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1
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Wietsma MFT, Molloy C, Bhimani N, de Savornin Lohman EAJ, Gill AJ, Andrici J, Samra J, de Reuver PR, Hugh TJ. Gallbladder carcinoma outcomes in an Australian tertiary referral hospital. ANZ J Surg 2021; 91:603-608. [PMID: 33604992 DOI: 10.1111/ans.16663] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 01/31/2021] [Accepted: 02/02/2021] [Indexed: 12/19/2022]
Abstract
BACKGROUND This study aimed to examine the presentation, treatment, and long-term outcomes of patients with gallbladder carcinoma (GBC) managed in a surgical unit of an Australian tertiary referral hospital of a 19-year period. METHODS A retrospective review of prospectively collected data of patients with GBC managed in the Royal North Shore Upper GI Surgical department from October 1999 to March 2018. RESULTS A total of 104 patients with GBC were identified: 36 patients underwent palliative treatment, 61 patients with gallbladder adenocarcinoma underwent resection with curative intent. Seven patients were excluded. 'Simple cholecystectomy' was undertaken in eight patients, 'standard radical cholecystectomy' in 37 and 'extended radical resection' in 16. The median survival in these patients was 35 months (95% confidence interval (CI) 21.29-55.10), with a median follow up of 60 months (95% CI 38.18-78.39). This compares with an overall median survival of only 4.00 months (95% CI 2.79-6.24) in patients who did not undergo a potentially curative resection. Independent predictors of poor long-term survival included an elevated preoperative serum tumour marker, advanced tumour stage (T3/T4) or node positive disease (N1/N2). CONCLUSION The biology and stage of GBC at presentation are major factors in determining patient outcome. There is a need for better pre- and post-operative predictors to improve risk stratification, and these are likely to be in the form of molecular markers. Although the focus of surgery should be to ensure an R0 resection, patients with advanced stage disease need to be carefully selected for surgical intervention, and ideally should be managed by a multidisciplinary team in a specialist centre.
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Affiliation(s)
| | - Charles Molloy
- Department of Upper Gastrointestinal Surgery, Royal North Shore Hospital, Sydney, New South Wales, Australia
| | - Nazim Bhimani
- Department of Upper Gastrointestinal Surgery, Royal North Shore Hospital, Sydney, New South Wales, Australia
| | | | - Anthony J Gill
- Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, New South Wales, Australia.,Northern Clinical School, University of Sydney, Sydney, New South Wales, Australia
| | - Juliana Andrici
- Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, New South Wales, Australia
| | - Jaswinder Samra
- Department of Upper Gastrointestinal Surgery, Royal North Shore Hospital, Sydney, New South Wales, Australia.,Northern Clinical School, University of Sydney, Sydney, New South Wales, Australia
| | - Philip R de Reuver
- Department of Surgery, Radboud University Medical Centre, Nijmegen, Netherlands
| | - Thomas J Hugh
- Department of Upper Gastrointestinal Surgery, Royal North Shore Hospital, Sydney, New South Wales, Australia.,Northern Clinical School, University of Sydney, Sydney, New South Wales, Australia
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2
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Guo J, Deng N, Xu Y, Li L, Kuang D, Li M, Li X, Xu Z, Xiang M, Xu C. Bmi1 drives the formation and development of intrahepatic cholangiocarcinoma independent of Ink4A/Arf repression. Pharmacol Res 2021; 164:105365. [PMID: 33307220 DOI: 10.1016/j.phrs.2020.105365] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 11/29/2020] [Accepted: 11/30/2020] [Indexed: 12/23/2022]
Abstract
Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the most prevalent types of primary liver cancer. Compared with HCC, for which several drugs have been approved, ICC is associated with shorter survival, and no drug has been approved for this type. Previously, we reported that Bmi1 drives HCC and is required for HCC development and growth. However, whether Bmi1 plays a critical role in ICC is not clear, although it reportedly is highly expressed in ICC. Therefore, we investigated its role in ICC. Here, we report that Bmi1 promotes ICC initiation and progression independent of the Ink4A/Arf pathway, a canonical downstream pathway of Bmi1. We found that Bmi1 is overexpressed in human ICC. Co-expression of Bmi1 and NRas induced ICC formation in mice. Knockdown or inactivation of Bmi1 inhibited ICC growth in vitro. Liver-specific knockout or inactivation of Bmi1 remarkably suppressed ICC tumor formation and development in vivo. Mechanistically, no correlation between Bmi1 and Ink4A/Arf levels was found in mouse and human ICC tissues. Together, our data indicate that Bmi1 functions as an oncogene independent of repression of the Ink4A/Arf locus in ICC and that it can serve as a target for ICC treatment.
