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Kim Y, Song J, Kim N, Sim T. Recent progress in emerging molecular targeted therapies for intrahepatic cholangiocarcinoma. RSC Med Chem 2025:d4md00881b. [PMID: 39925737 PMCID: PMC11800140 DOI: 10.1039/d4md00881b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Accepted: 01/11/2025] [Indexed: 02/11/2025] Open
Abstract
Cholangiocarcinoma (CCA) is a diverse group of epithelial malignant tumors arising from the biliary tract, characterized by high molecular heterogeneity. It is classified into intrahepatic (iCCA) and extrahepatic CCA (eCCA) based on the location of the primary tumor. CCA accounts for approximately 15% of all primary liver cancers, with iCCA comprising 10-20% of all CCAs. iCCA is especially known for its characteristic aggressiveness and refractoriness, leading to poor prognosis. Despite the increasing global incidence and mortality rates, surgery remains the only available standard treatment approach for a subset (25%) of patients with early-stage, resectable iCCA. The paucity of effective systemic medical therapies restricts therapeutic options for patients with advanced or metastatic iCCA. In the past decade, advances in the understanding of the molecular complexity of these tumors have provided fruitful insights for the identification of promising new druggable targets and the development of feasible therapeutic strategies that may improve treatment outcomes for patients with iCCA. In this review, we aim to highlight critical up-to-date studies and medicinal chemistry aspects, focusing on novel targeted approaches utilizing promising candidates for molecular targeted therapy in iCCA. These candidates include aberrations in isocitrate dehydrogenase (IDH) 1/2, fibroblast growth factor receptor (FGFR), B-Raf proto-oncogene (BRAF), neurotrophic tyrosine receptor kinase (NTRK), human epidermal growth factor receptor 2 (HER2), and programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1). Furthermore, this review provides an overview of potential inhibitors aimed at overcoming acquired drug resistance in these actionable targets for iCCA.
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Affiliation(s)
- Younghoon Kim
- KU-KIST Graduate School of Converging Science and Technology, Korea University 145 Anam-ro, Seongbuk-gu Seoul 02841 Korea
- Department of Biomedical Sciences, Yonsei University College of Medicine 50 Yonsei-ro, Seodaemun-gu Seoul 03722 Republic of Korea +822 2228 0797
- Clinical Candidate Discovery & Development Institute, Yonsei University College of Medicine Seoul Korea
| | - Jaewon Song
- Graduate School of Clinical Drug Discovery & Development, Yonsei University College of Medicine 50 Yonsei-ro, Seodaemun-gu Seoul 03722 Republic of Korea
| | - Namkyoung Kim
- Department of Biomedical Sciences, Yonsei University College of Medicine 50 Yonsei-ro, Seodaemun-gu Seoul 03722 Republic of Korea +822 2228 0797
| | - Taebo Sim
- KU-KIST Graduate School of Converging Science and Technology, Korea University 145 Anam-ro, Seongbuk-gu Seoul 02841 Korea
- Department of Biomedical Sciences, Yonsei University College of Medicine 50 Yonsei-ro, Seodaemun-gu Seoul 03722 Republic of Korea +822 2228 0797
- Clinical Candidate Discovery & Development Institute, Yonsei University College of Medicine Seoul Korea
- Graduate School of Clinical Drug Discovery & Development, Yonsei University College of Medicine 50 Yonsei-ro, Seodaemun-gu Seoul 03722 Republic of Korea
- Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine 50 Yonsei-ro, Seodaemun-gu Seoul 03722 Republic of Korea
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Bai M, Jiang N, Fu W, Huang C, Tian L, Mi N, Gao L, Ma H, Lu Y, Cao J, Zhang C, Yue P, Zhang Y, Lin Y, Meng W, Li X. Establishment and characterization of a novel hilar cholangiocarcinoma cell line, CBC3T-1. Hum Cell 2024; 37:364-375. [PMID: 37966669 PMCID: PMC10764469 DOI: 10.1007/s13577-023-01003-4] [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: 09/11/2023] [Accepted: 10/24/2023] [Indexed: 11/16/2023]
Abstract
Cholangiocarcinoma (CCA) is a group of malignant heterogeneous cancer arising from the biliary tree. The tumor is characterized by insidious onset, high degree of malignancy, poor prognosis, and high recurrence rate. Immortalized cancer cell lines are the best and easiest models for in vitro cancer research. Here, we established a naturally immortalized highly tumorigenic hilar cholangiocarcinoma (hCCA) cell line, CBC3T-1. The CBC3T-1 cell line was cultured for over 60 passages. Thorough analysis showed that CBC3T-1 cells share characteristics similar to original tumor cells from patients with cholangiocarcinoma and display a stable phenotype, including features of epithelial origin, stem cell-like properties, as well as a high invasive and migratory capability and tumorigenicity in mice. Furthermore, this cell line showed the best sensitivity to paclitaxel, followed by gemcitabine. RNA sequencing and whole‑exome sequencing showed that cancer-associated pathways and somatic mutations played a dominant role in the development of CCA. We established and characterized a new hCCA cell line, CBC3T-1, which contributes to a better understanding of bile duct cancer, and can be used to study tumorigenesis and progression and the role of anticancer drugs.
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Affiliation(s)
- Mingzhen Bai
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Ningzu Jiang
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Wenkang Fu
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Chongfei Huang
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Liang Tian
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Ningning Mi
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Long Gao
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Haidong Ma
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Yawen Lu
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Jie Cao
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Chao Zhang
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Ping Yue
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730030, Gansu, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Yong Zhang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Yanyan Lin
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, 730030, Gansu, China.
| | - Wenbo Meng
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, 730030, Gansu, China.
- Gansu Province Key Laboratory of Biological Therapy and Regenerative Medicine Transformation, Lanzhou, 730030, Gansu, China.
| | - Xun Li
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, 730030, Gansu, China
- Gansu Province Key Laboratory of Biological Therapy and Regenerative Medicine Transformation, Lanzhou, 730030, Gansu, China
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Cai X, Tacke F, Guillot A, Liu H. Cholangiokines: undervalued modulators in the hepatic microenvironment. Front Immunol 2023; 14:1192840. [PMID: 37261338 PMCID: PMC10229055 DOI: 10.3389/fimmu.2023.1192840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 05/02/2023] [Indexed: 06/02/2023] Open
Abstract
The biliary epithelial cells, also known as cholangiocytes, line the intra- and extrahepatic bile ducts, forming a barrier between intra- and extra-ductal environments. Cholangiocytes are mostly known to modulate bile composition and transportation. In hepatobiliary diseases, bile duct injury leads to drastic alterations in cholangiocyte phenotypes and their release of soluble mediators, which can vary depending on the original insult and cellular states (quiescence, senescence, or proliferation). The cholangiocyte-secreted cytokines (also termed cholangiokines) drive ductular cell proliferation, portal inflammation and fibrosis, and carcinogenesis. Hence, despite the previous consensus that cholangiocytes are bystanders in liver diseases, their diverse secretome plays critical roles in modulating the intrahepatic microenvironment. This review summarizes recent insights into the cholangiokines under both physiological and pathological conditions, especially as they occur during liver injury-regeneration, inflammation, fibrosis and malignant transformation processes.
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Affiliation(s)
- Xiurong Cai
- Department of Hematology, Oncology and Tumor Immunology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany
| | - Adrien Guillot
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany
| | - Hanyang Liu
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany
- Center of Gastrointestinal Diseases, Changzhou Second People's Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou, China
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Tagliaferri AR, Ansari N, Cavanagh Y. A Unique Case of Gallbladder Agenesis and Cholangiocarcinoma. Cureus 2023; 15:e35224. [PMID: 36968855 PMCID: PMC10032556 DOI: 10.7759/cureus.35224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/18/2023] [Indexed: 02/22/2023] Open
Abstract
Gallbladder agenesis is a rare congenital anomaly of the biliary tract, due to failure of the gallbladder and cystic duct budding off of the common bile duct during fetal development. Cholangiocarcinoma (CCA) is a malignant tumor arising from the biliary ducts in patients with underlying chronic biliary tract inflammation, primary sclerosing cholangitis, or other diseases. Although few studies have reported cases of cholelithiasis in patients with congenital gallbladder agenesis, there is only one other known case of concomitant cholangiocarcinoma and congenital gallbladder agenesis. Herein we present a case of recurrent gallstones in a male, diagnosed with gallbladder agenesis intraoperatively and with pathology consistent with cholangiocarcinoma.
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Chen J, Jin H, Zhou H, Liu K. Effects of Metformin on Risk and Prognosis of Biliary Tract Cancer: A Systematic Review and Meta-Analysis. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:298. [PMID: 36837499 PMCID: PMC9967261 DOI: 10.3390/medicina59020298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Revised: 01/25/2023] [Accepted: 02/03/2023] [Indexed: 02/09/2023]
Abstract
Background and Objectives: Metformin has been found to potentially reduce the risk and improve the prognosis of a variety of tumors, but these findings remain controversial in biliary tract cancer (BTC). Therefore, this systematic review and meta-analysis was conducted to investigate the association between metformin and BTC. Materials and Methods: Two independent researchers comprehensively searched PubMed, Embase, the Cochrane Library, and Web of Science for eligible studies published from their inception to 31 March 2022. Comparisons of risk, overall survival (OS), and disease-free survival (DFS) for patients with BTC were selected as the endpoints of interest and pooled by random or fixed-effects models. Results: Eleven studies with a total of 24,788,738 participants were eligible for this analysis. The overall pooled effects showed no significant differences in biliary tract cancer risk (hazard ratio (HR) = 0.82, 95% confidence interval (CI): 0.50-1.35, p = 0.436), OS (HR = 0.88, 95% CI: 0.74-1.04, p = 0.135), or DFS (HR = 1.03, 95% CI: 0.79-1.34, p = 0.829) between metformin users and non-users. When restricting participants to those with diabetes, a similar negative result was found, demonstrating that metformin use was not significantly associated with a lower risk of developing BTC compared with a lack of metformin use (HR = 0.65, 95% CI: 0.39-1.07, p = 0.089); notably, the included studies exhibited significant heterogeneity in the selection of participants and the definition of metformin users. Conclusions: Metformin may not be able to reduce the risk of BTC and improve prognosis in certain populations. Based on the limited quantity and quality of the included studies, the present results should be interpreted within their limitations, and further studies are warranted to determine the optimal timing, dose, duration, and scenario of metformin administration.
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Affiliation(s)
| | | | | | - Kai Liu
- Department of Hepatobiliary and Pancreatic Surgery II, General Surgery Center, The First Hospital of Jilin University, Changchun 130021, China
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Yamashita M, Adachi T, Ono S, Yoshino K, Imamura H, Matsushima H, Tanaka T, Kosaka T, Soyama A, Hidaka M, Kanetaka K, Eguchi S. Helicobacter bilis infection induces oxidative stress in and enhances the proliferation of human cholangiocytes. Helicobacter 2022; 27:e12908. [PMID: 35661483 DOI: 10.1111/hel.12908] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 05/02/2022] [Accepted: 05/17/2022] [Indexed: 12/26/2022]
Abstract
BACKGROUND Helicobacter bilis, an enterohepatic Helicobacter species, represents a carcinogenic risk factor for cholangiocytes owing to the prevalence of infections in patients with biliary tract cancer, cholecystitis, and pancreaticobiliary maljunction. However, the effect of H. bilis infection on cholangiocytes and the process and mechanism of carcinogenesis are not known. We aimed to determine the effects of H. bilis on cholangiocytes, focusing on inflammation and oxidative stress. MATERIALS AND METHODS Helicobacter bilis and MMNK-1 cells were cocultured for 24 h and inflammatory cytokine secretion was evaluated. Furthermore, MMNK-1 cell proliferation, intracellular reactive oxidant species (ROS) production, and DNA damage caused by ROS were investigated. All factors were compared with and without H. bilis infection. RESULTS Interleukin (IL)-6 and IL-8 secretion were significantly increased in MMNK-1 cocultures with H. bilis (IL-6, 24.3 ± 12.2 vs. 271.1 ± 286.4 pg/ml; IL-8, 167.6 ± 78.7 vs. 1085.1 ± 1047.1 pg/ml, p < .05). MMNK-1 proliferation was also significantly higher in H. bilis cocultures (1.05 ± 0.02 vs. 1.00-fold, respectively; p < .05). Coculturing enhanced the production of ROS in MMNK-1 cells depending on the cell concentration of H. bilis (1.0 vs. 1.17 ± 0.06, p < .05); however, DNA injury was not observed in cocultures with H. bilis (5.35 ± 0.87 vs. 6.08 ± 0.55 pg/μl, p = .06). CONCLUSIONS Helicobacter bilis infection induced ROS production in and enhanced the proliferation of cholangiocytes.
