR-129-2 and members of the miR-200 family (miR-200a, miR-200b, and miR-429) as novel tumor suppressors and oncomiRs, respectively, in CC. Tumor suppressor genes deleted in liver cancer 1 (DLC1), F-box/WD-repeat-containing protein 7 (FBXW7), and cadherin-6 (CDH6) were identified as presumed targets in CC. Tissue microarrays of a representative and well-characterized cohort of biliary tract cancers (n=212) displayed stepwise downregulation of CDH6 and association with poor patient outcome. Ectopic expression of CDH6 on the other hand, delayed growth in the CC cell lines EGI-1 and TFK-1, together suggesting a tumor suppressive function of CDH6. Our work represents a valuable repository for the study of epigenetically altered miRNAs in cholangiocarcinogenesis and novel putative, CC-related tumor suppressive miRNAs and oncomiRs.
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Affiliation(s)
| | - Christina Ernst
- b Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ) , Heidelberg , Germany
| | - Constance Baer
- b Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ) , Heidelberg , Germany
| | | | - Marcus Renner
- a Institute of Pathology, University Hospital Heidelberg , Germany
| | - Arianeb Mehrabi
- c Department of General , Visceral, and Transplantation Surgery, University Hospital Heidelberg , Germany
| | - Mohammadreza Hafezi
- c Department of General , Visceral, and Transplantation Surgery, University Hospital Heidelberg , Germany
| | - Anita Pathil
- d Department of Internal Medicine IV, Gastroenterology and Hepatology , University Hospital Heidelberg , Germany
| | - Arne Warth
- a Institute of Pathology, University Hospital Heidelberg , Germany
| | | | - Wilko Weichert
- e Technical University of Munich, University Hospital, Institute for General Pathology and Pathological Anatomy , Germany
| | - Marion Bähr
- b Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ) , Heidelberg , Germany
| | - Rainer Will
- f Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ) , Heidelberg , Germany
| | | | - Christoph Plass
- b Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ) , Heidelberg , Germany
| | - Dieter Weichenhan
- b Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ) , Heidelberg , Germany
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Chen MH, Yen CC, Cheng CT, Wu RC, Huang SC, Yu CS, Chung YH, Liu CY, Chang PMH, Chao Y, Chen MH, Chen YF, Chiang KC, Yeh TS, Chen TC, Huang CYF, Yeh CN. Identification of SPHK1 as a therapeutic target and marker of poor prognosis in cholangiocarcinoma. Oncotarget 2016; 6:23594-608. [PMID: 26090720 PMCID: PMC4695139 DOI: 10.18632/oncotarget.4335] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2014] [Accepted: 05/30/2015] [Indexed: 01/01/2023] Open
Abstract
Cholangiocarcinoma (CCA) is characterized by a uniquely aggressive behavior and lack of effective targeted therapies. After analyzing the gene expression profiles of seven paired intrahepatic CCA microarrays, a novel sphingosine kinase 1 (SPHK1)/sphingosine-1-phosphate (S1P) pathway and a novel target gene, SPHK1, were identified. We hypothesized that therapeutic targeting of this pathway can be used to kill intrahepatic cholangiocarcinoma (CCA) cells. High levels of SPHK1 protein expression, which was evaluated by immunohistochemical staining of samples from 96 patients with intrahepatic CCA, correlated with poor overall survival. The SPHK1 inhibitor SK1-I demonstrated potent antiproliferative activity in vitro and in vivo. SK1-I modulated the balance of ceramide-sphinogosine-S1P and induced CCA apoptosis. Furthermore, SK1-I combined with JTE013, an antagonist of the predominant S1P receptor S1PR2, inhibited the AKT and ERK signaling pathways in CCA cells. Our preclinical data suggest SPHK1/S1P pathway targeting may be an effective treatment option for patients with CCA.