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Affiliation(s)
- Jun Guo
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Nan Deng
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yong Xu
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Lei Li
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Dong Kuang
- Department of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Min Li
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022. China
| | - Xiaolei Li
- Department of Thyroid and Breast Surgery, The 960th Hospital of the PLA, Jinan, 250031, China
| | - Zhong Xu
- Department of Infectious Diseases, Guizhou Provincial People's Hospital, Guiyang, 550002, China
| | - Ming Xiang
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Chuanrui Xu
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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3
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Banxia Xiexin Decoction () Combined with Afatinib in Treatment of Advanced Gallbladder Cancer: Case Report and Literature Review. Chin J Integr Med 2019; 25:303-306. [PMID: 30707412 DOI: 10.1007/s11655-019-3152-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Indexed: 01/02/2023]
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Abstract
BACKGROUND Cholangiocarcinomas (CCAs) are aggressive malignancies that display features of biliary differentiation. According to their anatomical location, CCAs are commonly classified as intrahepatic and extrahepatic tumors, the latter entity being further subdivided into perihilar CCAs, also termed as Klatskin tumors, and distal tumors. While a majority of CCAs occur sporadically, established risk factors such as liver fluke infestation or primary sclerosing cholangitis exist. SUMMARY Due to lack of efficient early screening markers, CCAs are frequently diagnosed at an advanced stage when curative surgical resection is not an option. Chemotherapy with gemcitabine and cisplatin is currently the standard palliative treatment that prolongs overall survival by 3.6 months as compared to monotherapy with gemcitabine. For CCA patients who progress under gemcitabine/cisplatin, the paucity of prospective, randomized trials is detrimental, and there is currently no recommended second-line regimen with respect to chemotherapy or loco-regional treatment modalities. Molecular profiling of CCAs supports the implementation of targeted approaches, and it is reasonable that personalized therapy will become a mainstay of CCA treatment. In addition, the advent of immunotherapy holds considerable promise, yet, similar to targeted treatment, needs to be prospectively evaluated in clinically and genetically thoroughly characterized patients. KEY POINTS (1) CCA is a genetically diverse and highly aggressive malignancy. (2) Gemcitabine in combination with cisplatin or oxaliplatin is the current first-line chemotherapy in non-resectable patients. (3) Loco-regional treatment modalities exist but need to be evaluated in prospective randomized trials in the context of systemic chemotherapy. (4) Targeted therapies in molecularly defined subgroups of patients and immunotherapies alone or in combinations will most likely improve survival in the future.
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Affiliation(s)
- Arndt Vogel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
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5
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Liu Q, Wu N, Zhou N. Port-Site Resection in Surgical Management of Incidental Gallbladder Cancer: A Still Unresolved Question. Ann Surg Oncol 2017; 24:646. [PMID: 29159740 DOI: 10.1245/s10434-017-6226-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2017] [Indexed: 11/18/2022]
Affiliation(s)
- Quanda Liu
- Department of Hepatobiliary Surgery, Second Artillery General Hospital PLA, Beijing, China.
| | - Naixin Wu
- Shanghai Jiao Tong University, Shanghai, China
| | - Ningxin Zhou
- Department of Hepatobiliary Surgery, Second Artillery General Hospital PLA, Beijing, China
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6
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Sicklick JK, Fanta PT, Shimabukuro K, Kurzrock R. Genomics of gallbladder cancer: the case for biomarker-driven clinical trial design. Cancer Metastasis Rev 2017; 35:263-75. [PMID: 26857926 DOI: 10.1007/s10555-016-9602-8] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND AND AIMS Gallbladder carcinoma is a rare, aggressive malignancy of the biliary tract associated with a poor prognosis. Despite the deployment of targeted therapies that have demonstrated marked survival benefits in many tumor types, traditional cytotoxic chemotherapy has remained the mainstay of treatment for unresectable and metastatic gallbladder cancer. METHODS Systematic review of ongoing and prior clinical studies shows a paucity of biomarker-driven therapeutic trials using targeted agents in gallbladder cancer. In fact, over the past 6 years, of the 38 therapeutic biliary tract protocols listed on clinicaltrials.gov, only 6 (21 %) utilized targeted therapies based upon tumor biomarkers or genomics. Now that we have entered the era of next-generation sequencing and precision medicine, we are beginning to identify common and specific genetic alterations in gallbladder carcinomas. RESULTS A review of the literature reveals alterations in ARID1A, BRAF, CDKN2A/B, EGFR, ERBB2-4, HKN-RAS, PIK3CA, PBRM1, and TP53. Given the widespread use of tumor genomic profiling and the fact that most of the aforementioned alterations are pharmacologically tractable, these observations suggest the potential for new therapeutic strategies in this aggressive malignancy. CONCLUSIONS Taken together, further understanding of the genomic landscape of gallbladder cancer coupled with biomarker-driven clinical trials that match therapies to targets are urgently needed.
