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Wang Z, Wang S, Jia Z, Zhao Y, Yang M, Yan W, Chen T, Xiang D, Shao R, Liu Y. Establishment and characterization of an immortalized epithelial cell line from human gallbladder. Front Oncol 2022; 12:994087. [PMID: 36387215 PMCID: PMC9650220 DOI: 10.3389/fonc.2022.994087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 09/26/2022] [Indexed: 11/25/2022] Open
Abstract
Background Although a plethora of studies have employed multiple gallbladder cancer (GBC) cell lines, it is surprisingly noted that there is still lack of a normal gallbladder epithelial cell line as a normal counterpart, thus impeding substantially the progress of mechanistic studies on the transformation of normal epithelial cells to cancer. Here, we created a normal gallbladder epithelial cell line named L-2F7 from human gallbladder tissue. Methods Gallbladder tissues from a diagnosed cholecystitis female patient were collected, and epithelial cells were enriched by magnetic cell sorting. Then, the cells were immortalized by co-introduction of human telomerase reverse transcriptase (hTERT) and Simian virus 40 large T antigen (LT-SV40) via a lentivirus infection system. After clonal selection and isolation, L-2F7 cells were tested for epithelial markers CK7, CK19, CK20, and CD326, genomic feature, cell proliferation, and migration using Western blot, immunofluorescence, whole genome sequencing, karyotyping, and RNA sequencing. L-2F7 cells were also transplanted to Nude (nu/nu) mice to determine tumorigenicity. Results We successfully identified one single-cell clone named L-2F7 which highly expressed epithelial markers CD326, CK7, CK19, and CK20. This cell line proliferated with a doubling time of 23 h and the epithelial morphology sustained over 30 passages following immortalization. Transient gene transduction of L-2F7 cells led to expression of exogenous GFP and FLAG protein. L-2F7 cells exhibited both distinct non-synonymous mutations from those of gallbladder cancer tissues and differential non-cancerous gene expression patterns similar to normal tissue. Although they displayed unexpected mobility, L-2F7 cells still lacked the ability to develop tumors. Conclusion We developed a non-cancerous gallbladder epithelial cell line, offering a valuable system for the study of gallbladder cancer and other gallbladder-related disorders.
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Affiliation(s)
- Ziyi Wang
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Cancer Institute, State Key Laboratory of Oncogenes and Related Genes, Shanghai, China
- Shanghai Key Laboratory of Biliary Tract Disease, Renji Hospital, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Renji Hospital, Shanghai, China
| | - Shijia Wang
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Cancer Institute, State Key Laboratory of Oncogenes and Related Genes, Shanghai, China
- Shanghai Key Laboratory of Biliary Tract Disease, Renji Hospital, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Renji Hospital, Shanghai, China
| | - Ziheng Jia
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Cancer Institute, State Key Laboratory of Oncogenes and Related Genes, Shanghai, China
- Shanghai Key Laboratory of Biliary Tract Disease, Renji Hospital, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Renji Hospital, Shanghai, China
| | - Yuhao Zhao
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Cancer Institute, State Key Laboratory of Oncogenes and Related Genes, Shanghai, China
- Shanghai Key Laboratory of Biliary Tract Disease, Renji Hospital, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Renji Hospital, Shanghai, China
| | - Mao Yang
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Cancer Institute, State Key Laboratory of Oncogenes and Related Genes, Shanghai, China
- Shanghai Key Laboratory of Biliary Tract Disease, Renji Hospital, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Renji Hospital, Shanghai, China
| | - Weikang Yan
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Cancer Institute, State Key Laboratory of Oncogenes and Related Genes, Shanghai, China
- Shanghai Key Laboratory of Biliary Tract Disease, Renji Hospital, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Renji Hospital, Shanghai, China
| | - Tao Chen
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Cancer Institute, State Key Laboratory of Oncogenes and Related Genes, Shanghai, China
- Shanghai Key Laboratory of Biliary Tract Disease, Renji Hospital, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Renji Hospital, Shanghai, China
| | - Dongxi Xiang
- Shanghai Cancer Institute, State Key Laboratory of Oncogenes and Related Genes, Shanghai, China
- Shanghai Key Laboratory of Biliary Tract Disease, Renji Hospital, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Renji Hospital, Shanghai, China
- *Correspondence: Dongxi Xiang, ; Rong Shao, ; Yingbin Liu,
| | - Rong Shao