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Affiliation(s)
- Ming-Huang Chen
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.,Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Chueh-Chuan Yen
- Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Chi-Tung Cheng
- Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan
| | - Ren-Chin Wu
- Department of Pathology, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan
| | - Shih-Chiang Huang
- Department of Pathology, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan
| | - Chung-Shan Yu
- Department of Biomedical Engineering and Environmental Sciences, National Tsing-Hua University, Hsinchu, Taiwan
| | - Yi-Hsiu Chung
- Center for Advanced Molecular Imaging and Translation, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Chun-Yu Liu
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.,Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Peter Mu-Hsin Chang
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.,Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yee Chao
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.,Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Ming-Han Chen
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Yu-Fen Chen
- Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Kun-Chun Chiang
- Department of General Surgery, Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Ta-Sen Yeh
- Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan
| | - Tzu Chi Chen
- Institute of Clinical Medicine and Institute of Biopharmaceutical Sciences National Yang-Ming University, Taipei, Taiwan
| | - Chi-Ying F Huang
- Institute of Clinical Medicine and Institute of Biopharmaceutical Sciences National Yang-Ming University, Taipei, Taiwan
| | - Chun-Nan Yeh
- Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan
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Induction of MITF expression in human cholangiocarcinoma cells and hepatocellular carcinoma cells by cyclopamine, an inhibitor of the Hedgehog signaling. Biochem Biophys Res Commun 2016; 470:144-149. [PMID: 26773496 DOI: 10.1016/j.bbrc.2016.01.010] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Accepted: 01/04/2016] [Indexed: 12/23/2022]
Abstract
Microphthalmia-associated transcription factor (MITF) is a key regulator of differentiation of melanocytes and retinal pigment epithelial cells, but it also has functions in non-pigment cells. MITF consists of multiple isoforms, including widely expressed MITF-A and MITF-H. In the present study, we explored the potential role played by the Hedgehog signaling on MITF expression in two common types of primary liver cancer, using human cholangiocarcinoma cell lines, the KKU-100 and HuCCT1, along with the HepG2 human hepatocellular carcinoma cell line. Importantly, cholangiocarcinoma is characterized by the activated Hedgehog signaling. Here we show that MITF-A mRNA is predominantly expressed in all three human liver cancer cell lines examined. Moreover, cyclopamine, an inhibitor of the Hedgehog signalling, increased the expression levels of MITF proteins in HuCCT1 and HepG2 cells, but not in KKU-100 cells, suggesting that MITF expression may be down-regulated in some liver cancer cases.
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50
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Moeini A, Sia D, Bardeesy N, Mazzaferro V, Llovet JM. Molecular Pathogenesis and Targeted Therapies for Intrahepatic Cholangiocarcinoma. Clin Cancer Res 2015; 22:291-300. [PMID: 26405193 DOI: 10.1158/1078-0432.ccr-14-3296] [Citation(s) in RCA: 170] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2015] [Accepted: 08/06/2015] [Indexed: 12/17/2022]
Abstract
Intrahepatic cholangiocarcinoma (iCCA) is a molecularly heterogeneous hepatobiliary neoplasm with poor prognosis and limited therapeutic options. The incidence of this neoplasm is growing globally. One third of iCCA tumors are amenable to surgical resection, but most cases are diagnosed at advanced stages with chemotherapy as the only established standard of practice. No molecular therapies are currently available for the treatment of this neoplasm. The poor understanding of the biology of iCCA and the lack of known oncogenic addiction loops has hindered the development of effective targeted therapies. Studies with sophisticated animal models defined IDH mutation as the first gatekeeper in the carcinogenic process and led to the discovery of striking alternative cellular origins. RNA- and exome-sequencing technologies revealed the presence of recurrent novel fusion events (FGFR2 and ROS1 fusions) and somatic mutations in metabolic (IDH1/2) and chromatin-remodeling genes (ARID1A, BAP1). These latest advancements along with known mutations in KRAS/BRAF/EGFR and 11q13 high-level amplification have contributed to a better understanding of the landscape of molecular alterations in iCCA. More than 100 clinical trials testing molecular therapies alone or in combination with chemotherapy including iCCA patients have not reported conclusive clinical benefits. Recent discoveries have shown that up to 70% of iCCA patients harbor potential actionable alterations that are amenable to therapeutic targeting in early clinical trials. Thus, the first biomarker-driven trials are currently underway.
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Affiliation(s)
- Agrin Moeini
- Liver Cancer Translational Research Laboratory, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, CIBERehd, Universitat de Barcelona, Barcelona, Catalonia, Spain. Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Daniela Sia
- Liver Cancer Translational Research Laboratory, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, CIBERehd, Universitat de Barcelona, Barcelona, Catalonia, Spain. Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York. Gastrointestinal Surgery and Liver Transplantation Unit, Department of Surgery, National Cancer Institute IRCCS Foundation, Milan, Italy
| | - Nabeel Bardeesy
- Cancer Center, Center for Regenerative Medicine, and Department of Molecular Biology, Massachusetts General Hospital, Harvard University, Boston, Massachusetts
| | - Vincenzo Mazzaferro
- Gastrointestinal Surgery and Liver Transplantation Unit, Department of Surgery, National Cancer Institute IRCCS Foundation, Milan, Italy
| | - Josep M Llovet
- Liver Cancer Translational Research Laboratory, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, CIBERehd, Universitat de Barcelona, Barcelona, Catalonia, Spain. Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York. Institució Catalana de Recerca i Estudis Avançats, Barcelona, Catalonia, Spain.
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