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Affiliation(s)
- Jason K Sicklick
- Center for Personalized Cancer Therapy, San Diego, CA, USA. .,Division of Surgical Oncology, Department of Surgery, University of California, San Diego Moores Cancer Center, 3855 Health Sciences Drive, MC 0987, La Jolla, CA, 92093-0987, USA.
| | - Paul T Fanta
- Center for Personalized Cancer Therapy, San Diego, CA, USA.,Division of Hematology and Oncology, University of California, San Diego Moores Cancer Center, 3855 Health Sciences Drive, MC 0987, La Jolla, 92093-0987, CA, USA
| | - Kelly Shimabukuro
- Center for Personalized Cancer Therapy, San Diego, CA, USA.,Division of Hematology and Oncology, University of California, San Diego Moores Cancer Center, 3855 Health Sciences Drive, MC 0987, La Jolla, 92093-0987, CA, USA
| | - Razelle Kurzrock
- Center for Personalized Cancer Therapy, San Diego, CA, USA.,Division of Hematology and Oncology, University of California, San Diego Moores Cancer Center, 3855 Health Sciences Drive, MC 0987, La Jolla, 92093-0987, CA, USA
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7
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Yokoyama M, Ohnishi H, Ohtsuka K, Matsushima S, Ohkura Y, Furuse J, Watanabe T, Mori T, Sugiyama M. KRAS Mutation as a Potential Prognostic Biomarker of Biliary Tract Cancers. JAPANESE CLINICAL MEDICINE 2016; 7:33-39. [PMID: 28008299 PMCID: PMC5156551 DOI: 10.4137/jcm.s40549] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/11/2016] [Revised: 08/31/2016] [Accepted: 09/02/2016] [Indexed: 12/25/2022]
Abstract
BACKGROUND The aim of this study was to identify the unique molecular characteristics of biliary tract cancer (BTC) for the development of novel molecular-targeted therapies. MATERIALS AND METHODS We performed mutational analysis of KRAS, BRAF, PIK3CA, and FBXW7 and immunohistochemical analysis of EGFR and TP53 in 63 Japanese patients with BTC and retrospectively evaluated the association between the molecular characteristics and clinicopathological features of BTC. RESULTS KRAS mutations were identified in 9 (14%) of the 63 BTC patients; no mutations were detected within the analyzed regions of BRAF, PIK3CA, and FBXW7. EGFR overexpression was observed in 5 (8%) of the 63 tumors, while TP53 overexpression was observed in 48% (30/63) of the patients. Overall survival of patients with KRAS mutation was significantly shorter than that of patients with the wild-type KRAS gene (P = 0.005). By multivariate analysis incorporating molecular and clinicopathological features, KRAS mutations and lymph node metastasis were identified to be independently associated with shorter overall survival (KRAS, P = 0.004; lymph node metastasis, P = 0.015). CONCLUSIONS Our data suggest that KRAS mutation is a poor prognosis predictive biomarker for the survival in BTC patients.
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Affiliation(s)
- Masaaki Yokoyama
- Department of Surgery, Kyorin University School of Medicine, Tokyo, Japan
| | - Hiroaki Ohnishi
- Department of Laboratory Medicine, Kyorin University School of Medicine, Tokyo, Japan
| | - Kouki Ohtsuka
- Department of Laboratory Medicine, Kyorin University School of Medicine, Tokyo, Japan
| | - Satsuki Matsushima
- Department of Laboratory Medicine, Kyorin University School of Medicine, Tokyo, Japan
| | - Yasuo Ohkura
- Department of Pathology, Kyorin University School of Medicine, Tokyo, Japan
| | - Junji Furuse
- Department of Medical Oncology, Kyorin University School of Medicine, Tokyo, Japan
| | - Takashi Watanabe
- Department of Laboratory Medicine, Kyorin University School of Medicine, Tokyo, Japan
| | - Toshiyuki Mori
- Department of Surgery, Kyorin University School of Medicine, Tokyo, Japan
| | - Masanori Sugiyama
- Department of Surgery, Kyorin University School of Medicine, Tokyo, Japan
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8
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Wang J, Xie C, Pan S, Liang Y, Han J, Lan Y, Sun J, Li K, Sun B, Yang G, Shi H, Li Y, Song R, Liu X, Zhu M, Yin D, Wang H, Song X, Lu Z, Jiang H, Zheng T, Liu L. N-myc downstream-regulated gene 2 inhibits human cholangiocarcinoma progression and is regulated by leukemia inhibitory factor/MicroRNA-181c negative feedback pathway. Hepatology 2016; 64:1606-1622. [PMID: 27533020 DOI: 10.1002/hep.28781] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Accepted: 07/18/2016] [Indexed: 12/19/2022]
Abstract
UNLABELLED Increasing evidence supports a role for N-myc downstream-regulated gene 2 (NDRG2) deregulation in tumorigenesis. We investigated the roles and mechanisms of NDRG2 in human cholangiocarcinoma (CCA) progression. In the present study, expression of NDRG2, microRNA (miR)-181c and leukemia inhibitory factor (LIF) in human CCA and adjacent nontumor tissues were examined. The effects of NDRG2 on CCA tumor growth and metastasis were determined both in vivo and in vitro. The role of the NDRG2/LIF/miR-181c signaling pathway in cholangiocarcinogenesis and metastasis were investigated both in vivo and in vitro. The results showed that human CCA tissues exhibited decreased levels of NDRG2 and increased levels of miR-181c and LIF compared with nontumor tissues. NDRG2 could inhibit CCA cell proliferation, chemoresistance, and metastasis both in vitro and in vivo. We found that NDRG2 is a target gene of miR-181c, and the down-regulation of NDRG2 was attributed to miR-181c overexpression in CCA. Furthermore, miR-181c can be activated by LIF treatment, whereas NDRG2 could inhibit LIF transcription through disrupting the binding between Smad, small mothers against decapentaplegic complex and LIF promoter. Down-regulation of NDRG2 and overexpression of miR-181c or LIF are significantly associated with a poorer overall survival (OS) in CCA patients. Finally, we found that a combination of NDRG2, miR-181c, and LIF expression is a strong predictor of prognosis in CCA patients. CONCLUSION These results establish the counteraction between NDRG2 and LIF/miR-181c as a key mechanism that regulates cholangiocarcinogenesis and metastasis. Our results elucidated a novel pathway in NDRG2-mediated inhibition of cholangiocarcinogenesis and metastasis and suggest new therapeutic targets, including NDRG2, LIF, miR-181c, and transforming growth factor beta, in CCA prevention and treatment. (Hepatology 2016;64:1606-1622).