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Affiliation(s)
- Mampei Yamashita
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Tomohiko Adachi
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Shinichiro Ono
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Kyohei Yoshino
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Hajime Imamura
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Hajime Matsushima
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Takayuki Tanaka
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Taichiro Kosaka
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Akihiko Soyama
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Masaaki Hidaka
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Kengo Kanetaka
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Susumu Eguchi
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
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Trifylli EM, Koustas E, Papadopoulos N, Sarantis P, Aloizos G, Damaskos C, Garmpis N, Garmpi A, Karamouzis MV. An Insight into the Novel Immunotherapy and Targeted Therapeutic Strategies for Hepatocellular Carcinoma and Cholangiocarcinoma. Life (Basel) 2022; 12:life12050665. [PMID: 35629333 PMCID: PMC9146702 DOI: 10.3390/life12050665] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 04/28/2022] [Accepted: 04/29/2022] [Indexed: 02/05/2023] Open
Abstract
Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) constitute highly malignant forms of primary liver cancers. Hepatocellular and bile duct carcinogenesis is a multiplex process, caused by various genetic and epigenetic alterations, the influence of environmental factors, as well as the implication of the gut microbiome, which was undervalued in the previous years. The molecular and immunological analysis of the above malignancies, as well as the identification of the crucial role of intestinal microbiota for hepatic and biliary pathogenesis, opened the horizon for novel therapeutic strategies, such as immunotherapy, and enhanced the overall survival of cancer patients. Some of the immunotherapy strategies that are either clinically applied or under pre-clinical studies include monoclonal antibodies, immune checkpoint blockade, cancer vaccines, as well as the utilization of oncolytic viral vectors and Chimeric antigen, receptor-engineered T (CAR-T) cell therapy. In this current review, we will shed light on the recent therapeutic modalities for the above primary liver cancers, as well as on the methods for the enhancement and optimization of anti-tumor immunity.
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Affiliation(s)
- Eleni-Myrto Trifylli
- 1st Department of Internal Medicine, 417 Army Share Fund Hospital, 11521 Athens, Greece; (E.K.); (N.P.); (G.A.)
- Division of Molecular Oncology, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.S.); (M.V.K.)
- Correspondence:
| | - Evangelos Koustas
- 1st Department of Internal Medicine, 417 Army Share Fund Hospital, 11521 Athens, Greece; (E.K.); (N.P.); (G.A.)
- Division of Molecular Oncology, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.S.); (M.V.K.)
| | - Nikolaos Papadopoulos
- 1st Department of Internal Medicine, 417 Army Share Fund Hospital, 11521 Athens, Greece; (E.K.); (N.P.); (G.A.)
| | - Panagiotis Sarantis
- Division of Molecular Oncology, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.S.); (M.V.K.)
| | - Georgios Aloizos
- 1st Department of Internal Medicine, 417 Army Share Fund Hospital, 11521 Athens, Greece; (E.K.); (N.P.); (G.A.)
| | - Christos Damaskos
- N.S. Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
- Renal Transplantation Unit, Laiko General Hospital, 11527 Athens, Greece
| | - Nikolaos Garmpis
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11572 Athens, Greece;
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Anna Garmpi
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Michalis V. Karamouzis
- Division of Molecular Oncology, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.S.); (M.V.K.)
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Cadamuro M, Strazzabosco M. Inflammatory pathways and cholangiocarcinoma risk mechanisms and prevention. Adv Cancer Res 2022; 156:39-73. [PMID: 35961707 PMCID: PMC10916841 DOI: 10.1016/bs.acr.2022.02.001] [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] [Indexed: 11/19/2022]
Abstract
Cholangiocarcinoma (CCA), a neoplasm burdened by a poor prognosis and currently lacking adequate therapeutic treatments, can originate at different levels of the biliary tree, in the intrahepatic, hilar, or extrahepatic area. The main risk factors for the development of CCA are the presence of chronic cholangiopathies of various etiology. To date, the most studied prodromal diseases of CCA are primary sclerosing cholangitis, Caroli's disease and fluke infestations, but other conditions, such as metabolic syndrome, nonalcoholic fatty liver disease and obesity, are emerging as associated with an increased risk of CCA development. In this review, we focused on the analysis of the pro-inflammatory mechanisms that induce the development of CCA and on the role of cells of the immune response in cholangiocarcinogenesis. In very recent times, these cellular mechanisms have been the subject of emerging studies aimed at verifying how the modulation of the inflammatory and immunological responses can have a therapeutic significance and how these can be used as therapeutic targets.
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Affiliation(s)
| | - Mario Strazzabosco
- Liver Center, Department of Internal Medicine, Yale University, New Haven, CT, United States.
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Prasopdee S, Yingchutrakul Y, Roytrakul S, Pholhelm M, Phanaksri T, Kunjantarachot A, Kulsantiwong J, Butthongkomvong K, Tesana S, Sathavornmanee T, Thitapakorn V. Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta as a potential biomarker for Opisthorchis viverrini infection and cholangiocarcinoma. Parasitology 2022; 149:171-180. [PMID: 35234600 PMCID: PMC11010463 DOI: 10.1017/s0031182021001694] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
The human liver fluke Opisthorchis viverrini (Ov), the primary risk factor for cholangiocarcinoma (CHCA), is a parasite endemic to southeast Asian countries. With no effective treatments for CHCA currently available, early diagnosis and treatment of Ov infection remains the only practical method for the prevention of CHCA. In this study, plasma phosphoproteomes of patients in the non-Ov infection, non-cholangiocarcinoma subject group (non-OVCCA), the asymptomatic Ov infected group (OV), and the CHCA group (CCA), were investigated to identify potential biomarkers for Ov infection and CHCA. The AKT signalling pathway was found to be up-regulated. Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform (PIK3CB), an upstream signalling molecule, was selected as a potential biomarker and evaluated using indirect enzyme-linked immunosorbent assay (ELISA). Results demonstrated evidence that levels of PIK3CB in both the OV group and CCA group was statistically different compared to the non-OVCCA group (P < 0.01). However, the levels of PIK3CB between the OV group and the CCA group were found not to be statistically different. Sensitivity and specificity for OV using OD450 cut-off at >1.570 was 76 and 72%, respectively. For CCA, sensitivity and specificity using OD450 cut-off at >1.398 was 68 and 76%, respectively. Application of indirect ELISA detecting plasma PIK3CB will be of great benefit for screening of opisthorchiasis and CHCA.
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Affiliation(s)
- Sattrachai Prasopdee
- Thammasat University Research Unit in Opisthorchiasis, Cholangiocarcinoma, and Neglected Parasitic Diseases, Thammasat University, Pathum Thani, 12120, Thailand
- Chulabhorn International College of Medicine, Thammasat University, Pathum Thani, 12120, Thailand
| | - Yodying Yingchutrakul
- Proteomics Research Team, National Omics Center, NSTDA, Pathum Thani, 12120, Thailand
| | - Sittiruk Roytrakul
- Proteomics Research Laboratory, National Center for Genetic Engineering and Biotechnology (BIOTEC), NSTDA, Pathum Thani, 12120, Thailand
| | - Montinee Pholhelm
- Chulabhorn International College of Medicine, Thammasat University, Pathum Thani, 12120, Thailand
| | - Teva Phanaksri
- Chulabhorn International College of Medicine, Thammasat University, Pathum Thani, 12120, Thailand
| | - Anthicha Kunjantarachot
- Chulabhorn International College of Medicine, Thammasat University, Pathum Thani, 12120, Thailand
| | | | | | - Smarn Tesana
- Chulabhorn International College of Medicine, Thammasat University, Pathum Thani, 12120, Thailand
| | | | - Veerachai Thitapakorn
- Thammasat University Research Unit in Opisthorchiasis, Cholangiocarcinoma, and Neglected Parasitic Diseases, Thammasat University, Pathum Thani, 12120, Thailand
- Chulabhorn International College of Medicine, Thammasat University, Pathum Thani, 12120, Thailand
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Intrahepatic Cholangiocarcinoma: A Summative Review of Biomarkers and Targeted Therapies. Cancers (Basel) 2021; 13:cancers13205169. [PMID: 34680318 PMCID: PMC8533913 DOI: 10.3390/cancers13205169] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 10/08/2021] [Accepted: 10/14/2021] [Indexed: 01/07/2023] Open
Abstract
Simple Summary Intrahepatic cholangiocarcinoma is the second most common primary liver malignancy. Among patients with operable disease, surgical resection is the cornerstone of therapy. Among the majority of patients who present with advanced disease treatment, systemic or targeted therapy is indicated. Recent advancements have provided more novel therapeutic approaches to a subset of patients with intrahepatic cholangiocarcinoma. Abstract Although rare, intrahepatic cholangiocarcinoma (ICC) is the second most common primary hepatic malignancy and the incidence of ICC has increased 14% per year in recent decades. Treatment of ICC remains difficult as most people present with advanced disease not amenable to curative-intent surgical resection. Even among patients with operable disease, margin-negative surgical resection can be difficult to achieve and the incidence of recurrence remains high. As such, there has been considerable interest in systemic chemotherapy and targeted therapy for ICC. Over the last decade, the understanding of the molecular and genetic foundations of ICC has reshaped treatment approaches and strategies. Next-generation sequencing has revealed that most ICC tumors have at least one targetable mutation. These advancements have led to multiple clinical trials to examine the safety and efficacy of novel therapeutics that target tumor-specific molecular and genetic aberrations. While these advancements have demonstrated survival benefit in early phase clinical trials, continued investigation in randomized larger-scale trials is needed to further define the potential clinical impact of such therapy.
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11
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Koustas E, Trifylli EM, Sarantis P, Papavassiliou AG, Karamouzis MV. Role of autophagy in cholangiocarcinoma: An autophagy-based treatment strategy. World J Gastrointest Oncol 2021; 13:1229-1243. [PMID: 34721764 PMCID: PMC8529918 DOI: 10.4251/wjgo.v13.i10.1229] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 04/28/2021] [Accepted: 08/03/2021] [Indexed: 02/06/2023] Open
Abstract
Cholangiocarcinomas (CCAs) are diverse biliary epithelial tumours involving the intrahepatic, perihilar and distal parts of the biliary tree. The three entirely variable entities have distinct epidemiology, molecular characteristics, prognosis and strategy for clinical management. However, many cholangiocarcinoma tumor-cells appear to be resistant to current chemotherapeutic agents. The role of autophagy and the therapeutic value of autophagy-based therapy are largely unknown in CCA. The multistep nature of autophagy offers a plethora of regulation points, which are prone to be deregulated and cause different human diseases, including cancer. However, it offers multiple targetable points for designing novel therapeutic strategies. Tumor cells have evolved to use autophagy as an adaptive mechanism for survival under stressful conditions such as energy imbalance and hypoxic region of tumors within the tumor microenvironment, but also to increase invasiveness and resistance to chemotherapy. The purpose of this review is to summarize the current knowledge regarding the interplay between autophagy and cholangiocarcinogenesis, together with some preclinical studies with agents that modulate autophagy in order to induce tumor cell death. Altogether, a combinatorial strategy, which comprises the current anti-cancer agents and autophagy modulators, would represent a positive CCA patient approach.
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Affiliation(s)
- Evangelos Koustas
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Eleni-Myrto Trifylli
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Panagiotis Sarantis
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Athanasios G Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Michalis V Karamouzis
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
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Huang J, Yang H, Wang M, Zhao X, Shao S, Zhang F, Que R, Hu Q, Liang T. Gallbladder Adenosquamous Cancer with Situs Inversus Totalis: A Case Report and Literature Review. Onco Targets Ther 2021; 14:4299-4304. [PMID: 34349522 PMCID: PMC8327361 DOI: 10.2147/ott.s319030] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Accepted: 07/13/2021] [Indexed: 12/11/2022] Open
Abstract
Background Situs inversus totalis (SIT) is a rare genetic congenital disease, characterized with complete right-to-left inversion of all the internal organs. We herein describe a meaningful case which was diagnosed as gallbladder adenosquamous carcinoma, a rare histology type of gallbladder cancer, with SIT. Case Presentation A 59-year-old Chinese woman was admitted for persistent epigastric distention and intermittent abdominal pain. The abdominal CT scan revealed a huge mass at the gallbladder bottom, involving the adjacent transverse colon and liver. En-bloc radical resection of the gallbladder cancer, including partial colectomy and hepatectomy with regional node dissection, followed by colocolostomy and Roux-en-Y choledochojejunostomy, was successfully performed. Pathology analysis indicated an adenosquamous carcinoma with positive adenocarcinoma markers (CK7, CK19) and squamous carcinoma markers (CK5/6, P63). Conclusion The SIT anomaly might increase the risk of malignancies by sharing genome mutations, suggesting the importance of surveillance in the SIT settings.