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Cancer Institute, State Key Laboratory of Oncogenes and Related Genes, Shanghai, China
- Shanghai Key Laboratory of Biliary Tract Disease, Renji Hospital, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Renji Hospital, Shanghai, China
- Department of Pharmacology and Biochemistry, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Dongxi Xiang, ; Rong Shao, ; Yingbin Liu,
| | - Yingbin Liu
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Cancer Institute, State Key Laboratory of Oncogenes and Related Genes, Shanghai, China
- Shanghai Key Laboratory of Biliary Tract Disease, Renji Hospital, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Renji Hospital, Shanghai, China
- *Correspondence: Dongxi Xiang, ; Rong Shao, ; Yingbin Liu,
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Teng TZJ, Chua BQY, Shelat VG. Carcinosarcoma of gallbladder: A world review. World J Clin Oncol 2021; 12:1244-1263. [PMID: 35070742 PMCID: PMC8716988 DOI: 10.5306/wjco.v12.i12.1244] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Revised: 05/14/2021] [Accepted: 11/24/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Gallbladder carcinosarcoma is a rare hepatobiliary tumor comprising of both carcinomatous and sarcomatous components. Due to its rarity, the literature with regards to the topic is scarce and currently lacking, spanning less than 100 cases. AIM To summarize the current literature on gallbladder carcinosarcoma. METHODS A literature review was performed on the PubMed database using the keywords "Gallbladder" AND "Carcinosarcoma" from 1970 to 2021. Additionally, similar searches were performed on MEDLINE and Web of Science. RESULTS Risk factors noted include female gender, gallstones and chronic cholecystitis. In the absence of any diagnostic biochemical testing or tumor markers, imaging modality serves as the key initial impression tool, which can be histologically confirmed only post-resection. While surgery is the only curative option, the use of adjunctive chemotherapy has been considered on top of excision in recent years, with some success. CONCLUSION While this study has taken steps to bridge the gap in the literature, more cases should be reported to further ascertain the current associations and management potential for gallbladder carcinosarcoma.
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Affiliation(s)
- Thomas Zheng Jie Teng
- Department of General Surgery, Tan Tock Seng Hospital, Singapore 308433, Singapore
- Undergraduate Medicine, Lee Kong Chian School of Medicine, Singapore 308232, Singapore
| | - Branden Qi Yu Chua
- Department of General Surgery, Tan Tock Seng Hospital, Singapore 308433, Singapore
| | - Vishal G Shelat
- Department of General Surgery, Tan Tock Seng Hospital, Singapore 308433, Singapore
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Wu Y, Meng D, You Y, Sun R, Yan Q, Bao J, Sun Y, Yun D, Li Y, Sun D. Increased expression of RBMS3 predicts a favorable prognosis in human gallbladder carcinoma. Oncol Rep 2020; 44:55-68. [PMID: 32627033 PMCID: PMC7251710 DOI: 10.3892/or.2020.7594] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2019] [Accepted: 03/22/2020] [Indexed: 01/18/2023] Open
Abstract
Multiple regions in the short arm of chromosome 3 are frequently deleted in a variety of solid tumors including gallbladder carcinoma (GBC). RNA binding motif, single‑stranded interacting protein 3 (RBMS3), a tumor suppressor gene (TSG), is located in this region. However, the role of RBMS3 in GBC remains unclear. Reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and western blotting were performed to evaluate the mRNA and protein expression levels of RBMS3 in 41 fresh frozen GBC tissues and paired normal tissues. An immunohistochemical assay was performed on a tissue microarray (TMA, consisting of 125 cases GBC and 47 normal controls). Microvessel density (MVD) counts were determined using CD34 immunohistochemical staining. Moreover, univariate and multivariate analyses were performed to determine the correlations between RBMS3 expression, MVD and patient prognosis. Cellular functions including proliferation, clonogenicity and apoptosis, were assessed to further identify in vitro roles of RBMS3. It was revealed that both mRNA and protein expression levels of RBMS3 were significantly lower in GBC tissues than in normal controls. Multivariate Cox regression analyses demonstrated cytoplasmic RBMS3 expression as an independent prognostic factor correlated with GBC angiogenesis, histopathological differentiation and TNM stage. Kaplan‑Meier curves revealed that patients with lower cytoplasmic RBMS3 levels had a significantly worse OS than patients with higher cytoplasmic RBMS3 expression. Additionally, ectopic expression of RBMS3 markedly suppressed GBC cell proliferation and clonogenicity and promoted apoptosis in vitro. These findings indicated the potential of cytoplasmic RBMS3 as a tumor prognostic biomarker and a promising therapeutic target for GBC.