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Affiliation(s)
- Jiabei Wang
- Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, China
| | - Changming Xie
- Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, China
| | - Shangha Pan
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yingjian Liang
- Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, China
| | - Jihua Han
- Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, China
| | - Yaliang Lan
- Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, China
| | - Jing Sun
- Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, China
| | - Keyu Li
- Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, China
| | - Boshi Sun
- Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, China
| | - Guangchao Yang
- Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, China
| | - Huawen Shi
- Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, China
| | - Yuejin Li
- Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, China
| | - Ruipeng Song
- Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, China
| | - Xirui Liu
- Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, China
| | - Mingxi Zhu
- Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, China
| | - Dalong Yin
- Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, China
| | - Huanlai Wang
- Department of General Surgery, Qiqihaer City Hospital of Traditional Chinese Medicine, Qiqihaer, China
| | - Xuan Song
- Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, China
| | - Zhaoyang Lu
- Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, China
| | - Hongchi Jiang
- Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, China
| | - Tongsen Zheng
- Department of Gastrointestinal Medical Oncology, The Affiliated Tumour Hospital of Harbin Medical University, Harbin, China.
| | - Lianxin Liu
- Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, China. .,Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, China.
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9
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Yin DL, Liang YJ, Zheng TS, Song RP, Wang JB, Sun BS, Pan SH, Qu LD, Liu JR, Jiang HC, Liu LX. EF24 inhibits tumor growth and metastasis via suppressing NF-kappaB dependent pathways in human cholangiocarcinoma. Sci Rep 2016; 6:32167. [PMID: 27571770 PMCID: PMC5004153 DOI: 10.1038/srep32167] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Accepted: 08/02/2016] [Indexed: 02/06/2023] Open
Abstract
A synthetic monoketone analog of curcumin, termed 3, 5-bis (2-flurobenzylidene) piperidin-4-one (EF24), has been reported to inhibit the growth of a variety of cancer cells both in vitro and in vivo. However, whether EF24 has anticancer effects on cholangiocarcinoma (CCA) cells and the mechanisms remain to be investigated. The aim of our study was to evaluate the molecular mechanisms underlying the anticancer effects of EF24 on CCA tumor growth and metastasis. Cell proliferation, apoptosis, migration, invasion, tumorigenesis and metastasis were examined. EF24 exhibited time- and dose-dependent inhibitory effects on HuCCT-1, TFK-1 and HuH28 human CCA cell lines. EF24 inhibited CCA cell proliferation, migration, and induced G2/M phase arrest. EF24 induced cell apoptosis along with negative regulation of NF-κB- X-linked inhibitor of apoptosis protein (XIAP) signaling pathway. XIAP inhibition by lentivirus mediated RNA interference enhanced EF24-induced apoptosis, while XIAP overexpression reduced it in CCA cells. In vivo, EF24 significantly suppressed the growth of CCA tumor xenografts and tumor metastasis while displaying low toxicity levels. Our findings indicate that EF24 is a potent antitumor agent that inhibits tumor growth and metastasis by inhibiting NF-κB dependent signaling pathways. EF24 may represent a novel approach for CCA treatment.