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Affiliation(s)
- Junming Huang
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, People's Republic of China
| | - Hanjin Yang
- Department of Pathology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, People's Republic of China
| | - Meng Wang
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, People's Republic of China
| | - Xinyu Zhao
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, People's Republic of China
| | - Shiyi Shao
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, People's Republic of China
| | - Fu Zhang
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, People's Republic of China
| | - Risheng Que
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, People's Republic of China
| | - Qida Hu
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, People's Republic of China
| | - Tingbo Liang
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, People's Republic of China
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13
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Kiya Y, Nagakawa Y, Takishita C, Osakabe H, Nishino H, Akashi M, Yamaguchi H, Nagao T, Oono R, Katsumata K, Tsuchida A. Neuroendocrine carcinoma of the common bile duct associated with congenital bile duct dilatation: a case report. BMC Gastroenterol 2021; 21:257. [PMID: 34118881 PMCID: PMC8196520 DOI: 10.1186/s12876-021-01777-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Accepted: 04/20/2021] [Indexed: 01/03/2023] Open
Abstract
Background Cholangiocarcinoma is frequently observed in patients with congenital bile duct dilatation (CBDD). Most cholangiocarcinomas are adenocarcinomas. Other types, especially neuroendocrine carcinomas (NECs), are rare. To the best of our knowledge, this is the third reported case of an NEC of the common bile duct associated with CBDD and the first to receive adjuvant chemotherapy for advanced disease. Case presentation
A 29-year-old woman presented with upper abdominal pain. Preoperative imaging indicated marked dilatation of the common bile duct and a tumor in the middle portion of the common bile duct. She was suspected of having distal cholangiocarcinoma associated with CBDD and underwent pylorus-preserving pancreaticoduodenectomy. Pathological and immunohistological findings led to a final diagnosis of large-cell NEC (pT3aN1M0 pStageIIB). The postoperative course was uneventful, and she was administered cisplatin and irinotecan every 4 weeks (four cycles) as adjuvant chemotherapy. She has remained recurrence-free for 16 months. Conclusions NEC might be a differential diagnosis in cases of cholangial tumor associated with congenital bile duct dilatation. This presentation is rare and valuable, and to establish better treatment for NEC, further reports are necessary.
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Affiliation(s)
- Yoshitaka Kiya
- Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, 6-7-1 Nishi-shinjuku, Shinjuku- ku, Tokyo, 160-0023, Japan.
| | - Yuichi Nagakawa
- Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, 6-7-1 Nishi-shinjuku, Shinjuku- ku, Tokyo, 160-0023, Japan
| | - Chie Takishita
- Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, 6-7-1 Nishi-shinjuku, Shinjuku- ku, Tokyo, 160-0023, Japan
| | - Hiroaki Osakabe
- Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, 6-7-1 Nishi-shinjuku, Shinjuku- ku, Tokyo, 160-0023, Japan
| | - Hitoe Nishino
- Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, 6-7-1 Nishi-shinjuku, Shinjuku- ku, Tokyo, 160-0023, Japan
| | - Masanori Akashi
- Department of Surgery, Kurume University School of Medicine, 67 Asahicho, 830-0011, Kurume, Fukuoka, Japan
| | - Hiroshi Yamaguchi
- Department of Pathology, Saitama Medical University, 38 Morohongo, Moroyama-machi, Iruma-gun, Saitama, 350-0495, Japan
| | - Toshitaka Nagao
- Department of Anatomical Pathology, Tokyo Medical University, 6-7-1 Nishi-shinjuku, Shinjuku-ku, Tokyo, 160- 0023, Japan
| | - Ryo Oono
- Department of Digestive Surgery, Nitobe Memorial Nakano General Hospital, 4-59-16 Chuo, Nakano-ku, Tokyo, 164-8607, Japan
| | - Kenji Katsumata
- Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, 6-7-1 Nishi-shinjuku, Shinjuku- ku, Tokyo, 160-0023, Japan
| | - Akihiko Tsuchida
- Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, 6-7-1 Nishi-shinjuku, Shinjuku- ku, Tokyo, 160-0023, Japan
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Wnt/β-catenin signaling as an emerging potential key pharmacological target in cholangiocarcinoma. Biosci Rep 2021; 40:222119. [PMID: 32140709 PMCID: PMC7953494 DOI: 10.1042/bsr20193353] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 01/07/2020] [Accepted: 01/31/2020] [Indexed: 02/06/2023] Open
Abstract
Cholangiocarcinoma (CCA) is a fatal malignant tumor of biliary epithelial cells involving intra- or extra-hepatic bile ducts. The prognosis of CCA is generally poor due to its diagnosis at the late stages. The currently employed chemotherapeutic agents do not increase the survival rate in patients with unresectable CCA. Accordingly, there is a need to identify new therapeutic agents for the effective management of intra- and extra-hepatic CCA. Clinical as well as preclinical studies have suggested the key role of the activation of Wnt/β-catenin signaling pathway in the induction and progression of CCA. There is an up-regulation of different Wnt ligands including Wnt2, Wnt3, Wnt5, Wnt7 and Wnt10 along with redistribution of β-catenin (more expression in the nucleus and lesser on the cell surface due to nuclear translocation of β-catenin) in different types of malignant biliary tumors. Apart from the role of this pathway in the induction and progression of CCA, this pathway is also involved in inducing multidrug resistance by inducing the expression of P-glycoprotein efflux pump on the cancer cells. These deleterious effects of Wnt/β-catenin signaling are mediated in association with other signaling pathways involving microRNAs (miRNAs), PI3K/AKT/PTEN/GSK-3β, retinoic acid receptors (RARs), dickkopf-1 (DKK1), protein kinase A regulatory subunit 1 α (PRKAR1A/PKAI), (SLAP), liver kinase B1 (LKB1) and CXCR4. The selective inhibitors of Wnt/β-catenin signaling may be potentially employed to overcome multidrug-resistant, fatal CCA. The present review discusses the role of Wnt/β-catenin along with its relation with other signaling pathways in the induction and progression of CCA.
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15
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Kontis EA. Biology of Liver Tumors and Outcomes of Liver Surgery. ANESTHESIA FOR HEPATICO-PANCREATIC-BILIARY SURGERY AND TRANSPLANTATION 2021:303-313. [DOI: 10.1007/978-3-030-51331-3_18] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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16
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Tseng CH. Metformin and Biliary Tract Cancer in Patients With Type 2 Diabetes. Front Oncol 2020; 10:587666. [PMID: 33194743 PMCID: PMC7653020 DOI: 10.3389/fonc.2020.587666] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 10/07/2020] [Indexed: 12/13/2022] Open
Abstract
Aim This retrospective cohort study evaluated whether metformin use in patients with type 2 diabetes mellitus might reduce the risk of biliary tract cancer (BTC); and explored whether metformin use might affect the overall survival in patients who developed BTC. Methods New-onset type 2 diabetes patients aged 25–75 years during 1999–2005 were enrolled from the Taiwan’s National Health Insurance and followed up until December 31, 2011. A total of 287,995 ever users and 16,229 never users were identified (unmatched original cohort) and a 1:1 matched pairs of 16,229 ever users and 16,229 never users based on propensity score (PS) were created (matched cohort). Hazard ratios were estimated by three Cox regression models: 1) adjusted for PS; 2) incorporated with the inverse probability of treatment weighting using PS; and 3) all covariates treated as independent variables. Overall survival was compared between ever users and never users of metformin who developed BTC. Results In the unmatched cohort, 73 never users and 523 ever users developed BTC, with respective incidence of 100.36 and 38.06 per 100,000 person-years. An overall risk reduction was observed in metformin users in all three regression models with respective hazard ratio (95% confidence interval) of 0.442 (0.344-0.568), 0.377 (0.295-0.481), and 0.477 (0.370-0.615). The tertile analyses showed a dose-response pattern with a neutral effect in the first tertile when metformin use was <2 years and a significant risk reduction in the second and third tertiles. Findings in the matched cohort were consistent with those observed in the unmatched cohort. The overall survival did not differ significantly between ever and never users of metformin among patients who developed BTC. Conclusions Metformin significantly reduces the overall risk of BTC by 50%–60%. A dose-response effect is observed and users of approximately 2 years show significantly reduced risk. However, metformin does not affect the overall survival in patients with BTC.
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Affiliation(s)
- Chin-Hsiao Tseng
- Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.,Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Division of Environmental Health and Occupational Medicine of the National Health Research Institutes, Zhunan, Taiwan
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17
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Uno S, Kataoka TR, Okajima H, Taura K, Sakurai T, Haga H. Perihilar cholangiocarcinoma in an explanted liver after Kasai operation for biliary atresia: A case report and literature review. Pathol Int 2020; 70:888-892. [PMID: 32936992 DOI: 10.1111/pin.13016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 08/11/2020] [Accepted: 08/17/2020] [Indexed: 12/24/2022]
Abstract
Kasai operation is widely performed for biliary atresia (BA), as it improves the prognosis. Biliary tract cancer has rarely been reported as a complication after Kasai operation. A 17-year-old man underwent liver transplantation for progressive jaundice and liver dysfunction after Kasai operation for BA. A macroscopic examination of the explanted liver revealed a 3.6-cm-diameter mass in the hilus of the explanted liver. The tumor consisted of an atypical proliferation of glandular cells in the collagenous stroma. The differential diagnosis included a florid ductular reaction and primary adenocarcinoma. Immunohistochemistry revealed that the glandular cells were diffusely positive for IGF2BP3 and S100P, but negative for CDX2. A diagnosis of extrahepatic cholangiocarcinoma arising from the liver hilus was made. To our knowledge, this is the third case of perihilar cholangiocarcinoma after Kasai operation for BA. The previously reported cases had a poor prognosis, but the current case did not recur during a 15-year follow-up. Cholangiocarcinoma and hepatocellular carcinoma can occur as a late complication of BA after Kasai operation, and early detection and liver transplantation may improve the prognosis.
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Affiliation(s)
- Shunsuke Uno
- Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan
| | - Tatsuki R Kataoka
- Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan
| | - Hideaki Okajima
- Department of Pediatric Surgery, Kanazawa Medical University, Ishikawa, Japan.,Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kojiro Taura
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Takaki Sakurai
- Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan.,Department of Diagnostic Pathology, Kansai Electric Power Hospital, Osaka, Japan
| | - Hironori Haga
- Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan
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18
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Morita T, Matsumori T, Uza N. Gallbladder carcinoma associated with unique distribution of intraductal papillary neoplasm of bile duct accompanied by pancreaticobiliary maljunction. Dig Endosc 2020; 32:432. [PMID: 31667882 DOI: 10.1111/den.13574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Toshihiro Morita
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Tomoaki Matsumori
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Norimitsu Uza
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
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19
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Lee H, Lee HK, Min SK, Lee WH. 16S rDNA microbiome composition pattern analysis as a diagnostic biomarker for biliary tract cancer. World J Surg Oncol 2020; 18:19. [PMID: 31980025 PMCID: PMC6982396 DOI: 10.1186/s12957-020-1793-3] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Accepted: 01/16/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The aim of this study is to investigate the composition of microbiota in biliary tract cancer patients and healthy adults by metagenome analysis and evaluate its potential values as biomarkers for biliary tract cancer. METHODS Patients who were diagnosed with biliary tract cancer or benign inflammation were enrolled in this study. The control group consisted of healthy adults who presented with no history of significant medical issues. We isolated bacteria-derived extracellular vesicles in the plasma. The microbiome composition was investigated with 16S rDNA metagenome analysis. We evaluated each microbiome to ensure suitability for the biliary tract cancer prediction model. RESULTS A total of 155 patients were included in this study: 24 patients with diagnosed biliary tract cancers, 43 diagnosed with cholecystitis or cholangitis, and 88 healthy adults. The microbiome composition pattern of the biliary tract cancer differed from the microbiome composition pattern seen in healthy adult group in beta diversity analysis. The percent composition of microbiota was found to be different from the phylum to genus level. Differences in the composition of the Bifidobacteriaceae and Pseudomonaceae families and Corynebacteriaceae Corynebacterium, Oxalobacteraceae Ralstonia and Comamonadaceae Comamonas species may be used to develop predictive models for biliary tract cancer. CONCLUSION Biliary tract cancer patients have altered microbiome composition, which represents a promising biomarker to differentiate malignant biliary tract disease from normal control group.
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Affiliation(s)
- Huisong Lee
- Department of Surgery, Ewha Womans University College of Medicine, 1071 Anyangcheon-ro, Yangcheon-gu, Seoul, 07985, South Korea
| | - Hyeon Kook Lee
- Department of Surgery, Ewha Womans University College of Medicine, 1071 Anyangcheon-ro, Yangcheon-gu, Seoul, 07985, South Korea.
| | - Seog Ki Min
- Department of Surgery, Ewha Womans University College of Medicine, 1071 Anyangcheon-ro, Yangcheon-gu, Seoul, 07985, South Korea
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Narahara C, Saeheng T, Chaijaroenkul W, Dumre SP, Na-Bangchang K, Karbwang J. β-Eudesmol induces the expression of apoptosis pathway proteins in cholangiocarcinoma cell lines. JOURNAL OF RESEARCH IN MEDICAL SCIENCES 2020; 25:7. [PMID: 32055247 PMCID: PMC7003544 DOI: 10.4103/jrms.jrms_291_19] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Revised: 08/25/2019] [Accepted: 10/23/2019] [Indexed: 12/23/2022]
Abstract
Background: Cholangiocarcinoma (CCA) is a neglected disease prevalent in developing countries with high burden and mortality rate, and there is no effective treatment. We aimed to investigate β-eudesmol molecular target of action in human CCA cell lines using the selected key molecules of apoptotic pathways. Materials and Methods: Two CCA cell lines (HuH28 and HuCCT1) were assessed at different time points after β-eudesmol treatment for mRNA and protein expression profiles of caspase-3, -8, -9, p53, p21, Bcl-2, and Bax by real-time polymerase chain reaction and western blot, respectively. Results: β-eudesmol induced expressions of p21 and p53 in mRNA/protein level in HuH28 and HuCCT1 cells. These CCA cells also expressed caspase-3, -8, -9 and bax (mRNA and/or protein level) among others after β-eudesmol treatment indicating its role in both intrinsic and extrinsic caspase-dependent apoptotic pathways. Conclusion: The study demonstrated that β-eudesmol induced the expression of apoptosis pathway proteins, suggesting its potential role in promoting the caspase-dependent apoptotic pathway, and induction of the cell cycle arrest in CCA cell lines. β-eudesmol can be considered as a potential compound for further investigation as an anti-CCA agent.
