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Mohamed NM, Mohamed RH, Kennedy JF, Elhefnawi MM, Hamdy NM. A comprehensive review and in silico analysis of the role of survivin (BIRC5) in hepatocellular carcinoma hallmarks: A step toward precision. Int J Biol Macromol 2025; 311:143616. [PMID: 40306500 DOI: 10.1016/j.ijbiomac.2025.143616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Revised: 04/25/2025] [Accepted: 04/27/2025] [Indexed: 05/02/2025]
Abstract
Hepatocellular carcinoma (HCC) is a complex malignancy driven by the dysregulation of multiple cellular pathways. Survivin, a key member of the inhibitor of apoptosis (IAP) family, plays a central role in HCC tumorigenesis and progression. Despite significant research, a comprehensive understanding of the contributions of survivin to the hallmarks of cancer, its molecular network, and its potential as a therapeutic target remains incomplete. In this review, we integrated bioinformatics analysis with an extensive literature review to provide deeper insights into the role of survivin in HCC. Using bioinformatics tools such as the Human Protein Atlas, GEPIA, STRING, TIMER, and Metascape, we analyzed survivin expression and its functional associations and identified the top 20 coexpressed genes in HCC. These include TK1, SPC25, SGO2, PTTG1, PRR11, PLK1, NCAPH, KPNA2, KIF2C, KIF11, HJURP, GTSE1, FOXM1, CEP55, CENPA, CDCA3, CDC45, CCNB2, CCNB1 and CTD-2510F5.4. Our findings also revealed significant protein-protein interactions among these genes, which were enriched in pathways associated with the FOXM1 oncogenic signaling cascade, and biological processes such as cell cycle regulation, mitotic checkpoints, and diseases such as liver neoplasms. We also discussed the involvement of survivin in key oncogenic pathways, including the PI3K/AKT, WNT/β-catenin, Hippo, and JAK/STAT3 pathways, and its role in modulating cell cycle checkpoints, apoptosis, and autophagy. Furthermore, we explored its interactions with the tumor microenvironment, particularly its impact on immune modulation through myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages, and natural killer cell function in HCC. Additionally, we highlighted its involvement in alkylglycerone phosphate synthase (AGPS)-mediated lipid reprogramming and identified important gaps in the survivin network that warrant further investigation. This review also examined the role of survivin in cancer stemness, inflammation, and virally mediated hepatocarcinogenesis. We evaluated its potential as a diagnostic, prognostic, predictive, and pharmacodynamic biomarker in HCC, emphasizing its relevance in precision medicine. Finally, we summarized emerging survivin-targeted therapeutics and ongoing clinical trials, underscoring the need for novel strategies to effectively target survivin in HCC.
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Affiliation(s)
- Nermin M Mohamed
- Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, Abassia, 11566 Cairo, Egypt
| | - Rania Hassan Mohamed
- Department of Biochemistry, Faculty of Science, Ain Shams University, Abassia, 11566 Cairo, Egypt
| | - John F Kennedy
- Chembiotech Laboratories, Kyrewood House, Tenbury Wells, Worcestershire, United Kingdom
| | - Mahmoud M Elhefnawi
- Biomedical Informatics and Chemoinformatics Group, Informatics and Systems Department, National Research Centre, Cairo, Egypt.
| | - Nadia M Hamdy
- Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, Abassia, 11566 Cairo, Egypt.
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2
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Narayan NJC, Requena D, Lalazar G, Ramos-Espiritu L, Ng D, Levin S, Shebl B, Wang R, Hammond WJ, Saltsman JA, Gehart H, Torbenson MS, Clevers H, LaQuaglia MP, Simon SM. Human liver organoids for disease modeling of fibrolamellar carcinoma. Stem Cell Reports 2022; 17:1874-1888. [PMID: 35803261 PMCID: PMC9391427 DOI: 10.1016/j.stemcr.2022.06.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 06/04/2022] [Accepted: 06/07/2022] [Indexed: 11/29/2022] Open
Abstract
Fibrolamellar carcinoma (FLC) is a rare, often lethal, liver cancer affecting adolescents and young adults, for which there are no approved therapeutics. The development of therapeutics is hampered by a lack of in vitro models. Organoids have shown utility as a model system for studying many diseases. In this study, tumor tissue and the adjacent non-tumor liver were obtained at the time of surgery. The tissue was dissociated and grown as organoids. We developed 21 patient-derived organoid lines: 12 from metastases, three from the liver tumor and six from adjacent non-tumor liver. These patient-derived FLC organoids recapitulate the histologic morphology, immunohistochemistry, and transcriptome of the patient tumor. Patient-derived FLC organoids were used in a preliminary high-throughput drug screen to show proof of concept for the identification of therapeutics. This model system has the potential to improve our understanding of this rare cancer and holds significant promise for drug testing and development.