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Affiliation(s)
- Youliang Wu
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Delong Meng
- Department of Molecular Biology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Yexiang You
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Ruochuan Sun
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Qiang Yan
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Junjun Bao
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Yanjun Sun
- Department of General Surgery, The Armed Police Corps Hospital of Anhui, Hefei, Anhui 230041, P.R. China
| | - Dapeng Yun
- Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Yongxiang Li
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Dengqun Sun
- Department of General Surgery, The Armed Police Corps Hospital of Anhui, Hefei, Anhui 230041, P.R. China
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Wang SH, Zhang WJ, Wu XC, Zhang MD, Weng MZ, Zhou D, Wang JD, Quan ZW. Long non-coding RNA Malat1 promotes gallbladder cancer development by acting as a molecular sponge to regulate miR-206. Oncotarget 2018; 7:37857-37867. [PMID: 27191262 PMCID: PMC5122355 DOI: 10.18632/oncotarget.9347] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Accepted: 04/26/2016] [Indexed: 12/30/2022] Open
Abstract
Long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (Malat1) functions as an oncogene in many types of human cancer. In this study, we show that Malat1 is overexpressed in gallbladder cancer (GBC) tissue and cells. The high Malat1 levels correlated positively with tumor size and lymphatic metastasis, and correlated negatively with overall survival. We also show that Malat1 functions as a competing endogenous RNA (ceRNA) for miR-206. Because miR-206 directly suppresses expression of ANXA2 and KRAS, which are thought to promote GBC progression, Malat1 binding of miR-206 in GBC tissue and cells has an oncogenic effect. Conversely, Malat1 knockdown inhibits proliferation and invasion by GBC cells while increasing apoptosis. In vivo, silencing Malat1 decreases tumor volume. These results suggest Malat1 could potentially serve as a therapeutic target and prognostic marker for GBC.
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Affiliation(s)
- Shou-Hua Wang
- Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200000, China
| | - Wen-Jie Zhang
- Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200000, China
| | - Xiao-Cai Wu
- Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200000, China
| | - Ming-Di Zhang
- Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200000, China
| | - Ming-Zhe Weng
- Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200000, China
| | - Di Zhou
- Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200000, China
| | - Jian-Dong Wang
- Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200000, China
| | - Zhi-Wei Quan
- Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200000, China
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Sharma A, Sharma KL, Gupta A, Yadav A, Kumar A. Gallbladder cancer epidemiology, pathogenesis and molecular genetics: Recent update. World J Gastroenterol 2017; 23:3978-3998. [PMID: 28652652 PMCID: PMC5473118 DOI: 10.3748/wjg.v23.i22.3978] [Citation(s) in RCA: 259] [Impact Index Per Article: 32.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2016] [Revised: 02/01/2017] [Accepted: 06/01/2017] [Indexed: 02/06/2023] Open
Abstract
Gallbladder cancer is a malignancy of biliary tract which is infrequent in developed countries but common in some specific geographical regions of developing countries. Late diagnosis and deprived prognosis are major problems for treatment of gallbladder carcinoma. The dramatic associations of this orphan cancer with various genetic and environmental factors are responsible for its poorly defined pathogenesis. An understanding to the relationship between epidemiology, molecular genetics and pathogenesis of gallbladder cancer can add new insights to its undetermined pathophysiology. Present review article provides a recent update regarding epidemiology, pathogenesis, and molecular genetics of gallbladder cancer. We systematically reviewed published literature on gallbladder cancer from online search engine PubMed (http://www.ncbi.nlm.nih.gov/pubmed). Various keywords used for retrieval of articles were Gallbladder, cancer Epidemiology, molecular genetics and bullion operators like AND, OR, NOT. Cross references were manually searched from various online search engines (http://www.ncbi.nlm.nih.gov/pubmed,https://scholar.google.co.in/, http://www.medline.com/home.jsp). Most of the articles published from 1982 to 2015 in peer reviewed journals have been included in this review.
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Gallbladder Cancer in the 21st Century. JOURNAL OF ONCOLOGY 2015; 2015:967472. [PMID: 26421012 PMCID: PMC4569807 DOI: 10.1155/2015/967472] [Citation(s) in RCA: 185] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/13/2015] [Revised: 08/07/2015] [Accepted: 08/12/2015] [Indexed: 02/07/2023]
Abstract
Gallbladder cancer (GBC) is an uncommon disease in the majority of the world despite being the most common and aggressive malignancy of the biliary tree. Early diagnosis is essential for improved prognosis; however, indolent and nonspecific clinical presentations with a paucity of pathognomonic/predictive radiological features often preclude accurate identification of GBC at an early stage. As such, GBC remains a highly lethal disease, with only 10% of all patients presenting at a stage amenable to surgical resection. Among this select population, continued improvements in survival during the 21st century are attributable to aggressive radical surgery with improved surgical techniques. This paper reviews the current available literature of the 21st century on PubMed and Medline to provide a detailed summary of the epidemiology and risk factors, pathogenesis, clinical presentation, radiology, pathology, management, and prognosis of GBC.