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Affiliation(s)
- Chisato Narahara
- Department of Clinical Product Development, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan
| | - Teerachat Saeheng
- Department of Clinical Product Development, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan
| | - Wanna Chaijaroenkul
- Graduate Studies, Chulabhorn International College of Medicine, Thammasat University, Pathumthani, Thailand
| | - Shyam Prakash Dumre
- Department of Immunogenetics, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan
| | - Kesara Na-Bangchang
- Graduate Studies, Chulabhorn International College of Medicine, Thammasat University, Pathumthani, Thailand.,Center of Excellence in Pharmacology and Molecular Biology of Malaria and Cholangiocarcinoma, Chulabhorn International College of Medicine, Thammasat University, Pathumthani, Thailand
| | - Juntra Karbwang
- Department of Clinical Product Development, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan.,Center of Excellence in Pharmacology and Molecular Biology of Malaria and Cholangiocarcinoma, Chulabhorn International College of Medicine, Thammasat University, Pathumthani, Thailand
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The Diagnostic Yield of Malignancy Comparing Cytology, FISH, and Molecular Analysis of Cell Free Cytology Brush Supernatant in Patients With Biliary Strictures Undergoing Endoscopic Retrograde Cholangiography (ERC): A Prospective Study. J Clin Gastroenterol 2019; 53:686-692. [PMID: 30106834 PMCID: PMC6768606 DOI: 10.1097/mcg.0000000000001118] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
BACKGROUND Routine cytology of biliary stricture brushings obtained during endoscopic retrograde cholangiopancreatography (ERCP) has suboptimal sensitivity for malignancy. We compared the individual and combined ability of cytology, fluorescence in situ hybridization (FISH) analysis and PCR-based mutation profiling (MP) to detect malignancy in standard biliary brushings. METHODS We performed a prospective study of patients undergoing ERCP using histology or 1 year follow-up to determine patient outcomes. MP was performed on free-DNA from biliary brushing specimens using normally discarded supernatant fluid. MP examined KRAS point mutations and tumor suppressor gene associated loss of heterozygosity mutations at 10 genomic loci. FISH examined chromosome specific gains or losses. RESULTS A total of 101 patients were included in final analysis and 69% had malignancy. Cytology had 26% sensitivity and 100% specificity for malignancy. Using either FISH or MP in combination with cytology increased sensitivity to 44% and 56%, respectively. The combination of all 3 tests (cytology, FISH, and MP) had the highest sensitivity for malignancy (66%). There was no difference in the specificity of cytology, FISH or MP testing when examined alone or in combination. MP improved diagnostic yield of each procedure from 22% to 100%; FISH improved yield to 90%. MP detected 21 malignancies beyond that identified by cytology; FISH detected an additional 13. The combination of FISH and MP testing detected an additional 28 malignancies. CONCLUSIONS Both MP and FISH are complimentary molecular tests that can significantly increase detection of biliary malignancies when used in combination with routine cytology of standard biliary brush specimens.
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Wu HJ, Chu PY. Role of Cancer Stem Cells in Cholangiocarcinoma and Therapeutic Implications. Int J Mol Sci 2019; 20:ijms20174154. [PMID: 31450710 PMCID: PMC6747544 DOI: 10.3390/ijms20174154] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 08/12/2019] [Accepted: 08/23/2019] [Indexed: 02/06/2023] Open
Abstract
Cholangiocarcinoma (CCA) is the second most common type of liver cancer, and is highly aggressive with very poor prognosis. CCA is classified into intrahepatic cholangiocarcinoma (iCCA) and extra-hepatic cholangiocarcinoma (eCCA), which is further stratified into perihilar (pCCA) and distal (dCCA). Cancer stem cells (CSCs) are a subpopulation of cancer cells capable of tumor initiation and malignant growth, and are also responsible for chemoresistance. Thus, CSCs play an important role in CCA carcinogenesis. Surface markers such as CD133, CD24, CD44, EpCAM, Sox2, CD49f, and CD117 are important for identifying and isolating CCA CSCs. CSCs are present in the tumor microenvironment (TME), termed ‘CSC niche’, where cellular components and soluble factors interact to promote tumor initiation. Epithelial-to-mesenchymal transition (EMT) is another important mechanism underlying carcinogenesis, involved in the invasiveness, metastasis and chemoresistance of cancer. It has been demonstrated that EMT plays a critical role in generating CSCs. Therapies targeting the surface markers and signaling pathways of CCA CSCs, proteins involved in TME, and immune checkpoint proteins are currently under investigation. Therefore, this review focuses on recent studies on the roles of CSCs in CCA; the possible therapeutic strategies targeting CSCs of CCA are also discussed.
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Affiliation(s)
- Hsing-Ju Wu
- Research Assistant Center, Show Chwan Memorial Hospital, Changhua 500, Taiwan
- Department of Medical Research, Chang Bing Show Chwan Memorial Hospital, Lukang Town, Changhua County 505, Taiwan
| | - Pei-Yi Chu
- Graduate Institute of Biomedical Engineering, National Chung Hsing University, Taichung 402, Taiwan.
- School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City 231, Taiwan.
- Department of Pathology, Show Chwan Memorial Hospital, Changhua 500, Taiwan.
- Department of Health Food, Chung Chou University of Science and Technology, Changhua 510, Taiwan.
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Ursu S, Majid S, Garger C, de Semir D, Bezrookove V, Desprez PY, McAllister S, Soroceanu L, Nosrati M, Yimam K, Hassoun A, Osorio R, Kashani-Sabet M, Dar AA. Novel tumor suppressor role of miRNA-876 in cholangiocarcinoma. Oncogenesis 2019; 8:42. [PMID: 31409772 PMCID: PMC6692334 DOI: 10.1038/s41389-019-0153-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Revised: 04/17/2019] [Accepted: 05/16/2019] [Indexed: 01/06/2023] Open
Abstract
Cholangiocarcinoma (CCA) is a rare, highly invasive malignancy, and its incidence is increasing globally. MicroRNAs (miRNAs) mediate a wide array of cellular and biological processes and are dysregulated in various tumors. The functional and biological roles of miRNAs in CCA have not been fully elucidated. In this study, we show that miR-876 expression levels and copy number are significantly attenuated in the TCGA cohort of CCA tissue samples. TCGA expression data was consistent with the observed substantial decrease in miR-876 expression in patient samples and CCA cell lines. In-silico algorithm databases revealed BCL-XL as a potential target of miR-876. We observed miR-876 expression to be downregulated, whereas, BCL-XL upregulated in CCA cell lines. BCL-XL was identified as a direct functional target of miR-876 in CCA. miR-876-mediated reduction of BCL-XL regulated cell survival, induced apoptosis and caspase 3/7 expression in CCA. BCL-XL overexpression reversed the miR-876 mediated effect on CCA cell growth and apoptosis. Stable overexpression of miR-876 produced potent tumor suppressor activity and in vivo tumor cell growth reduction. Overexpression of miR-876 in a patient-derived xenograft (PDX) cell line significantly suppressed BCL-XL expression and spheroid formation with a concomitant induction of caspase 3/7 activity and apoptosis. This study demonstrates a novel tumor suppressor role for miR-876 in CCA, identifies BCL-XL as an actionable target, and suggests a potential therapeutic role for miR-876 in CCA.
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Affiliation(s)
- Sarah Ursu
- California Pacific Medical Center Research Institute, 475 Brannan St, Suite 130, San Francisco, CA, 94107, USA
| | - Shahana Majid
- Department of Urology, Veterans Affairs Medical Center and University of California San Francisco, San Francisco, CA, 94121, USA
| | - Caroline Garger
- California Pacific Medical Center Research Institute, 475 Brannan St, Suite 130, San Francisco, CA, 94107, USA
| | - David de Semir
- California Pacific Medical Center Research Institute, 475 Brannan St, Suite 130, San Francisco, CA, 94107, USA
| | - Vladimir Bezrookove
- California Pacific Medical Center Research Institute, 475 Brannan St, Suite 130, San Francisco, CA, 94107, USA
| | - Pierre-Yves Desprez
- California Pacific Medical Center Research Institute, 475 Brannan St, Suite 130, San Francisco, CA, 94107, USA
| | - Sean McAllister
- California Pacific Medical Center Research Institute, 475 Brannan St, Suite 130, San Francisco, CA, 94107, USA
| | - Liliana Soroceanu
- California Pacific Medical Center Research Institute, 475 Brannan St, Suite 130, San Francisco, CA, 94107, USA
| | - Mehdi Nosrati
- California Pacific Medical Center Research Institute, 475 Brannan St, Suite 130, San Francisco, CA, 94107, USA
| | - Kidist Yimam
- California Pacific Medical Center Research Institute, 475 Brannan St, Suite 130, San Francisco, CA, 94107, USA
| | - Assad Hassoun
- California Pacific Medical Center Research Institute, 475 Brannan St, Suite 130, San Francisco, CA, 94107, USA
| | - Robert Osorio
- California Pacific Medical Center Research Institute, 475 Brannan St, Suite 130, San Francisco, CA, 94107, USA
| | - Mohammed Kashani-Sabet
- California Pacific Medical Center Research Institute, 475 Brannan St, Suite 130, San Francisco, CA, 94107, USA
| | - Altaf A Dar
- California Pacific Medical Center Research Institute, 475 Brannan St, Suite 130, San Francisco, CA, 94107, USA.
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Roos E, Soer E, Klompmaker S, Meijer L, Besselink M, Giovannetti E, Heger M, Kazemier G, Klümpen H, Takkenberg R, Wilmink H, Würdinger T, Dijk F, van Gulik T, Verheij J, van de Vijver M. Crossing borders: A systematic review with quantitative analysis of genetic mutations of carcinomas of the biliary tract. Crit Rev Oncol Hematol 2019; 140:8-16. [PMID: 31158800 DOI: 10.1016/j.critrevonc.2019.05.011] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Accepted: 05/21/2019] [Indexed: 12/11/2022] Open
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Won J, Cho Y, Lee D, Jeon BY, Ju JW, Chung S, Pak JH. Clonorchis sinensis excretory-secretory products increase malignant characteristics of cholangiocarcinoma cells in three-dimensional co-culture with biliary ductal plates. PLoS Pathog 2019; 15:e1007818. [PMID: 31121000 PMCID: PMC6550432 DOI: 10.1371/journal.ppat.1007818] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2018] [Revised: 06/05/2019] [Accepted: 05/07/2019] [Indexed: 12/16/2022] Open
Abstract
Clonorchis sinensis is a carcinogenic human liver fluke, prolonged infection which provokes chronic inflammation, epithelial hyperplasia, periductal fibrosis, and even cholangiocarcinoma (CCA). These effects are driven by direct physical damage caused by the worms, as well as chemical irritation from their excretory-secretory products (ESPs) in the bile duct and surrounding liver tissues. We investigated the C. sinensis ESP-mediated malignant features of CCA cells (HuCCT1) in a three-dimensional microfluidic culture model that mimics an in vitro tumor microenvironment. This system consisted of a type I collagen extracellular matrix, applied ESPs, GFP-labeled HuCCT1 cells and quiescent biliary ductal plates formed by normal cholangiocytes (H69 cells). HuCCT1 cells were attracted by a gradient of ESPs in a concentration-dependent manner and migrated in the direction of the ESPs. Meanwhile, single cell invasion by HuCCT1 cells increased independently of the direction of the ESP gradient. ESP treatment resulted in elevated secretion of interleukin-6 (IL-6) and transforming growth factor-beta1 (TGF-β1) by H69 cells and a cadherin switch (decrease in E-cadherin/increase in N-cadherin expression) in HuCCT1 cells, indicating an increase in epithelial-mesenchymal transition-like changes by HuCCT1 cells. Our findings suggest that C. sinensis ESPs promote the progression of CCA in a tumor microenvironment via the interaction between normal cholangiocytes and CCA cells. These observations broaden our understanding of the progression of CCA caused by liver fluke infection and suggest a new approach for the development of chemotherapeutic for this infectious cancer. The oriental liver fluke, Clonorchis sinensis, is a biological carcinogen of humans and is the cause of death of infectious cancer patients in China and Korea. Its chronic infection promotes cholangiocarcinogenesis due to direct contact of host tissues with the worms and their excretory-secretory products (ESPs); however, the specific mechanisms underlying this pathology remain unclear. To assess its contribution to the progression of cholangiocarcinoma (CCA), we developed a 3-dimensional (3D) in vitro culture model that consists of CCA cells (HuCCT1) in direct contact with normal cholangiocytes (H69), which are subsequently exposed to C. sinensis ESPs; therefore, this model represents a C. sinensis-associated CCA microenvironment. Co-cultured HuCCT1 cells exhibited increased motility in response to C. sinensis ESPs, suggesting that this model may recapitulate some aspects of tumor microenvironment complexity. Proinflammatory cytokines such as IL-6 and TGF-β1 secreted by H69 cells exhibited a crosstalk effect regarding the epithelial-mesenchymal transition of HuCCT1 cells, thus, promoting an increase in the metastatic characteristics of CCA cells. Our findings enable an understanding of the mechanisms underlying the etiology of C. sinensis-associated CCA, and, therefore, this approach will contribute to the development of new strategies for the reduction of its high mortality rate.