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Affiliation(s)
- Da-long Yin
- Department of General Surgery, the First Affiliated Hospital of Harbin Medical University; Key Laboratory of Hepatosplenic Surgery, Ministry of Education. No23, Youzheng Street, Nangang District, Harbin, Heilongjiang Province, 150001, P.R.China
- Department of Pharmacology, The State-Province Key Laboratories of Biomedicine- Pharmaceutics of China, Harbin Medical University, Harbin, Heilongjiang 150081, PR China
| | - Ying-jian Liang
- Department of General Surgery, the First Affiliated Hospital of Harbin Medical University; Key Laboratory of Hepatosplenic Surgery, Ministry of Education. No23, Youzheng Street, Nangang District, Harbin, Heilongjiang Province, 150001, P.R.China
| | - Tong-sen Zheng
- Department of General Surgery, the First Affiliated Hospital of Harbin Medical University; Key Laboratory of Hepatosplenic Surgery, Ministry of Education. No23, Youzheng Street, Nangang District, Harbin, Heilongjiang Province, 150001, P.R.China
| | - Rui-peng Song
- Department of General Surgery, the First Affiliated Hospital of Harbin Medical University; Key Laboratory of Hepatosplenic Surgery, Ministry of Education. No23, Youzheng Street, Nangang District, Harbin, Heilongjiang Province, 150001, P.R.China
- Department of Pharmacology, The State-Province Key Laboratories of Biomedicine- Pharmaceutics of China, Harbin Medical University, Harbin, Heilongjiang 150081, PR China
| | - Jia-bei Wang
- Department of General Surgery, the First Affiliated Hospital of Harbin Medical University; Key Laboratory of Hepatosplenic Surgery, Ministry of Education. No23, Youzheng Street, Nangang District, Harbin, Heilongjiang Province, 150001, P.R.China
| | - Bo-shi Sun
- Department of General Surgery, the First Affiliated Hospital of Harbin Medical University; Key Laboratory of Hepatosplenic Surgery, Ministry of Education. No23, Youzheng Street, Nangang District, Harbin, Heilongjiang Province, 150001, P.R.China
| | - Shang-ha Pan
- Department of General Surgery, the First Affiliated Hospital of Harbin Medical University; Key Laboratory of Hepatosplenic Surgery, Ministry of Education. No23, Youzheng Street, Nangang District, Harbin, Heilongjiang Province, 150001, P.R.China
| | - Lian-dong Qu
- National Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin, P.R. China
| | - Jia-ren Liu
- Department of Anaesthesia, Harvard Medical School, Boston, MA, USA
| | - Hong-chi Jiang
- Department of General Surgery, the First Affiliated Hospital of Harbin Medical University; Key Laboratory of Hepatosplenic Surgery, Ministry of Education. No23, Youzheng Street, Nangang District, Harbin, Heilongjiang Province, 150001, P.R.China
| | - Lian-xin Liu
- Department of General Surgery, the First Affiliated Hospital of Harbin Medical University; Key Laboratory of Hepatosplenic Surgery, Ministry of Education. No23, Youzheng Street, Nangang District, Harbin, Heilongjiang Province, 150001, P.R.China
- Department of Pharmacology, The State-Province Key Laboratories of Biomedicine- Pharmaceutics of China, Harbin Medical University, Harbin, Heilongjiang 150081, PR China
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10
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Pei T, Li Y, Wang J, Wang H, Liang Y, Shi H, Sun B, Yin D, Sun J, Song R, Pan S, Sun Y, Jiang H, Zheng T, Liu L. YAP is a critical oncogene in human cholangiocarcinoma. Oncotarget 2016; 6:17206-20. [PMID: 26015398 PMCID: PMC4627302 DOI: 10.18632/oncotarget.4043] [Citation(s) in RCA: 111] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2015] [Accepted: 04/30/2015] [Indexed: 12/15/2022] Open
Abstract
Yes-associated protein (YAP), a transcriptional co-activator, has important regulatory roles in cell signaling and is dysregulated in a number of cancers. However, the role of YAP in cholangiocarcinoma (CCA) progression remains unclear. Here, we demonstrated that YAP was overexpressed in CCA cells and human specimens. High levels of nuclear YAP (nYAP) correlated with histological differentiation, TNM stage, metastasis and poor prognosis in CCA. Silencing YAP increased tumor sensitivity to chemotherapy and inhibited CCA tumorigenesis and metastasis both in vivo and in vitro. YAP overexpression in vivo and in vitro promoted CCA tumorigenesis and metastasis. Additionally, we found that YAP induced epithelial-mesenchymal transition (EMT) and formed a regulatory circuit with miR-29c, IGF1, AKT and gankyrin to promote the progression of CCA. Results of CCA tissue microarray showed positive correlations between nYAP and gankyrin or p-AKT expression. Combination of nYAP and gankyrin or p-AKT exhibited improved prognostic accuracy for CCA patients. In conclusion, YAP promotes carcinogenesis and metastasis by up-regulating gankyrin through activation of the AKT pathway.
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Affiliation(s)
- Tiemin Pei
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yuejin Li
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Jiabei Wang
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Huanlai Wang
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.,Department of General Surgery, Qiqihaer City Hospital of Traditional Chinese Medicine, Qiqihaer, China
| | - Yingjian Liang
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Huawen Shi
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Boshi Sun
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Dalong Yin
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Jing Sun
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Ruipeng Song
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Shangha Pan
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yu Sun
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Hongchi Jiang
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Tongsen Zheng
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Lianxin Liu
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
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11
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Kakaei F, Beheshtirouy S, Nejatollahi SM, Zarrintan S, Mafi MR. Surgical treatment of gallbladder carcinoma: a critical review. Updates Surg 2015; 67:339-51. [PMID: 26563387 DOI: 10.1007/s13304-015-0328-x] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2015] [Accepted: 09/10/2015] [Indexed: 12/13/2022]
Abstract
Gallbladder carcinoma is a relatively uncommon cancer of gastrointestinal (GI) tract. Medical literature is full of nihilistic reports about the treatment of gallbladder carcinoma, especially due to its resistance to current radiotherapeutic or chemotherapeutic treatment modalities and difficult surgical approach for complete resection of these tumors. Herein, we review current diagnostic and therapeutic approaches to this rare GI cancer.