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Dwivedi AND, Jain S, Dixit R. Gall bladder carcinoma: Aggressive malignancy with protean loco-regional and distant spread. World J Clin Cases 2015; 3:231-244. [PMID: 25789296 PMCID: PMC4360495 DOI: 10.12998/wjcc.v3.i3.231] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2014] [Revised: 11/21/2014] [Accepted: 12/16/2014] [Indexed: 02/05/2023] Open
Abstract
The most common malignancy of biliary tract is gallbladder cancer (GBC) which is the third most common cancer in gastrointestinal tract. It is a lethal disease for most patients in spite of growing awareness and improved diagnostic techniques. GBC has a very poor prognosis and the 5 year survival rate is < 10%. Although etiology of the carcinoma of the gallbladder is still obscure, various factors have been implicated, cholelithiasis being the most frequent. The incidence of GBC worldwide is based on the gender, geography and ethnicity which suggest that both genetic and environmental factors can cause GBC. The major route of spread of gallbladder cancer (GC) is loco-regional rather than distant. It spreads by lymphatic, vascular, neural, intraperitoneal, and intraductal routes. Sonography is usually the most common imaging test to evaluate symptoms of biliary tract disease including suspected GC. With recent advances in imaging modalities like multi-detector computed tomography (CT) scanners, magnetic resonance imaging-positron emission tomography/CT diagnosis of gallbladder cancer has improved. Studies have also targeted molecular and genetic pathways. Treatment options have included extended and radical surgeries and adjuvant chemotherapy. This review article deals in detail with important aspects of carcinoma gallbladder and its manifestations and challenges. Role of various imaging modalities in characterization and accurate staging has been discussed. The loco-regional spread of this aggressive malignancy is dealt explicitly.
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Sequential occurrence of preneoplastic lesions and accumulation of loss of heterozygosity in patients with gallbladder stones suggest causal association with gallbladder cancer. Ann Surg 2015; 260:1073-80. [PMID: 24827397 DOI: 10.1097/sla.0000000000000495] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Causal association of gallbladder stones with gallbladder cancer (GBC) is not yet well established. OBJECTIVE To study the frequency of occurrence of preneoplastic histological lesions and loss of heterozygosity (LOH) of tumor suppressor genes in patients with gallstones. METHODS All consecutive patients with gallstones undergoing cholecystectomy from 2007-2011 were included prospectively. Histological examination of the gallbladder specimens was done for preneoplastic lesions. LOH at 8 loci, that is 3p12, 3p14.2, 5q21, 9p21, 9q, 13q, 17p13, and 18q for tumor suppressor genes (DUTT1, FHIT, APC, p16, FCMD, RB1, p53, and DCC genes) that are associated with GBC was tested from microdissected preneoplastic lesions using microsatellite markers. These LOH were also tested in 30 GBC specimens. RESULTS Of the 350 gallbladder specimens from gallstone patients, hyperplasia was found in 32%, metaplasia in 47.8%, dysplasia in 15.7%, and carcinoma in situ in 0.6%. Hyperplasia, metaplasia, and dysplasia alone were found in 11.7%, 24.6%, and 1.4% of patients, respectively. A combination of hyperplasia and dysplasia, metaplasia and dysplasia, and hyperplasia, metaplasia, and dysplasia was found in 3.4%, 6.3%, and 4.3% of patients, respectively. LOH was present in 2.1% to 47.8% of all the preneoplastic lesions at different loci. Fractional allelic loss was significantly higher in those with dysplasia compared with other preneoplastic lesions (0.31 vs 0.22; P = 0.042). No preneoplastic lesion or LOH was found in normal gallbladders. CONCLUSIONS Patients with gallstones had a high frequency of preneoplastic lesions and accumulation of LOH at various tumor suppressor genes, suggesting a possible causal association of gallstones with GBC.
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Geng ZM, Zhang M, Pan XT, Wang L. Bcl-2 gene silencing by RNA interference inhibits the growth of the human gallbladder carcinoma cell line GBC-SD in vitro and in vivo. Oncol Rep 2013; 30:793-800. [PMID: 23784204 DOI: 10.3892/or.2013.2539] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2013] [Accepted: 05/20/2013] [Indexed: 11/06/2022] Open
Abstract
Gallbladder carcinoma is the most common malignant tumor in the biliary system; however, the underlying mechanisms of tumor initiation, progression and metastasis are not fully understood to date. The B-cell lymphoma/leukemia-2 (Bcl-2) gene, which is highly expressed in gallbladder carcinoma tissue, is one of the most important regulatory factors in cell apoptosis, and plays an important role in the initiation and progression of gallbladder carcinoma. In the present study, we constructed a eukaryotic expression vector of small interference RNA (siRNA) specific to the Bcl-2 gene and transfected it into GBC-SD human gallbladder carcinoma cells. We demonstrated that the constructed Bcl-2 siRNA vector effectively silenced Bcl-2 gene expression in the GBC-SD human gallbladder carcinoma cells, inhibited cell proliferation, induced cell apoptosis, increased chemotherapeutic sensitivity to 5-fluorouracil and inhibited tumor growth in vivo. Collectively, these data reveal an important contribution of Bcl-2 to gallbladder carcinoma. Thus, the use of a synthetic inhibitor of Bcl-2 may be a promising approach for the treatment of gallbladder carcinoma.