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Affiliation(s)
- Jihee Won
- School of Mechanical Engineering, Korea University, Seoul, Republic of Korea
| | - Youngkyu Cho
- Department of IT Convergence, Korea University, Seoul, Republic of Korea
| | - Dahyun Lee
- Department of Convergence Medicine, University of Ulsan College of Medicine and Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea
| | - Bo Young Jeon
- Department of Convergence Medicine, University of Ulsan College of Medicine and Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea
| | - Jung-Won Ju
- Division of Vectors & Parasitic Diseases, Korean Centers for Disease Control and Prevention, Osong, Republic of Korea
| | - Seok Chung
- School of Mechanical Engineering, Korea University, Seoul, Republic of Korea
- Department of IT Convergence, Korea University, Seoul, Republic of Korea
- KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, Republic of Korea
- * E-mail: (SC); (JHP)
| | - Jhang Ho Pak
- Department of Convergence Medicine, University of Ulsan College of Medicine and Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea
- * E-mail: (SC); (JHP)
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Tian X, Gu T, Patel S, Bode AM, Lee MH, Dong Z. CRISPR/Cas9 - An evolving biological tool kit for cancer biology and oncology. NPJ Precis Oncol 2019; 3:8. [PMID: 30911676 PMCID: PMC6423228 DOI: 10.1038/s41698-019-0080-7] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Accepted: 01/18/2019] [Indexed: 12/13/2022] Open
Abstract
The development of genetic engineering in the 1970s marked a new frontier in genome-editing technology. Gene-editing technologies have provided a plethora of benefits to the life sciences. The clustered regularly interspaced short palindromic repeats/CRISPR associated protein 9 (CRISPR/ Cas9) system is a versatile technology that provides the ability to add or remove DNA in the genome in a sequence-specific manner. Serious efforts are underway to improve the efficiency of CRISPR/Cas9 targeting and thus reduce off-target effects. Currently, various applications of CRISPR/Cas9 are used in cancer biology and oncology to perform robust site-specific gene editing, thereby becoming more useful for biological and clinical applications. Many variants and applications of CRISPR/Cas9 are being rapidly developed. Experimental approaches that are based on CRISPR technology have created a very promising tool that is inexpensive and simple for developing effective cancer therapeutics. This review discusses diverse applications of CRISPR-based gene-editing tools in oncology and potential future cancer therapies.
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Affiliation(s)
- Xueli Tian
- Basic Medical College, Zhengzhou University, 450001 Zhengzhou, Henan China
- China-US (Henan) Hormel Cancer Institute, No.127, Dongming Road, Jinshui District, 450008 Zhengzhou, Henan China
| | - Tingxuan Gu
- China-US (Henan) Hormel Cancer Institute, No.127, Dongming Road, Jinshui District, 450008 Zhengzhou, Henan China
| | - Satyananda Patel
- China-US (Henan) Hormel Cancer Institute, No.127, Dongming Road, Jinshui District, 450008 Zhengzhou, Henan China
| | - Ann M. Bode
- The Hormel Institute, University of Minnesota, Austin, 55912 USA
| | - Mee-Hyun Lee
- Basic Medical College, Zhengzhou University, 450001 Zhengzhou, Henan China
- China-US (Henan) Hormel Cancer Institute, No.127, Dongming Road, Jinshui District, 450008 Zhengzhou, Henan China
- The Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, China
| | - Zigang Dong
- Basic Medical College, Zhengzhou University, 450001 Zhengzhou, Henan China
- China-US (Henan) Hormel Cancer Institute, No.127, Dongming Road, Jinshui District, 450008 Zhengzhou, Henan China
- The Hormel Institute, University of Minnesota, Austin, 55912 USA
- The Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, China
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Molecular Diagnostics in the Neoplasms of the Pancreas, Liver, Gallbladder, and Extrahepatic Biliary Tract: 2018 Update. Clin Lab Med 2019; 38:367-384. [PMID: 29776636 DOI: 10.1016/j.cll.2018.03.003] [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: 02/07/2023]
Abstract
Pancreatic neoplasms, including ductal adenocarcinoma, solid pseudopapillary neoplasm, pancreatic endocrine neoplasms, acinar cell carcinoma, and pancreatoblastoma, are associated with different genetic abnormalities. Hepatic adenomas with beta-catenin exon 3 mutation are associated with a high risk of malignancy. Hepatic adenoma with arginosuccinate synthetase 1 expression or sonic hedgehog mutations are associated with a risk of bleeding. Hepatocellular carcinoma and choangiocarcinoma display heterogeneity at both morphologic and molecular levels Cholangiocellular carcinoma is most commonly associated with IDH 1/2 mutations.
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Zong C, Kimura Y, Kinoshita K, Takasu S, Zhang X, Sakurai T, Sekido Y, Ichihara S, Endo G, Ichihara G. Exposure to 1,2-Dichloropropane Upregulates the Expression of Activation-Induced Cytidine Deaminase (AID) in Human Cholangiocytes Co-Cultured With Macrophages. Toxicol Sci 2018; 168:137-148. [DOI: 10.1093/toxsci/kfy280] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Affiliation(s)
- Cai Zong
- Department of Occupational and Environmental Health, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda 278-8510, Japan
| | - Yusuke Kimura
- Department of Occupational and Environmental Health, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda 278-8510, Japan
| | - Kazuo Kinoshita
- Evolutionary Medicine, Shiga Medical Center Research Institute, Moriyama 524-8524, Japan
| | - Shigetada Takasu
- Department of Occupational and Environmental Health, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda 278-8510, Japan
| | - Xiao Zhang
- Department of Occupational and Environmental Health, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda 278-8510, Japan
| | - Toshihiro Sakurai
- Department of Occupational and Environmental Health, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda 278-8510, Japan
| | | | - Sahoko Ichihara
- Department of Environmental and Preventive Medicine, Jichi Medical University School of Medicine, Shimotsuke 329-0498, Japan
| | - Ginji Endo
- Osaka Occupational Health Service Centre, Japan Industrial Safety and Health Association, Osaka 550-0001, Japan
| | - Gaku Ichihara
- Department of Occupational and Environmental Health, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda 278-8510, Japan
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Lendvai G, Szekerczés T, Illyés I, Dóra R, Kontsek E, Gógl A, Kiss A, Werling K, Kovalszky I, Schaff Z, Borka K. Cholangiocarcinoma: Classification, Histopathology and Molecular Carcinogenesis. Pathol Oncol Res 2018; 26:3-15. [PMID: 30448973 DOI: 10.1007/s12253-018-0491-8] [Citation(s) in RCA: 74] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Accepted: 10/10/2018] [Indexed: 02/06/2023]
Abstract
Cholangiocarcinoma (CC) is the second most common tumor of the liver, originating from the biliary system with increasing incidence and mortality worldwide. Several new classifications review the significance of tumor localization, site of origin, proliferation and biomarkers in the intrahepatic, perihilar and distal forms of the lesion. Based on growth pattern mass-forming, periductal-infiltrating, intraductal, undefined and mixed types are differentiated. There are further subclassifications which are applied for the histological features, in particular for intrahepatic CC. Recognition of the precursors and early lesions of CC including biliary intraepithelial neoplasia (BilIN), intraductal papillary neoplasm of the bile ducts (IPNB), biliary mucinous cystic neoplasm (MCNB) and the candidate precursors, such as bile duct adenoma and von Meyenburg complex is of increasing significance. In addition to the previously used biliary markers detected by immunohistochemistry, several new markers have been added to the differentiation of both the benign and malignant lesions, which can be used to aid in the subclassification in association with the outcome of CC. Major aspects of biliary carcinogenesis have been revealed, yet, the exact way of this diverse process is still unclear. The factors contributing to molecular cholangiocarcinogenesis include various risk factors, different anatomical localizations, multiple cellular origins, genetic and epigenetic alterations, tumor microenvironment, heterogeneity and clonal evolution. Driver mutations have been identified, implying that they are optimal candidates for targeted therapy. The most promising therapeutic candidates have entered clinical trials.
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Affiliation(s)
- Gábor Lendvai
- 2nd Department of Pathology, Semmelweis University, Üllői út 93, Budapest, H-1091, Hungary
| | - Tímea Szekerczés
- 2nd Department of Pathology, Semmelweis University, Üllői út 93, Budapest, H-1091, Hungary
| | - Idikó Illyés
- 2nd Department of Pathology, Semmelweis University, Üllői út 93, Budapest, H-1091, Hungary
| | - Réka Dóra
- 2nd Department of Pathology, Semmelweis University, Üllői út 93, Budapest, H-1091, Hungary
| | - Endre Kontsek
- 2nd Department of Pathology, Semmelweis University, Üllői út 93, Budapest, H-1091, Hungary
| | - Alíz Gógl
- 2nd Department of Pathology, Semmelweis University, Üllői út 93, Budapest, H-1091, Hungary
| | - András Kiss
- 2nd Department of Pathology, Semmelweis University, Üllői út 93, Budapest, H-1091, Hungary
| | - Klára Werling
- 2nd Department of Internal Medicine, Semmelweis University, Budapest, 1085, Hungary
| | - Ilona Kovalszky
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, 1085, Hungary
| | - Zsuzsa Schaff
- 2nd Department of Pathology, Semmelweis University, Üllői út 93, Budapest, H-1091, Hungary.
| | - Katalin Borka
- 2nd Department of Pathology, Semmelweis University, Üllői út 93, Budapest, H-1091, Hungary
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Virani S, Akers A, Stephenson K, Smith S, Kennedy L, Alpini G, Francis H. Comprehensive Review of Molecular Mechanisms during Cholestatic Liver Injury and Cholangiocarcinoma. JOURNAL OF LIVER 2018; 7:231. [PMID: 30613437 PMCID: PMC6319937 DOI: 10.4172/2167-0889.1000231] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Cholestatic liver injury is characterized by damage induced on the biliary tree and cholangiocytes, the cells lining the biliary tree, thus they are termed "cholangiopathies". Cholangiopathies include diseases such as Primary Biliary Cholangitis, Primary Sclerosing Cholangitis, Biliary Atresia and Cholangiocarcinoma. These pathologies lack viable therapies and most patients are diagnosed during late stage disease progression (with the exception of Biliary Atresia, which is found shortly after birth). The lack of therapies for these diseases has put a significant burden on the need for liver transplantation as this is the only indicative "cure" for cholangiopathies. The molecular mechanisms for cholangiopathies have been extensively studied; however, and unfortunately, the lack of effective biomarkers and therapeutics remains. In this review article we highlight the latest studies to investigate the molecular mechanisms regulating cholangiopathies and the potential therapeutics that might be discovered.