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Affiliation(s)
- Farzad Kakaei
- Section of Organ Transplantation, Imam Reza Hospital, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of General & Vascular Surgery, Imam Reza Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Samad Beheshtirouy
- Department of Cardiothoracic Surgery, Imam Reza Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Sina Zarrintan
- Department of General & Vascular Surgery, Imam Reza Hospital, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Mohammad Reza Mafi
- Department of General & Vascular Surgery, Imam Reza Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
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12
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Onesti CE, Romiti A, Roberto M, Falcone R, Marchetti P. Recent advances for the treatment of pancreatic and biliary tract cancer after first-line treatment failure. Expert Rev Anticancer Ther 2015; 15:1183-98. [PMID: 26325474 DOI: 10.1586/14737140.2015.1081816] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Here, we evaluate clinical trials on chemotherapy for patients with pancreatic or biliary tract cancer after first-line treatment failure. Clinical trials on conventional and innovative medical treatments for progressive pancreatic and biliary cancer were analyzed. Metronomic chemotherapy, which consists of the administration of continuative low-dose of anticancer drugs, was also considered. A significant extension of overall survival was achieved with second-line, regimens in patients with gemcitabine-refractory pancreatic cancer. Moreover, many Phase II studies, including chemotherapy and target molecules and immunotherapy, have reported promising results, in both pancreatic and biliary cancer. However, data in these patients' setting are very heterogeneous, and only few randomized studies are available.
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Affiliation(s)
| | | | - Michela Roberto
- a Clinical and Molecular Medicine Department, Sapienza University, Rome, Italy
| | - Rosa Falcone
- a Clinical and Molecular Medicine Department, Sapienza University, Rome, Italy
| | - Paolo Marchetti
- a Clinical and Molecular Medicine Department, Sapienza University, Rome, Italy
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13
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Systemic therapy of cholangiocarcinoma: From chemotherapy to targeted therapies. Best Pract Res Clin Gastroenterol 2015; 29:345-53. [PMID: 25966433 DOI: 10.1016/j.bpg.2015.01.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2014] [Accepted: 01/06/2015] [Indexed: 01/31/2023]
Abstract
Cholangiocarcinomas (CCA) are rare tumors of the liver with poor prognosis. The standard of care in patients with unresectable tumors or metastatic disease is combination chemotherapy (CT) with gemcitabine and cisplatin. Targeted therapies inhibiting EGFR, VEGF, MEK and others are broadly tested in CCA but to date, the existing data from randomized and nonrandomized trials do not justify the application of small molecules outside of clinical trials. In clinical practice, many patients receive second-line CT after failure of gemcitabine/cisplatin, although there is so far no evidence to support second-line CT. This review summarizes current chemotherapy protocols and ongoing studies, including conventional chemotherapy and targeted therapies.
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14
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Zhao Q, Qian S, Zhu L, Qu XD, Zhang W, Yan ZP, Cheng JM, Liu QX, Liu R, Wang JH. Transcatheter arterial chemoembolization with gemcitabine and oxaliplatin for the treatment of advanced biliary tract cancer. Onco Targets Ther 2015; 8:595-600. [PMID: 25792843 PMCID: PMC4360827 DOI: 10.2147/ott.s79316] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Background The aim of this study was to determine the therapeutic efficacy and safety of transarterial chemoembolization (TACE) with gemcitabine and oxaliplatin in patients with advanced biliary tract cancer (BTC). Methods We retrospectively analyzed the outcomes for 65 patients with advanced BTC treated by TACE with gemcitabine 1,000 mg/m2 and oxaliplatin 100 mg/m2. Follow-up laboratory tests and computed tomography or magnetic resonance imaging were performed routinely to evaluate the response of the tumor to treatment. All patients were assessed for adverse effects. Results Of the 65 patients, 19 (29.2%) achieved a partial response, 36 (55.4%) showed stable disease, and ten (15.4%) showed progressive disease. The overall response rate was 29.2%. At the end of this study, five patients were still alive. The median overall survival was 12.0 months (95% confidence interval 8.5–15.5). There were no serious complications after TACE. Conclusion The disease control rate and overall survival in this retrospective study were consistent with those in previous reports. TACE with gemcitabine and oxaliplatin was well tolerated and highly effective in patients with advanced BTC.