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Affiliation(s)
- Zhi-Min Geng
- Department of Hepatobiliary Surgery, First Affiliated Hospital of the Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China.
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Kim HH, Hur YH, Jeong EH, Park EK, Koh YS, Kim JC, Kim HJ, Kim JW, Cho CK. Carcinosarcoma of the gallbladder: report of two cases. Surg Today 2012; 42:670-5. [PMID: 22391981 DOI: 10.1007/s00595-012-0160-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2011] [Accepted: 06/17/2011] [Indexed: 12/28/2022]
Abstract
Adenocarcinoma is the predominant histological type of carcinoma of the gallbladder, accounting for more than 80% of all gallbladder carcinomas. In contrast, carcinosarcoma of the gallbladder is an extremely atypical subset of gallbladder malignancies. It is characterized by the presence of both epithelial and mesenchymal components. Currently, fewer than 100 cases have been reported in the English literature. Therefore, knowledge and experience regarding this disease are limited. Recently, we experienced two cases of gallbladder carcinosarcoma, which were diagnosed as gallbladder carcinoma based on the preoperative clinical and radiological examinations. Cholecystectomies were performed in both cases, and the malignant tumor cells included carcinomatous and sarcomatous components histologically. The final pathological diagnoses were carcinosarcoma of the gallbladder. We herein report these two cases of gallbladder carcinosarcoma and review the previous pertinent literature.
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Affiliation(s)
- Ho-Hyun Kim
- Department of Surgery, Chonnam National University Medical School, 160, Ilsim-ri, Hwasun-eup, Hwasun-gun, Jellanam-do, Gwangju, 519-809, Korea
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Maurya SK, Tewari M, Mishra RR, Shukla HS. Genetic abberations in gallbladder cancer. Surg Oncol 2012; 21:37-43. [DOI: 10.1016/j.suronc.2010.09.003] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2010] [Revised: 08/07/2010] [Accepted: 09/06/2010] [Indexed: 12/20/2022]
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Munding J, Tannapfel A. [Pathological anatomical characteristics of Klatskin tumors. Classification, current molecular biological aspects, prognosis factors]. Chirurg 2012; 83:208-14. [PMID: 22290222 DOI: 10.1007/s00104-011-2175-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Klatskin tumors are a distinct subgroup of cholangiocarcinomas which are a surgical challenge due to their special localization. Different localizations do not show great differences concerning histomorphology and precursor lesions. With respect to molecular alterations there are only small differences. Accurate clinical and histomorphological diagnosis is important for therapy and especially the prediction of prognosis as well as standardized processing of the resection specimen if the carcinoma is resectable. Additionally, accurate lymph node dissection is necessary. Concerning molecular markers further investigations are needed to develop individualized therapy regimes.
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Affiliation(s)
- J Munding
- Institut für Pathologie, BG-Universitätsklinikum Bergmannsheil, Ruhr-Universität Bochum, Bürkle-de-la-Camp-Platz 1, 44789 Bochum.