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Affiliation(s)
- Shohaib Virani
- Department of Medical Physiology, College of Medicine Texas A&M Health Science Center, Temple, Texas, USA
| | - Austin Akers
- Department of Internal Medicine, Baylor Scott & White Health, Texas, USA
| | - Kristen Stephenson
- Department of Internal Medicine, Baylor Scott & White Health, Texas, USA
| | - Steven Smith
- Department of Internal Medicine, Baylor Scott & White Health, Texas, USA
| | - Lindsey Kennedy
- Department of Medical Physiology, College of Medicine Texas A&M Health Science Center, Temple, Texas, USA
| | - Gianfranco Alpini
- Research, Central Texas Veterans Health Care System, Texas, USA
- Department of Medical Physiology, College of Medicine Texas A&M Health Science Center, Temple, Texas, USA
| | - Heather Francis
- Research, Central Texas Veterans Health Care System, Texas, USA
- Department of Medical Physiology, College of Medicine Texas A&M Health Science Center, Temple, Texas, USA
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31
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Mansini AP, Lorenzo Pisarello MJ, Thelen KM, Cruz-Reyes M, Peixoto E, Jin S, Howard BN, Trussoni CE, Gajdos GB, LaRusso NF, Perugorria MJ, Banales JM, Gradilone SA. MicroRNA (miR)-433 and miR-22 dysregulations induce histone-deacetylase-6 overexpression and ciliary loss in cholangiocarcinoma. Hepatology 2018; 68:561-573. [PMID: 29406621 PMCID: PMC6078832 DOI: 10.1002/hep.29832] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2017] [Revised: 01/05/2018] [Accepted: 01/25/2018] [Indexed: 12/21/2022]
Abstract
UNLABELLED Cholangiocytes normally express primary cilia, a multisensory organelle that detects signals from the cellular environment. Cilia are significantly reduced in cholangiocarcinoma (CCA) by a mechanism involving overexpression of histone deacetylase 6 (HDAC6). Despite HDAC6 overexpression in CCA, we found no differences in its mRNA level, suggesting a posttranscriptional regulation, possibly involving microRNAs (miRNAs). Here, we describe that at least two HDAC6-targeting miRNAs, miR-433 and miR-22, are down-regulated in CCA both in vitro and in vivo. Experimental restoration of these miRNAs in CCA cells reduced HDAC6 expression, induced ciliary restoration, and decreased the malignant phenotype. Furthermore, in contrast to the mature forms, levels of precursor forms of these miRNAs were higher in CCA compared to normal cholangiocytes and accumulated in the nuclei, suggesting a defective nuclear export. We assessed the expression of Exportin-5, the protein responsible for transporting miRNA precursors out of the nucleus, and found it to be reduced by 50% in CCA compared to normal cholangiocytes. Experimental overexpression of Exportin-5 in CCA cells restored precursor and mature forms of these miRNAs to normal levels, inducing a decrease in the expression of HDAC6 and a decrease in the malignant phenotype. Conversely, short hairpin RNA (shRNA) depletion of Exportin-5 in normal cholangiocytes resulted in increased nuclear retention of precursor miRNAs, decreased mature miRNAs, increased cell proliferation, and shorter cilia. CONCLUSION These data suggest that down-regulated Exportin-5 impairs the nuclear export of miR-433 and miR-22 precursor forms, causing a decrease in levels of mature miR-433 and miR-22 forms, and leading to overexpression of HDAC6 and ciliary loss in CCA. (Hepatology 2018).
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Affiliation(s)
- Adrian P. Mansini
- The Hormel Institute, University of Minnesota, Austin, MN, USA,Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
| | - Maria J. Lorenzo Pisarello
- Department of Medicine. Division of Gastroenterology and Hepatology. Mayo Center for Cell Signaling in Gastroenterology. Mayo Clinic, Rochester, MN USA
| | | | | | - Estanislao Peixoto
- The Hormel Institute, University of Minnesota, Austin, MN, USA,Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
| | - Sujeong Jin
- The Hormel Institute, University of Minnesota, Austin, MN, USA
| | - Brynn N. Howard
- Department of Medicine. Division of Gastroenterology and Hepatology. Mayo Center for Cell Signaling in Gastroenterology. Mayo Clinic, Rochester, MN USA
| | - Christy E. Trussoni
- Department of Medicine. Division of Gastroenterology and Hepatology. Mayo Center for Cell Signaling in Gastroenterology. Mayo Clinic, Rochester, MN USA
| | - Gabriella B. Gajdos
- Department of Medicine. Division of Gastroenterology and Hepatology. Mayo Center for Cell Signaling in Gastroenterology. Mayo Clinic, Rochester, MN USA
| | - Nicholas F. LaRusso
- Department of Medicine. Division of Gastroenterology and Hepatology. Mayo Center for Cell Signaling in Gastroenterology. Mayo Clinic, Rochester, MN USA
| | - Maria J. Perugorria
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute – Donostia University Hospital, Ikerbasque, CIBERehd, San Sebastian, Spain
| | - Jesus M. Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute – Donostia University Hospital, Ikerbasque, CIBERehd, San Sebastian, Spain
| | - Sergio A. Gradilone
- The Hormel Institute, University of Minnesota, Austin, MN, USA,Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA,Address correspondence to Sergio A Gradilone, PhD. Section Leader “Cancer Cell Biology and Translational Research.” The Hormel Institute, University of Minnesota. 801 16th Avenue NE. Austin, MN 55912, USA; Tel: +1-507-437-9628;
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Thongchot S, Ferraresi A, Vidoni C, Loilome W, Yongvanit P, Namwat N, Isidoro C. Resveratrol interrupts the pro-invasive communication between cancer associated fibroblasts and cholangiocarcinoma cells. Cancer Lett 2018; 430:160-171. [PMID: 29802929 DOI: 10.1016/j.canlet.2018.05.031] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Revised: 05/17/2018] [Accepted: 05/18/2018] [Indexed: 02/07/2023]
Abstract
Cholangiocarcinoma (CCA), the cancer arising from the epithelial cells of bile ducts, is a prototype of inflammatory-driven cancer. Cytokines released by cancer associated fibroblasts (CAFs) play a pivotal role in CCA progression, driving the epigenetic Epithelial-to-Mesenchymal transition and the growth and metastasization of CCA cells. Consistently, the conditioned medium from CCA-derived CAFs further stimulated the secretion of IL-6, and to a lesser extent of IL-8, by CCA cells. CCA has a poor prognosis, because of late diagnosis and of high resistance to radio- and chemo-therapy of CCA cells. Targeting the CAFs and their secretion could be an alternative option. We found that while IL-6 indeed promoted the cell migration of invasive CCA cells, the nutraceutical Resveratrol strongly counteracted this effect both in CCA cells and in immortalized cholangiocytes. More importantly, here we show that Resveratrol has the potential to abrogate the secretion of IL-6 by CAFs. While the conditioned medium from CAFs strongly induced IL-6 mediated motility of CCA cells, the conditioned medium from CAFs pre-treated with Resveratrol completely halted cancer cell motility and reverted the N-to E-cadherin switch in migrating cells. This effect was associated with stimulation of autophagy in the cancer cells. This is the first demonstration that CAFs secretory products directly affect the regulation of autophagy and consequently the behavior of CCA cells, and that a nutraceutical may revert the malignant phenotype of cancer cells by acting on CAFs metabolism and secretion.
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Affiliation(s)
- Suyanee Thongchot
- Laboratory of Molecular Pathology, Department of Health Sciences, Università Del Piemonte Orientale "A. Avogadro", Novara, 28100, Italy; Department of Biochemistry, Faculty of Medicine, Cholangiocarcinoma Research Institution, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Alessandra Ferraresi
- Laboratory of Molecular Pathology, Department of Health Sciences, Università Del Piemonte Orientale "A. Avogadro", Novara, 28100, Italy
| | - Chiara Vidoni
- Laboratory of Molecular Pathology, Department of Health Sciences, Università Del Piemonte Orientale "A. Avogadro", Novara, 28100, Italy
| | - Watcharin Loilome
- Department of Biochemistry, Faculty of Medicine, Cholangiocarcinoma Research Institution, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Puangrat Yongvanit
- Cholangiocarcinoma Research Institution, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Nisana Namwat
- Department of Biochemistry, Faculty of Medicine, Cholangiocarcinoma Research Institution, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Ciro Isidoro
- Laboratory of Molecular Pathology, Department of Health Sciences, Università Del Piemonte Orientale "A. Avogadro", Novara, 28100, Italy.
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Phase 1b investigation of the MEK inhibitor binimetinib in patients with advanced or metastatic biliary tract cancer. Invest New Drugs 2018; 36:1037-1043. [PMID: 29785570 DOI: 10.1007/s10637-018-0600-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Accepted: 04/03/2018] [Indexed: 12/20/2022]
Abstract
Background The MAPK pathway plays a central role in regulation of several cellular processes, and its dysregulation is a hallmark of biliary tract cancer (BTC). Binimetinib (MEK162), a potent, selective oral MEK1/2 inhibitor, was assessed in patients with advanced BTC. Patients and Methods An expansion cohort study in patients who received ≤1 line of therapy for advanced BTC was conducted after determination of the maximum tolerated dose in this Phase 1 trial. Patients received binimetinib 60 mg twice daily. The primary objectives were to characterize the safety profile and pharmacokinetics of binimetinib in advanced BTC. Secondary objectives included assessment of clinical efficacy, changes in weight and lean body mass, and pharmacodynamic effects. Tumor samples were assessed for mutations in relevant genes. Results Twenty-eight patients received binimetinib. Common adverse events (AEs) were mild, with rash (82%) and nausea (54%) being most common. Two patients experienced grade 4 AEs, one generalized edema and the other pulmonary embolism. The pharmacokinetics in this patient population were consistent with those previously reported (Bendell JC et al., Br J Cancer 2017;116:575-583). Twelve patients (43%) experienced stable disease and two had objective responses (1 complete response, 1 partial response) per Response Evaluation Criteria in Solid Tumors and stable metabolic disease by positron emission tomography/computed tomography. Most patients (18/25; 72%) did not have KRAS, BRAF, NRAS, PI3KCA, or PTEN mutations, nor was there correlation between mutation status and response. The average non-fluid weight gain was 1.3% for lean muscle and 4.7% for adipose tissue. Conclusion Binimetinib was well tolerated and showed promising evidence of activity in patients with BTC. Correlative studies suggested the potential for binimetinib to promote muscle gain in patients with BTC.
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Qian F, Guo J, Jiang Z, Shen B. Translational Bioinformatics for Cholangiocarcinoma: Opportunities and Challenges. Int J Biol Sci 2018; 14:920-929. [PMID: 29989102 PMCID: PMC6036745 DOI: 10.7150/ijbs.24622] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2017] [Accepted: 02/02/2018] [Indexed: 02/07/2023] Open
Abstract
Translational bioinformatics is becoming a driven force and a new scientific paradigm for cancer research in the era of big data. To promote the cross-disciplinary communication and research, we take cholangiocarcinoma as an example to review the present status and the future perspectives of the bioinformatics models applied in cancer study. We first summarize the present application of computational methods to the study of cholangiocarcinoma ranged from pattern recognition of biological data, knowledge based data annotation to systems biological level modeling and clinical translation. Then the future opportunities and challenges about database or knowledge base building, novel model developing and molecular mechanism exploring as well as the intelligent decision supporting system construction for the precision diagnosis, prognosis and treatment of cholangiocarcinoma are discussed.
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Affiliation(s)
- Fuliang Qian
- Center for Systems Biology, Soochow University, Suzhou 215006, China
| | - Junping Guo
- The Affiliated Yixing Hospital of Jiangsu University, Yixing, 214200, China
| | - Zhi Jiang
- Center for Systems Biology, Soochow University, Suzhou 215006, China
| | - Bairong Shen
- Center for Systems Biology, Soochow University, Suzhou 215006, China.,Guizhou University School of Medicine, Guiyang, 550025, China.,Institute for Systems Genetics, West China Hospital, Sichuan University, Chengdu, 610041, China
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Chi Z, Bhalla A, Saeed O, Cheng L, Curless K, Wang HL, Patil DT, Lin J. Mucinous intrahepatic cholangiocarcinoma: a distinct variant. Hum Pathol 2018; 78:131-137. [PMID: 29698701 DOI: 10.1016/j.humpath.2018.04.010] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2017] [Revised: 04/04/2018] [Accepted: 04/10/2018] [Indexed: 02/07/2023]
Abstract
Mucinous variant of intrahepatic cholangiocarcinoma (iCC) is rare, and its clinicopathological features and prognosis are far less clear. Six patients who had iCCs with more than 50% of mucinous component and 79 conventional iCCs were included in the study. The mean size of mucinous and conventional iCCs was 6.2 and 6.0 cm, respectively. Most patients (83%) with mucinous iCC presented at T3 stage or above compared with 28% of the conventional group (P < .01). Three patients with mucinous iCC (50%) died within 1 year. The average survival time of patients with mucinous iCCs was significantly reduced compared with that of the conventional group (9 months versus 2 years; P < .001). Immunohistochemistry was performed on 6 mucinous and 12 conventional iCCs with matched age, sex, and stage, which revealed positive immunoreactivity in MUC1 (83% versus 58%), MUC2 (33% versus 17%), MUC5AC (100% versus 42%), MUC6 (50% versus 0), CK7 (83% versus 83%), CK20 (0 versus 17%), CDX2 (17% versus 0), p53 (67% versus 67%), Smad4 (67% versus 58%), and EGFR (83% versus 42%) in mucinous and conventional iCCs, respectively. Molecular studies showed one mucinous iCC with KRAS G12C mutation and no BRAF or IDH1/2 mutations. Mucinous iCC is a unique variant that constitutes 7% of iCCs. It is more immunoreactive for MUC1, MUC2, MUC5AC, and MUC6. Unlike adenocarcinomas of colorectal primary, mucinous iCCs are often CK7+/CK20-/CDX2- and microsatellite stable. Patients with mucinous iCC likely present at advanced stage upon diagnosis with shorter survival time compared with the conventional counterparts.
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Affiliation(s)
- Zhikai Chi
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN - 46202, USA
| | - Amarpreet Bhalla
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN - 46202, USA
| | - Omer Saeed
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN - 46202, USA
| | - Liang Cheng
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN - 46202, USA
| | - Kendra Curless
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN - 46202, USA
| | - Hanlin L Wang
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA - 90095, USA
| | - Deepa T Patil
- Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH - 44195, USA
| | - Jingmei Lin
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN - 46202, USA.