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Affiliation(s)
- Qing Zhao
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Sheng Qian
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Liang Zhu
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Xu-Dong Qu
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Wei Zhang
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Zhi-Ping Yan
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Jie-Min Cheng
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Qing-Xin Liu
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Rong Liu
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Jian-Hua Wang
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
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15
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Wiesweg M, Aydin S, Koeninger A, Stein A, Schara U, van Roye C, Hense J, Welt A, Schuler M. Administration of Gemcitabine for Metastatic Adenocarcinoma during Pregnancy: A Case Report and Review of the Literature. AJP Rep 2014; 4:17-22. [PMID: 25032054 PMCID: PMC4078105 DOI: 10.1055/s-0034-1368091] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2013] [Accepted: 12/17/2013] [Indexed: 12/12/2022] Open
Abstract
We present the case of a 38-year-old woman diagnosed with metastatic adenocarcinoma of the biliary tract in the 18th week of pregnancy. Chemotherapy based on cisplatin and gemcitabine was administered, reaching disease stabilization until late-preterm delivery at 35 + 0 weeks of gestation. The infant was healthy and showed no malformations. Her head circumference was small, yet no neurological and behavioral defects have been detected. Development was normal during 14 months of follow-up. We discuss the implications of metastatic cancer in pregnancy with focus on therapeutic options for metastatic adenocarcinoma of the biliary tract. In this context, available data for the active regimens in biliary tract cancers-platinum compounds and gemcitabine-are discussed. This report is the fourth in the literature detailing the application of gemcitabine during pregnancy and the first presenting longer term follow-up, complementing available evidence that gemcitabine-based regimens are feasible in this situation.
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Affiliation(s)
- M Wiesweg
- Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - S Aydin
- Dipartimento di Ematologia ed Oncologia, Azienda ospedaliera Città della Salute e della Scienza di Torino, Torino, Italy
| | - A Koeninger
- Department of Gynecology and Obstetrics, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - A Stein
- Department of Neonatology, Clinic for Pediatrics I, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - U Schara
- Department of Neuropediatrics, Developmental Neurology and Social Pediatrics, Clinic for Pediatrics I, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - C van Roye
- Hematology/Oncology Group Practice, Koblenz, Germany
| | - J Hense
- Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - A Welt
- Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - M Schuler
- Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany
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16
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Zheng T, Hong X, Wang J, Pei T, Liang Y, Yin D, Song R, Song X, Lu Z, Qi S, Liu J, Sun B, Xie C, Pan S, Li Y, Luo X, Li S, Fang X, Bhatta N, Jiang H, Liu L. Gankyrin promotes tumor growth and metastasis through activation of IL-6/STAT3 signaling in human cholangiocarcinoma. Hepatology 2014; 59:935-46. [PMID: 24037855 DOI: 10.1002/hep.26705] [Citation(s) in RCA: 80] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2013] [Accepted: 08/21/2013] [Indexed: 12/30/2022]
Abstract
UNLABELLED Although gankyrin is involved in the tumorigenicity and metastasis of some malignancies, the role of gankyrin in cholangiocarcinoma (CCA) is unclear. In this study we investigated the expression of gankyrin in human CCA tissues and cell lines. The effects of gankyrin on CCA tumor growth and metastasis were determined both in vivo and in vitro. The results showed that gankyrin was overexpressed in CCA tissues and cell lines. Gankyrin expression was associated with CCA histological differentiation, TNM stage, and metastasis. The multivariate Cox analysis revealed that gankyrin was an independent prognostic indicator for overall survival. Gankyrin overexpression promoted CCA cell proliferation, migration, and invasion, while gankyrin knockdown inhibited CCA tumor growth, metastasis, and induced Rb-dependent senescence and G1 phase cell cycle arrest. Gankyrin increased the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and promoted the nuclear translocation of p-STAT3. Suppression of STAT3 signaling by small interfering RNA (siRNA) or STAT3 inhibitor interfered with gankyrin-mediated carcinogenesis and metastasis, while interleukin (IL)-6, a known upstream activator of STAT3, could restore the proliferation and migration of gankyrin-silenced CCA cells. The IL-6 level was decreased by gankyrin knockdown, while increased by gankyrin overexpression. Gankyrin regulated IL-6 expression by way of facilitating the phosphorylation of Rb; meanwhile, rIL-6 treatment increased the expression of gankyrin, suggesting that IL-6 was regulated by a positive feedback loop involving gankyrin in CCA. In the xenograft experiments, gankyrin overexpression accelerated tumor formation and increased tumor weight, whereas gankyrin knockdown showed the opposite effects. The in vivo spontaneous metastasis assay revealed that gankyrin promoted CCA metastasis through IL-6/STAT3 signaling pathway. CONCLUSION Gankyrin is crucial for CCA carcinogenesis and metastasis by activating IL-6/STAT3 signaling pathway through down-regulating Rb protein.