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Alvi AR, Siddiqui NA, Zafar H. Risk factors of gallbladder cancer in Karachi-a case-control study. World J Surg Oncol 2011; 9:164. [PMID: 22151791 PMCID: PMC3256117 DOI: 10.1186/1477-7819-9-164] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2011] [Accepted: 12/09/2011] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Gallbladder carcinoma (GC) is a relatively rare malignancy worldwide but is the second commonest gastrointestinal cancer in Pakistani women. Gallstones have a positive association with GC but other factors also influence in causation. METHODS This is a retrospective case control study over a period of 19 years. The cases (Group A) were patients with histopathological proven carcinoma gallbladder (N = 60) and controls were patients with cholelithiasis but no carcinoma gallbladder on histopathology (N = 120). Multivariate regression analysis was done to calculate the odds ratio, 95% confidence interval and P-Value. A positive relationship was found between size of stone > 1 cm, solitary stone, age > 55 years and multi-parity in women. RESULTS There were 60 patients in Group A and 120 patients in Group B. mean age of diagnosis in Group A patients was 57 ± 2.4 years while mean age of diagnosis in Group B patients was 48 ± 1.35 years. Sixty seven percent of cancer group patients were female as compared to 78% females in non-cancer group. In Group A, 69% of female patients were multiparous (parity of more than 5) while 43% of group B patients were multiparous. For body mass index (BMI), both groups were not very different in our study population i.e. around 78% patients in each group has BMI of more than 23 Kg/m2. In Group A, 37% (n = 22) have solitary stones as compared to 15% (n = 18) in group B. similarly Group A patients has larger stone size as compared to Group B i.e.59% (n = 36) patients in Group A have stones of more than 1 cm when compared to 35% (n = 41) patients in Group B. After using multivariate regression analysis, age more than 55 years (OR - 7.27, p value- < 0.001), solitary stone (OR - 3.33, p value - 0.002) and stone of more than 1 cm (OR - 2.73, p value - 0.004) were found to be independent risk factors for development of gallbladder cancer. CONCLUSION Most of the patients (78%) with GC were female, and the statistically significant risk factors were older age, solitary stones and stones size more than one centimeter. A case can be made for prophylactic cholecystectomy in such a high risk group. However a population based study is required to calculate the true incidence of GC in Karachi and a prospective multi center study is needed to produce strong evidence for screening and prophylactic cholecystectomy. TRIAL REGISTRATION As this was a retrospective review of medical records, as per institution policy, its gives waiver from any registration (ethical/trial).
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Affiliation(s)
- A Rehman Alvi
- Department of Surgery, Aga Khan University Hospital, Karachi-74800, Pakistan
| | | | - Hasnain Zafar
- Department of Surgery, Aga Khan University Hospital, Karachi-74800, Pakistan
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Abstract
Gallbladder carcinosarcoma is a rare gastrointestinal tract malignant tumour, which contains both epithelial cancer component and mesenchymal sarcoma component. Because of its unique anatomic location and unspecific medical presentation, preoperative diagnosis is difficult. The prognosis of gallbladder carcinoma is poor with median survival time of 5.5 months. T- and N-staging system has no role in cancer prognostic stratification. Currently, we still have limited experience in managing this form of notorious cancer. Surgical resection is the common practice in treating gallbladder carcinoma though recurrence rate is high (80%). Here, we report a 59-year-old female with new diagnosed gallbladder carcinosarcoma. She was found to have a carcinosarcoma masse at gallbladder extending into proximal bile ducts with no metastatic lesion. She underwent a radical cholangiocholecystocholedochectomy and Roux-en-Y hepatocholangioduodenostomy. Postsurgery, she received six cycles of adjuvant chemotherapy consisting of oxaliplatin and 5-fluorouracil. She maintains in complete remission 6 months after adjuvant chemotherapy.
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Affiliation(s)
- Jeffrey J Pu
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medicine, Baltimore, Maryland, USA.
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Lhee MJ, Woo JY. Mixed Endocrine-Exocrine Carcinoma of Gallbladder Derived from Dysplasia. KOREAN JOURNAL OF PATHOLOGY 2011. [DOI: 10.4132/koreanjpathol.2011.45.5.537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Affiliation(s)
- Min Jin Lhee
- Department of Pathology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea
| | - Ji Young Woo
- Department of Radiology, Hallym University College of Medicine, Seoul, Korea
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Miller G, Socci ND, Dhall D, D'Angelica M, DeMatteo RP, Allen PJ, Singh B, Fong Y, Blumgart LH, Klimstra DS, Jarnagin WR. Genome wide analysis and clinical correlation of chromosomal and transcriptional mutations in cancers of the biliary tract. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2009; 28:62. [PMID: 19435499 PMCID: PMC2698861 DOI: 10.1186/1756-9966-28-62] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/01/2009] [Accepted: 05/12/2009] [Indexed: 02/07/2023]
Abstract
BACKGROUND The pathogenesis of biliary cancers is ill-defined. This study investigates changes in gene expression and copy number in biliary cancers and correlates these changes with anatomical site of origin, histopathology and outcome. METHODS We performed gene expression and CGH analysis on 34 biliary tract cancer specimens. Results were confirmed by RT-PCR. Clinical-pathologic correlation was made using functional over-representation analysis of the top 100 mutations associated with each variable. RESULTS There were 545 genes with altered expression in extrahepatic cholangiocarcinoma, 2,354 in intrahepatic cholangiocarcinoma, and 1,281 in gallbladder cancer. Unsupervised hierarchical clustering analysis indicated there was no difference in the global gene expression patterns between each biliary cancer subgroup. CGH analysis revealed that short segments of chromosomes 1p, 3p, 6q, 8p, 9p, and 14q were commonly deleted across all cancer subtypes. Commonly amplified regions included segments of 1q, 3q, 5p, 7p, 7q, 8q, and 20q. Over-representation analysis revealed an association between altered expression of functional gene groupings and pathologic features. CONCLUSION This study defined regions of the genome associated with changes in DNA copy number and gene expression in specific subtypes of biliary cancers. The findings have implications for identification of therapeutic targets, screening, and prognostication.