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Role of inflammation and proinflammatory cytokines in cholangiocyte pathophysiology. Biochim Biophys Acta Mol Basis Dis 2018; 1864:1270-1278. [DOI: 10.1016/j.bbadis.2017.07.024] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2017] [Revised: 07/20/2017] [Accepted: 07/21/2017] [Indexed: 02/06/2023]
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Fan F, Lu J, Yu W, Zhang Y, Xu S, Pang L, Zhu B. MicroRNA-26b-5p regulates cell proliferation, invasion and metastasis in human intrahepatic cholangiocarcinoma by targeting S100A7. Oncol Lett 2018; 15:386-392. [PMID: 29387225 PMCID: PMC5768070 DOI: 10.3892/ol.2017.7331] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Accepted: 07/17/2017] [Indexed: 02/06/2023] Open
Abstract
The present study aimed to investigate the effects of microRNA expression in intrahepatic cholangiocarcinoma (ICC). It was identified that the expression of microRNA-26b-5p (miR-26b-5p) was downregulated in ICC tissues compared with matched adjacent non-tumor tissues. Furthermore, miR-26b-5p expression was downregulated in metastatic ICC tumor tissues and invasive ICC cell line subpopulations compared with non-metastatic tumor tissue and the parental ICC cells. In vitro studies demonstrated that transfection with an miR-26b-5p mimic inhibited the proliferation, migration and invasion of RBE and HCCC-9810 cells, whereas an miR-26b-5p inhibitor promoted these abilities. S100 calcium-binding protein A7 (S100A7) was predicted as a direct target of miR-26b-5p. Transfection with an miR-26b-5p mimic decreased S100A7 expression, whereas an miR-26b-5p inhibitor increased S100A7 expression. The result of a dual luciferase reporter assay also indicated this interaction. S100A7 was therefore confirmed as a direct target of miR-26b-5p in ICC. The knockdown of S100A7 abrogated the effect of miR-26b-5p on cell migration in RBE and HCCC-9810 cells. In conclusion, the present study demonstrated that miR-26b-5p suppresses the proliferation, migration and invasion of ICC cells by suppressing S100A7.
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Affiliation(s)
- Fei Fan
- Department of Special Treatment, Eastern Hepatobiliary Surgical Hospital, Second Military Medical University, Shanghai 200438, P.R. China
| | - Jiongjiong Lu
- Department of Special Treatment, Eastern Hepatobiliary Surgical Hospital, Second Military Medical University, Shanghai 200438, P.R. China
| | - Wenlong Yu
- Department of Biliary Surgery II, Eastern Hepatobiliary Surgical Hospital, Second Military Medical University, Shanghai 200438, P.R. China
| | - Yongjie Zhang
- Department of Biliary Surgery II, Eastern Hepatobiliary Surgical Hospital, Second Military Medical University, Shanghai 200438, P.R. China
| | - Suqian Xu
- Department of Special Treatment, Eastern Hepatobiliary Surgical Hospital, Second Military Medical University, Shanghai 200438, P.R. China
| | - Leilei Pang
- Department of Pathology, Maternal and Child Health Hospital of Weihai, Weihai, Shandong 264200, P.R. China
| | - Bin Zhu
- Department of Special Treatment, Eastern Hepatobiliary Surgical Hospital, Second Military Medical University, Shanghai 200438, P.R. China
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Sripa B, Tangkawattana S, Brindley PJ. Update on Pathogenesis of Opisthorchiasis and Cholangiocarcinoma. ADVANCES IN PARASITOLOGY 2018; 102:97-113. [PMID: 30442312 DOI: 10.1016/bs.apar.2018.10.001] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Infection with the food-borne liver fluke Opisthorchis viverrini causes cholangiocarcinoma (CCA). Whereas the cause of CCA in the West remains obscure, the principal risk factor in Thailand is opisthorchiasis. Here, we review recent findings on the pathogenesis of opisthorchiasis and CCA focusing on helminth molecules/toxic metabolites, host-parasite interaction, endocytosis, immunopathology/inflammatory responses, free radical production, molecular genetic alterations, and multifactorial including coinfections driving to CCA development.
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40
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Pan Y, Mao Y, Jin R, Jiang L. Crosstalk between the Notch signaling pathway and non-coding RNAs in gastrointestinal cancers. Oncol Lett 2017; 15:31-40. [PMID: 29285185 DOI: 10.3892/ol.2017.7294] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2016] [Accepted: 09/07/2017] [Indexed: 12/14/2022] Open
Abstract
The Notch signaling pathway is one of the main signaling pathways that mediates direct contact between cells, and is essential for normal development. It regulates various cellular processes, including cell proliferation, apoptosis, migration, invasion, angiogenesis and metastasis. It additionally serves an important function in tumor progression. Non-coding RNAs mainly include small microRNAs, long non-coding RNAs and circular RNAs. At present, a large body of literature supports the biological significance of non-coding RNAs in tumor progression. It is also becoming increasingly evident that cross-talk exists between Notch signaling and non-coding RNAs. The present review summarizes the current knowledge of Notch-mediated gastrointestinal cancer cell processes, and the effect of the crosstalk between the three major types of non-coding RNAs and the Notch signaling pathway on the fate of gastrointestinal cancer cells.
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Affiliation(s)
- Yangyang Pan
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Yuyan Mao
- Central Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Rong Jin
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Lei Jiang
- Central Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
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Histopathological evidence of neoplastic progression of von Meyenburg complex to intrahepatic cholangiocarcinoma. Hum Pathol 2017; 67:217-224. [PMID: 28823571 DOI: 10.1016/j.humpath.2017.08.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2017] [Revised: 08/04/2017] [Accepted: 08/10/2017] [Indexed: 12/15/2022]
Abstract
Von Meyenburg complex (VMC) is generally thought to be benign, although its preneoplastic potential for intrahepatic cholangiocarcinoma (iCC) has been a subject of contention. We retrospectively reviewed 86 hepatectomy specimens with a diagnosis of iCC. Morphologically, an association between iCC and VMC was appreciated in 35% of cases that illustrated a gradual neoplastic progression from benign VMC to dysplasia and then to iCC. Among them, 24 cases had VMC lined by epithelial cells with low-grade biliary dysplasia and 13 with high-grade biliary dysplasia. VMC-associated iCCs were smaller in size and well to moderately differentiated, with features of anastomosing glandular architecture, ductal carcinoma in situ-like growth pattern, peritumoral lymphocytic infiltrate, central fibrous scar, and complete pushing border. They often presented as T1 tumors. In contrast, non-VMC-associated iCCs were moderately to poorly differentiated with solid, cribriform or papillary growth patterns. They likely exhibited necrosis, perineural invasion, positive surgical margin, lymphovascular invasion, and high T stage. Additionally, Ki67 and p53 immunostains support the continuing neoplastic evolution from benign VMC to dysplasia and then to iCC. VMC could become neoplastic, serving as an in situ carcinoma lesion to transform to iCC. The underlying molecular alteration and clinical implication of this neoplastic transformation deserves further investigation.
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Mayr C, Ocker M, Ritter M, Pichler M, Neureiter D, Kiesslich T. Biliary tract cancer stem cells - translational options and challenges. World J Gastroenterol 2017; 23:2470-2482. [PMID: 28465631 PMCID: PMC5394510 DOI: 10.3748/wjg.v23.i14.2470] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Revised: 02/27/2017] [Accepted: 03/21/2017] [Indexed: 02/06/2023] Open
Abstract
Management of biliary tract cancer remains challenging. Tumors show high recurrence rates and therapeutic resistance, leading to dismal prognosis and short survival. The cancer stem cell model states that a tumor is a heterogeneous conglomerate of cells, in which a certain subpopulation of cells - the cancer stem cells - possesses stem cell properties. Cancer stem cells have high clinical relevance due to their potential contributions to development, progression and aggressiveness as well as recurrence and metastasis of malignant tumors. Consequently, reliable identification of as well as pharmacological intervention with cancer stem cells is an intensively investigated and promising research field. The involvement of cancer stem cells in biliary tract cancer is likely as a number of studies demonstrated their existence and the obvious clinical relevance of several established cancer stem cell markers in biliary tract cancer models and tissues. In the present article, we review and discuss the currently available literature addressing the role of putative cancer stem cells in biliary tract cancer as well as the connection between known contributors of biliary tract tumorigenesis such as oncogenic signaling pathways, micro-RNAs and the tumor microenvironment with cancer stem cells.
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43
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Tian F, Chen J, Zheng S, Li D, Zhao X, Jiang P, Li J, Wang S. miR-124 targets GATA6 to suppress cholangiocarcinoma cell invasion and metastasis. BMC Cancer 2017; 17:175. [PMID: 28270130 PMCID: PMC5339982 DOI: 10.1186/s12885-017-3166-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2016] [Accepted: 03/02/2017] [Indexed: 01/03/2023] Open
Abstract
Background Our previous study showed that GATA6 plays important roles in cholangiocarcinoma (CCA) cell invasion and metastasis. However, the regulation mechanism of GATA6 in CCA is not clear. In this study, we studied the potential function of miR-124 in CCA and the mechanism of GATA6 regulation. Methods The expression levels of miR-124 and GATA6 in cancerous tissues from 57 CCA patients was detected by RT-PCR and IHC. The impact of miR-124 on GATA6 expression in CCA cells was evaluated using cell transfection, xenotransplantation into nude mice and a luciferase reporter assay. Results miR-124 was decreased in 57 cancerous tissue samples compared with 38 matched paracancerous samples. The miR-124 level was inversely associated with lymph node involvement and distant metastasis. miR-124 significantly inhibited invasion and migration of CCA cells in vitro. Furthermore, miR-124 inhibited CCA cell metastasis in nude mice. miR-124 inhibited the luciferase activity of reporter genes containing the wild-type GATA6 3′-UTR, which was abrogated by mutation of the binding site. The protein levels of GATA6 were negatively regulated by miR-124. miR-124 expression was inversely associated with GATA6 in 57 cancerous samples. The miR-124-induced suppression of CCA invasion was abrogated by remedial expression of GATA6. GATA6 expression was decreased by miR-124 overexpression in liver masses from nude mice. Conclusions Our data suggested that miR-124 decreases GATA6 expression by targeting its 3′-UTR, which in turn inhibits CCA invasion and metastasis. Electronic supplementary material The online version of this article (doi:10.1186/s12885-017-3166-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Feng Tian
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, No. 29 Gaotanyan Street, Shapingba District, Chongqing, 400038, China
| | - Jian Chen
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, No. 29 Gaotanyan Street, Shapingba District, Chongqing, 400038, China
| | - Shuguo Zheng
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, No. 29 Gaotanyan Street, Shapingba District, Chongqing, 400038, China
| | - Dajiang Li
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, No. 29 Gaotanyan Street, Shapingba District, Chongqing, 400038, China
| | - Xin Zhao
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, No. 29 Gaotanyan Street, Shapingba District, Chongqing, 400038, China
| | - Peng Jiang
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, No. 29 Gaotanyan Street, Shapingba District, Chongqing, 400038, China
| | - Jianwei Li
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, No. 29 Gaotanyan Street, Shapingba District, Chongqing, 400038, China.
| | - Shuguang Wang
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, No. 29 Gaotanyan Street, Shapingba District, Chongqing, 400038, China
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44
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Pan QX, Su ZJ, Zhang JH, Wang CR, Ke SY. Glasgow Prognostic Score predicts prognosis of intrahepatic cholangiocarcinoma. Mol Clin Oncol 2017; 6:566-574. [PMID: 28413670 DOI: 10.3892/mco.2017.1166] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2016] [Accepted: 09/26/2016] [Indexed: 12/15/2022] Open
Abstract
High Glasgow Prognostic Score (GPS) has been associated with poor prognosis in patients with lung, ovarian, colorectal and renal cancer, as well as hepatocellular carcinoma. The aim of this study was to investigate the prognostic value of GPS in patients with intrahepatic cholangiocarcinoma (ICC) undergoing partial hepatectomy. A total of 72 patients with pathologically confirmed ICC were classified according to their GPS scores assigned based on the preoperative levels of C-reactive protein (CRP) and albumin. Their clinicopathological data were retrospectively assessed using univariate and multivariate analysis to determine their association with overall survival and recurrence. High GPS scores in ICC patients were associated with preoperative levels of CRP (P<0.001) and albumin (P<0.001), frequency of ascites accumulation (P=0.035), lymph node metastasis (P=0.002) and tumour size (P=0.005). On univariate analysis, preoperative levels of CRP (P<0.001), albumin (P=0.016) and carbohydrate antigen 19-9 (P=0.038), hepatitis B virus (HBV) positivity (P=0.009), occurrence of lymph node metastasis (P=0.001), Child-Pugh class B (P=0.013) and high tumour-node-metastasis (TNM) stage (P=0.002) were found to be associated with the 1- and 3-year overall survival. Multivariate analysis suggested that GPS score (HR=2.037, 95% CI: 1.092-3.799, P=0.025), TNM classification (HR=2.000, 95% CI: 1.188-3.367, P=0.009) and HBV positivity (HR=0.559 95% CI: 0.328-0.953, P=0.032) were independently associated with patient survival. High GPS scores also predicted ICC recurrence. In conclusion, our results demonstrated that GPS may serve as an independent marker of prognosis in patients with ICC following partial hepatectomy.