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Affiliation(s)
- Tongsen Zheng
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China
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Ramírez-Merino N, Aix SP, Cortés-Funes H. Chemotherapy for cholangiocarcinoma: An update. World J Gastrointest Oncol 2013; 5:171-176. [PMID: 23919111 PMCID: PMC3731530 DOI: 10.4251/wjgo.v5.i7.171] [Citation(s) in RCA: 119] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2012] [Accepted: 04/16/2013] [Indexed: 02/05/2023] Open
Abstract
Cholangiocarcinomas (bile duct cancers) are a heterogeneous group of malignancies arising from the epithelial cells of the intrahepatic, perihilar and extrahepatic bile ducts. Patients diagnosed with cholangiocarcinoma must be evaluated by a multidisciplinary team and be treated with individualized management. First of all, it is very important to define the potential resectability of the tumor because surgery is the main therapeutic option for these patients. Overall, cholangiocarcinomas have a very poor prognosis. The 5-year survival rate is 5%-10%. In cases with a potentially curative surgery, 5-year survival rates of 25%-30% are reported. Therefore, it is necessary to increase the cure rate from surgery, exploring the survival benefit of any adjuvant strategy. It is difficult to clarify the role of adjuvant treatment in localized and locally advanced cholangiocarcinomas. There are limited data and the role of adjuvant chemotherapy/chemoradiation in patients with resected biliary tract cancer is poorly defined. The most relevant studies in the adjuvant setting are one from Japan, the well known ESPAC-3 and BILCAP from the United Kingdom and a meta-analysis. We show the results of these trials. According to medical oncology guidelines, postoperative adjuvant therapy is widely recommended for all patients with intrahepatic or extrahepatic cholangiocarcinoma who have microscopically positive resection margins, as well as for those with a complete resection but node-positive disease. Clinical trials are ongoing. The locally advanced cholangiocarcinoma setting includes a heterogeneous mix of patients: (1) patients who have had surgery but with macroscopic residual disease; (2) patients with locally recurrent disease after potentially curative treatment; and (3) patients with locally unresectable disease at presentation. In these patients, surgery is not an option and chemoradiation therapy can prolong overall survival and provide control of symptoms due to local tumor effects. Nowadays, no neoadjuvant therapy can be considered a standard approach for the treatment of patients with cholangiocarcinoma. There are promising results and randomized trials are needed in patients with a metastatic cholangiocarcinoma. In systemic therapy, no single drug or combination has consistently increased median survival beyond the expected 8-12 mo. It is always recommended that patients enrol in clinical trials. Clinical trials have shown that the more standard chemotherapy for a first line regimen of gemcitabine plus cisplatin (or oxaliplatin as a potentially better tolerated agent) is superior to gemcitabine alone. Leucovorin-modulated 5-fluorouracil, capecitabine monotherapy or single agent gemcitabine are reasonable options for patients with a borderline performance status. After progression in patients with an adequate performance status, active regimens that could be considered include gemcitabine plus capecitabine, or erlotinib plus bevacizumab, for second line treatment.
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18
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Ge X, Wang Y, Li Q, Yu H, Ji G, Miao L. NK4 regulates 5-fluorouracil sensitivity in cholangiocarcinoma cells by modulating the intrinsic apoptosis pathway. Oncol Rep 2013; 30:448-54. [PMID: 23619566 DOI: 10.3892/or.2013.2427] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2013] [Accepted: 03/04/2013] [Indexed: 12/12/2022] Open
Abstract
The aim of the present study was to investigate the role of NK4, an antagonist for hepatocyte growth factor (HGF) and the Met receptor, in regulating the response of cholangiocarcinoma (CCA) cells to 5-fluorouracil (5-FU). We established the CCA cell line, HuCC-T1, to produce abundant NK4 (Hu-NK4). Cell proliferation, cell cycle distribution, apoptosis, 5-FU metabolism and intracellular signaling were examined. There were no significant differences in the mRNA levels of thymidylate synthase, thymidine phosphorylase and dihydropyrimidine dehydrogenase between the mock-transfected control Hu-Em cells and Hu-NK4 cells, suggesting that NK4 expression does not alter 5-FU metabolism. Moreover, cell cycle analysis showed that 5-FU treatment caused a decrease in the proportion of cells in the G2/M phase while NK4 gene expression had little effect on the cell cycle distribution. However, 5-FU-induced apoptosis was significantly increased in the Hu-NK4 cells when compared to that in the Hu-Em cells. Further investigation revealed that NK4 gene expression enhanced 5-FU-induced caspase-3 and caspase-9 activation, and that the apoptosis of cells was associated with modulation of expression of the Bcl-2 family members. Furthermore, western blot analysis revealed that both NK4 and 5-FU were inhibitors for HGF-induced phosphorylation of Met, but they may be independent factors. Collectively, these results suggest that following 5-FU treatment in CCA cell lines, NK4 was involved in apoptosis induction through the intrinsic mitochondrial pathway. This indicates that NK4 may be an important mediator of 5-FU-induced cell death. Moreover, downregulation of NK4 in response to 5-FU may represent an intrinsic mechanism of resistance to this anticancer drug.
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Affiliation(s)
- Xianxiu Ge
- Institute of Digestive Endoscopy and Medical Center for Digestive Diseases, Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210011, P.R. China
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