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Affiliation(s)
- George Miller
- Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
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Abstract
Gallbladder cancer (GBC) shows a marked geographical variation in its incidence, with the highest figures being seen in India and Chile and relatively low levels in many Western countries. Risk factors for its development include the presence of gallstones, infection and the presence of an anomalous pancreatobiliary ductal junction. It can arise from either a pathway involving metaplasia or dysplasia or one in which there is a pre-existing adenoma. The former is the more common and, because it is often not associated with a macroscopically recognizable lesion, leads to the recommendation that all gallbladders need to be examined microscopically. Accurate staging of invasive cancers is essential to determine prognosis and treatment, and this requires extensive tumour sampling. A number of genetic alterations have been identified in the preinvasive and invasive stages of GBC and they support the morphological evidence of there being two pathways by which tumours develop. Some of these genetic changes are associated with particular risk factors. For example, cases with anomalous pancreatobiliary ductal junction show a higher frequency of K-ras mutations. Some changes are associated with differences in prognosis. For example, cancers without expression of p21 but with expression for p27 have a better prognosis, whereas those that express c-erb-B2 have a worse one. Work has also been done on identifying clinical, imaging and other factors that indicate that patients have a higher risk of having GBC. This is particularly important in high-incidence areas in which GBC is a significant public health problem.
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Affiliation(s)
- Robert David Goldin
- Department of Histopathology, Imperial College Faculty of Medicine at St Mary's, London, UK.
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Uzun MA, Koksal N, Gunerhan Y, Celik A, Guneş P. Carcinosarcoma of the gallbladder: report of a case. Surg Today 2009; 39:168-71. [PMID: 19198999 DOI: 10.1007/s00595-008-3805-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2008] [Accepted: 05/16/2008] [Indexed: 12/21/2022]
Abstract
Gallbladder carcinosarcoma is one of the rarest subsets of gallbladder malignancies. To date, only 34 cases have been reported in the English literature. Therefore the knowledge and experience regarding this disease is limited. This report describes a 70-year-old male patient who was diagnosed by documenting the epithelial and mesenchymal components with histopathological and immunohistochemical methods, and treated by a radical cholecystectomy. The pediculated polypoid tumor had filled the lumen, originating from the gallbladder fundus. The tumor infiltrated the surrounding connective and adipose tissue overlapping the muscular layer of its primary site, but had not perforated the serosa nor invaded the liver. The patient, who was treated only surgically, has remained healthy after 54 months of follow-up, which is the longest documented survival for this disease. This case indicates that curative treatment of a tumor confined to the gallbladder without liver or serosa invasion, or lymph node involvement, is therefore possible.
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Affiliation(s)
- Mehmet Ali Uzun
- Second Department of General Surgery, Haydarpasa Numune Training and Research Hospital, Istanbul, Turkey
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Jiao X, Huang J, Wu S, Lv M, Hu Y, Su X, Luo C, Ce B. hOGG1 Ser326Cys polymorphism and susceptibility to gallbladder cancer in a Chinese population. Int J Cancer 2007; 121:501-5. [PMID: 17417784 DOI: 10.1002/ijc.22748] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
The human oxoguanine glycosylase 1(hOGG1) gene encodes a DNA glycosylase that is involved in excision repair of 8-OH-dG (8-hydroxy-2-deoxyguanine) from oxidatively-damaged DNA. To determine whether hOGG1 plays a role in the risk for adenocarcinoma of the gallbladder, we tested the association of this polymorphism with gallbladder cancer in a Chinese population-based, case control study of 204 cases and 209 controls. The subjects were genotyped with a polymerase chain reaction-restriction fragment length polymorphism (PCR-RELP) assay. The association between the genetic polymorphism of this gene and risk of the cancer was examined by using a multivariate analysis. We found that the distribution of hOGG1 Ser326Cys genotypes among controls (Ser/Ser, 