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Affiliation(s)
- Qun-Xiong Pan
- Department of Oncological Surgery, Quanzhou First Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian 362000, P.R. China
| | - Zi-Jian Su
- Department of Oncological Surgery, Quanzhou First Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian 362000, P.R. China
| | - Jian-Hua Zhang
- Department of Oncological Surgery, Quanzhou First Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian 362000, P.R. China
| | - Chong-Ren Wang
- Department of Oncological Surgery, Quanzhou First Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian 362000, P.R. China
| | - Shao-Ying Ke
- Department of Oncological Surgery, Quanzhou First Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian 362000, P.R. China
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45
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Antischistosomiasis Liver Fibrosis Effects of Chlorogenic Acid through IL-13/miR-21/Smad7 Signaling Interactions In Vivo and In Vitro. Antimicrob Agents Chemother 2017; 61:AAC.01347-16. [PMID: 27872076 DOI: 10.1128/aac.01347-16] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Accepted: 11/17/2016] [Indexed: 12/23/2022] Open
Abstract
This study investigated the antischistosomiasis liver fibrosis effects of chlorogenic acid (CGA) on interleukin 13 (IL-13)/microRNA-21 (miR-21)/Smad7 signaling interactions in the hepatic stellate LX2 cell line and schistosome-infected mice. The transfection was based on the ability of the GV273-miR-21-enhanced green fluorescent protein (EGFP) and GV369-miR-21-EGFP lentiviral system to up- or downregulate the miR-21 gene in LX2 cells. The mRNA expression of miR-21, Smad7, and connective tissue growth factor (CTGF) and the protein expression of Smad7, CTGF, Smad1, phosphor-Smad1 (p-Smad1), Smad2, p-Smad2, Smad2/3, p-Smad2/3, transforming growth factor β (TGF-β) receptor I, and α-smooth muscle actin (α-SMA) was assayed. Pathological manifestation of hepatic tissue was assessed for the degree of liver fibrosis in animals. The results showed that CGA could inhibit the mRNA expression of miR-21, promote Smad7, and inhibit CTGF mRNA expression. Meanwhile, CGA could significantly lower the protein levels of CTGF, p-Smad1, p-Smad2, p-Smad2/3, TGF-β receptor I, and α-SMA and elevate the Smad7 protein level. In vivo, with treatment with CGA, the signaling molecules of IL-13/miR-21/Smad7 interactions were markedly regulated. CGA could also reduce the degree of liver fibrosis in pathological manifestations. In conclusion, CGA could inhibit schistosomiasis-induced hepatic fibrosis through IL-13/miR-21/Smad7 signaling interactions in LX2 cells and schistosome-infected mice and might serve as an antifibrosis agent for treating schistosomiasis liver fibrosis.
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Ahn DH, Ozer HG, Hancioglu B, Lesinski GB, Timmers C, Bekaii-Saab T. Whole-exome tumor sequencing study in biliary cancer patients with a response to MEK inhibitors. Oncotarget 2017; 7:5306-12. [PMID: 26683364 PMCID: PMC4868687 DOI: 10.18632/oncotarget.6632] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Accepted: 12/12/2015] [Indexed: 12/13/2022] Open
Abstract
We previously conducted a phase-II study with selumetinib (AZD6244), a small molecule inhibitor of MEK1/2, in advanced biliary tract cancers (BTC), where the primary endpoint was response rate. Several patients experienced objective response. These findings were confirmed with MEK162 in a similar patient population. To assess for tumor-specific genetic variants that mediate sensitivity to MEK inhibition in BTC, we performed whole-exome sequencing in patients with an objective response to selumetinib. Normal and tumor DNA from FFPE tissue from two patients who experienced an objective response underwent whole-exome sequencing. Raw sequence reads were processed with GATK workflow and tumor specific variants were identified using MuTect and VarScan2. Ensemble Variant Effect Predictor was used to determine functional consequences of these variants. Copy number changes and potential gene fusion events were also screened. Findings were compared to assess for any commonality between the two tumor samples, and whether the identified variants were intrinsic to the MAPK pathway. 1169 and 628 tumor-specific variants were identified in the two samples. Further analysis demonstrated 60 and 53 functional and novel variants, respectively. Of the identified tumor-specific variants, fusion events or copy number changes, no commonality was seen. Several variants in genes associated with ERK signaling were present in each tumor sample. Although there were no common tumor-specific variants in the two patients who exhibited an objective response to selumetinib, several genes associated with ERK signaling were identified. Confirmatory studies investigating the role of the identified genes and other potential tumor independent factors need further investigation.
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Affiliation(s)
- Daniel H Ahn
- Department of Internal Medicine, Divison of Medical Oncology, Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | - Hatice Gulcin Ozer
- Department of Biomedical Informatics, Ohio State University, Columbus, OH, USA
| | - Baris Hancioglu
- Department of Biomedical Informatics, Ohio State University, Columbus, OH, USA
| | - Gregory B Lesinski
- Department of Internal Medicine, Divison of Medical Oncology, Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | - Cynthia Timmers
- Department of Internal Medicine, Divison of Medical Oncology, Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | - Tanios Bekaii-Saab
- Department of Internal Medicine, Divison of Medical Oncology, Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
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Dana P, Vaeteewoottacharn K, Kariya R, Matsuda K, Wongkham S, Okada S. Repurposing cimetidine for cholangiocarcinoma: Antitumor effects in vitro and in vivo. Oncol Lett 2017; 13:1432-1436. [PMID: 28454273 DOI: 10.3892/ol.2017.5563] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2015] [Accepted: 09/27/2016] [Indexed: 12/13/2022] Open
Abstract
Cimetidine is a histamine type-2 (H2) receptor antagonist that has been demonstrated to have antitumor effects on various types of malignancy. However, its effect on cholangiocarcinoma (CCA), a chemotherapy-resistant bile duct tumor, has yet to be investigated. In the present study, the antitumor activity of cimetidine in vitro and in vivo was evaluated. A methylthiotetrazole assay revealed that the proliferation of certain CCA cell lines was inhibited by cimetidine, which induced the caspase-dependent apoptosis of CCA cells via suppression of the protein kinase B signaling pathway. Suppression of Akt phosphorylation, caspase-3, -8 and -9 activation, phosphotidylserine exposure determined by Annexin V binding assay and the presence of a sub-G1 population were demonstrated by western blotting and flow cytometry analysis. In a CCA xenograft mouse model cimetidine inhibited the growth of CCA cells without observable adverse effects. These results suggest that cimetidine has the potential to be an effective antitumor agent for the treatment of CCA.
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Affiliation(s)
- Paweena Dana
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.,Department of Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand, Japan.,Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, Kumamoto 860-0811, Japan
| | - Kulthida Vaeteewoottacharn
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.,Department of Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand, Japan.,Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, Kumamoto 860-0811, Japan
| | - Ryusho Kariya
- Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, Kumamoto 860-0811, Japan
| | - Kouki Matsuda
- Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, Kumamoto 860-0811, Japan
| | - Sopit Wongkham
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.,Department of Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand, Japan
| | - Seiji Okada
- Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, Kumamoto 860-0811, Japan
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Yang L, Feng S, Yang Y. Identification of transcription factors (TFs) and targets involved in the cholangiocarcinoma (CCA) by integrated analysis. Cancer Gene Ther 2016; 23:439-445. [DOI: 10.1038/cgt.2016.64] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2016] [Revised: 04/25/2016] [Accepted: 04/26/2016] [Indexed: 12/24/2022]
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49
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Deregulated MicroRNAs in Biliary Tract Cancer: Functional Targets and Potential Biomarkers. BIOMED RESEARCH INTERNATIONAL 2016; 2016:4805270. [PMID: 27957497 PMCID: PMC5120202 DOI: 10.1155/2016/4805270] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Accepted: 10/10/2016] [Indexed: 02/07/2023]
Abstract
Biliary tract cancer (BTC) is still a fatal disease with very poor prognosis. The lack of reliable biomarkers for early diagnosis and of effective therapeutic targets is a major demanding problem in diagnosis and management of BTC. Due to the clinically silent and asymptomatic characteristics of the tumor, most patients are diagnosed at an already advanced stage allowing only for a palliative therapeutic approach. MicroRNAs are small noncoding RNAs well known to regulate various cellular functions and pathologic events including the formation and progression of cancer. Over the last years, several studies have shed light on the role of microRNAs in BTC, making them potentially attractive therapeutic targets and candidates as biomarkers. In this review, we will focus on the role of oncogenic and tumor suppressor microRNAs and their direct targets in BTC. Furthermore, we summarize and discuss data that evaluate the diagnostic power of deregulated microRNAs as possible future biomarkers for BTC.
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Wang SH, Ma F, Tang ZH, Wu XC, Cai Q, Zhang MD, Weng MZ, Zhou D, Wang JD, Quan ZW. Long non-coding RNA H19 regulates FOXM1 expression by competitively binding endogenous miR-342-3p in gallbladder cancer. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2016; 35:160. [PMID: 27716361 PMCID: PMC5048611 DOI: 10.1186/s13046-016-0436-6] [Citation(s) in RCA: 94] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/02/2016] [Accepted: 09/22/2016] [Indexed: 01/17/2023]
Abstract
Background Long non-coding RNA (lncRNA) H19 has been reported to involve in many kinds of human cancers and functions as an oncogene. Our previous study found that H19 was over-expressed in gallbladder cancer (GBC) and was shown to promote tumor development in GBC. However, the competing endogenous RNA (ceRNA) regulatory network involving H19 in GBC progression has not been fully elucidated. We aim to detect the role of H19 as a ceRNA in GBC. Methods and Results In this study, the expression of H19 and miR-342-3p were analyzed in 35 GBC tissues and matched normal tissues by using quantitative polymerase chain reaction (qRT-PCR). We demonstrated H19 was overexpressed and negatively correlated with miR-342-3p in GBC. By dual-luciferase reporter assays, RNA-binding protein immunoprecipitation (RIP) and RNA pull-down assays, we verified that H19 was identified as a direct target of miR-342-3p. QRT-PCR and Western-blotting assays demonstrated that H19 silencing down-regulated, whereas over-expression enhanced the expression of miR-342-3p targeting FOXM1 through competitively ‘sponging’ miR-342-3p. Furthermore, transwell invasion assays and cell cycle assays indicated that H19 knockdown inhibited both cells invasion and proliferation, but this effects was attenuated by co-transfection of siRNA-H19 and miR-342-3p inhibitor in GBC cells. In vivo, tumor volumes were decreased significantly in H19 silenced group compared to the control group, but was attenuated by co-transfection of shRNA-H19 and miR-342-3p inhibitor, which were stablely constructed through lenti-virus vector. Conclusion Our results suggest a potential ceRNA regulatory network involving H19 regulates FOXM1 expression by competitively binding endogenous miR-342-3p in GBC. This mechanism may contribute to a better understanding of GBC pathogenesis and provides potential therapeutic strategy for GBC.
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Affiliation(s)
- Shou-Hua Wang
- Department of General Surgery, Xinhua Hospital, Shanghai Jiao tong University School of Medicine, 1665 Kong Jiang Road, Shanghai, 200000, China
| | - Fei Ma
- Department of Oncology, Xinhua Hospital Affiliated to Shanghai Jiao tong University School of Medicine, Shanghai, 200092, China
| | - Zhao-Hui Tang
- Department of General Surgery, Xinhua Hospital, Shanghai Jiao tong University School of Medicine, 1665 Kong Jiang Road, Shanghai, 200000, China
| | - Xiao-Cai Wu
- Department of General Surgery, Xinhua Hospital, Shanghai Jiao tong University School of Medicine, 1665 Kong Jiang Road, Shanghai, 200000, China
| | - Qiang Cai
- Department of General Surgery, Xinhua Hospital, Shanghai Jiao tong University School of Medicine, 1665 Kong Jiang Road, Shanghai, 200000, China
| | - Ming-Di Zhang
- Department of General Surgery, Xinhua Hospital, Shanghai Jiao tong University School of Medicine, 1665 Kong Jiang Road, Shanghai, 200000, China
| | - Ming-Zhe Weng
- Department of General Surgery, Xinhua Hospital, Shanghai Jiao tong University School of Medicine, 1665 Kong Jiang Road, Shanghai, 200000, China
| | - Di Zhou
- Department of General Surgery, Xinhua Hospital, Shanghai Jiao tong University School of Medicine, 1665 Kong Jiang Road, Shanghai, 200000, China
| | - Jian-Dong Wang
- Department of General Surgery, Xinhua Hospital, Shanghai Jiao tong University School of Medicine, 1665 Kong Jiang Road, Shanghai, 200000, China.
| | - Zhi-Wei Quan
- Department of General Surgery, Xinhua Hospital, Shanghai Jiao tong University School of Medicine, 1665 Kong Jiang Road, Shanghai, 200000, China.
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