37.3%; Ser/Cys, 53.6% and Cys/Cys, 9.1%) was significantly different from that among gallbladder cancer cases (Ser/Ser, 43.1%; Ser/Cys, 36.3% and Cys/Cys, 20.6%). Significantly increased risk for gallbladder cancer was both the hOGG1 326Ser/Cys (Odds ratio [OR] = 1.9, 95% confidence interval (CI) = 1.0-3.7) and hOGG1 326Cys/Cys genotypes (OR = 4.5, 95% CI = 1.1-22.4). We observed no statistically significant association between hOGG1 genotype and gallbladder cancer association in gallstone absence. In contrast, a near-significant increase in risk for gallbladder cancer was observed for gallstone presence with the hOGG1 326Ser/Cys genotype (OR = 2.2, CI = 1.4-3.5) whereas a significant increase in association for gallbladder cancer was observed for gallstone presence with the 326Cys/Cys genotype (OR = 6.1, CI = 2.1-27.2). These data corresponded with the fact that a significant trend towards increased association for gallbladder cancer was observed with potentially higher-risk hOGG1 genotypes in gallstone presence(p < 0.001, chi(2) trend test)but not in gallstone absence(p = 0.89, chi(2) trend test). A significant increase in risk for gallbladder cancer was observed for larger gallstone (those with stone diameters 2 cm or greater) with the hOGG1 326Ser/Cys(OR = 1.9, 95% CI = 1.1-2.9) and hOGG1 326Cys/Cys genotypes(OR = 5.9, 95% CI = 1.6-18.0). These data are consistent with the observation that a significant trend towards increased risk for gallbladder cancer was observed with potentially higher-risk hOGG1 genotypes in gallbladder cancer patients with larger gallstone (p < 0.001, chi(2) trend test). However, we observed no statistically significant association between hOGG1 genotype and gallbladder cancer risk in gallbladder cancer patients with smaller gallstone (those with stone diameters 2 cm smaller) (hOGG1 326Ser/Cys:OR = 2.2, 95% CI = 0.8-4.0; hOGG1 326Cys/Cys:OR = 2.9, 95% CI = 0.6-29.4; p = 0.06, chi(2) tread test). These results suggest that hOGG1 Ser326Cys polymorphism is associated with gallbladder cancer risk.
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Affiliation(s)
- Xingyuan Jiao
- Department of Hepatobiliary Surgery, Second Affiliated Hospital, Guangzhou Medical College, Guangzhou, Guangdong Province, The People's Republic of China.
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Tu Z, Gui L, Wang J, Li X, Sun P, Wei L. Tumorigenesis of K-ras mutation in human endometrial carcinoma via upregulation of estrogen receptor. Gynecol Oncol 2006; 101:274-9. [PMID: 16303170 DOI: 10.1016/j.ygyno.2005.10.016] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2005] [Revised: 10/13/2005] [Accepted: 10/19/2005] [Indexed: 02/07/2023]
Abstract
OBJECTIVE To investigate the tumorigenesis of mutant [12Asp]-K-ras in endometrial carcinoma and its relationship with ER. METHODS We constructed pcDI-[12Asp]K-ras4B by inserting full-length [12Asp]K-ras4B from human endometrial carcinoma Hec-1A cells, into pcDI vector. Cell proliferation of NIH3T3 after transfection with pcDI-[12Asp]K-ras4B was measured by MTT assay. The cell transformation was determined by colony formation and tumor nodule development. [12Asp]-K-ras4B-NIH3T3 cells were transfected with constitutively active pCMV-RafCAAX and dominant-negative pCMV-RafS621A. Cell growth was measured by MTT assay and [3H]thymidine incorporation. After transfected with pcDI-[12Asp]K-ras4B or pCMV-RafS621A, the cells were harvested for Western blot and reporter assay to determine the expression and transcriptional activity of ERalpha and ERbeta, respectively. RESULTS [12Asp]-K-ras4B enhanced NIH3T3 cells proliferation after 48 h post-transfection (P < 0.05). More colonies were grown 10 days after incubating pcDI-[12Asp]-K-ras4B-NIH3T3 cells (13.48%) than pcDI-NIH3T3 (4.26%) or untreated NIH3T3 (2.33%). The pcDI-[12Asp]-K-ras4B-NIH3T3 cells injected to the nude mice Balb/C developed tumor nodules with poor-differentiated cells after 12 days. An increase of ERalpha and ERbeta was observed in pcDI-[12Asp]-K-ras4B-NIH3T3 cells. RafS621A downregulated ERalpha and ERbeta expression. Estrogen induced the ER transcriptional activity by 5-fold in pcDI-NIH3T3 cells, 13-fold in pcDI-[12Asp]K-ras4B-NIH3T3 and 19-fold in HEC-1A. RafS621A suppressed the ER transcriptional activity. CONCLUSIONS K-ras mutation induces tumorigenesis in endometrium, and this malignant transformation involves Raf signaling pathway and ER.
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Affiliation(s)
- Zheng Tu
- Department of Gynecology, Peking University People's Hospital, 11 Xizhimen South Street, Beijing 100044, China
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