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Affiliation(s)
- Nicole J C Narayan
- Pediatric Surgical Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Laboratory of Cellular Biophysics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA
| | - David Requena
- Laboratory of Cellular Biophysics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA
| | - Gadi Lalazar
- Laboratory of Cellular Biophysics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA
| | - Lavoisier Ramos-Espiritu
- High Throughput and Spectroscopy Center, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA
| | - Denise Ng
- Laboratory of Cellular Biophysics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA
| | - Solomon Levin
- Laboratory of Cellular Biophysics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA
| | - Bassem Shebl
- Laboratory of Cellular Biophysics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA
| | - Ruisi Wang
- Laboratory of Cellular Biophysics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA
| | - William J Hammond
- Pediatric Surgical Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Laboratory of Cellular Biophysics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA
| | - James A Saltsman
- Pediatric Surgical Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Laboratory of Cellular Biophysics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA
| | - Helmuth Gehart
- Hubrecht Institute, KNAW (Royal Netherlands Academy of Arts and Sciences), Utrecht, the Netherlands
| | - Michael S Torbenson
- Department of Laboratory Medicine and Anatomic Pathology, Mayo Clinic, Rochester, MN, USA
| | - Hans Clevers
- Hubrecht Institute, KNAW (Royal Netherlands Academy of Arts and Sciences), Utrecht, the Netherlands
| | - Michael P LaQuaglia
- Pediatric Surgical Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Sanford M Simon
- Laboratory of Cellular Biophysics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
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3
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Charneau J, Suzuki T, Shimomura M, Fujinami N, Nakatsura T. Peptide-Based Vaccines for Hepatocellular Carcinoma: A Review of Recent Advances. J Hepatocell Carcinoma 2021; 8:1035-1054. [PMID: 34513746 PMCID: PMC8424432 DOI: 10.2147/jhc.s291558] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Accepted: 08/10/2021] [Indexed: 12/14/2022] Open
Abstract
Primary liver cancer is the sixth most commonly diagnosed cancer and the third leading cause of cancer-related deaths worldwide. After surgery, up to 70% of patients experience relapses. The current first-line therapy for advanced cases of hepatocellular carcinoma (HCC) comprises sorafenib and lenvatinib administered as single-drug therapies. Regorafenib, cabozantinib, and ramucirumab are administered as second-line therapies. Recently, it has been reported that using the immune checkpoint inhibitors atezolizumab (anti-PDL1 antibody) and bevacizumab (anti-VEGF antibody) leads to longer overall survival of unresectable cases, when compared with the use of sorafenib. The role of cancer immunity against HCC has attracted the attention of clinicians. In this review, we describe our phase I/II clinical trials of peptide vaccines targeting GPC3 in HCC and discuss the potential of peptide vaccines targeting common cancer antigens that are highly expressed in HCC, such as WT-I, AFP, ROBO1, and FOXM1. Further, we introduce recent cancer vaccines targeting neoantigens, which have attracted attention in recent times, as well as present our preclinical studies, the results of which might aid to initiate a neoantigen vaccine clinical trial, which would be the first of its kind in Japan.
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Affiliation(s)
- Jimmy Charneau
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa City, Japan
| | - Toshihiro Suzuki
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa City, Japan.,Department of Pharmacology, School of Medicine, Teikyo University, Tokyo, Japan
| | - Manami Shimomura
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa City, Japan
| | - Norihiro Fujinami
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa City, Japan
| | - Tetsuya Nakatsura
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa City, Japan
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Bello HR, Mahdi ZK, Lui SK, Nandwana SB, Harri PA, Davarpanah AH. Hepatocellular Carcinoma With Atypical Imaging Features: Review of the Morphologic Hepatocellular Carcinoma Subtypes With Radiology-Pathology Correlation. J Magn Reson Imaging 2021; 55:681-697. [PMID: 33682266 DOI: 10.1002/jmri.27553] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 01/25/2021] [Accepted: 01/26/2021] [Indexed: 12/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the fastest growing cause of cancer death in the United States with the incidence rate more than doubling in 20 years. HCC is unique since a noninvasive diagnosis can be achieved with imaging alone when specific clinical criteria and imaging characteristics are met, obviating the need for tissue sampling. However, HCC is a highly heterogeneous neoplasm. Atypical HCC subtypes vary significantly in their morphology, which can be attributed to specific histologic and molecular features, and can cause deviations from the classic imaging characteristics. The different morphologic subtypes of HCC frequently present a diagnostic challenge for radiologists and pathologists since their imaging and pathologic features can overlap with those of non-HCC malignancies. Identifying an atypical subtype can have important clinical implications. Liver transplant, albeit a scarce and limited resource, is the optimal treatment for conventional HCC, potentially curing both the tumor and the underlying pre-malignant condition. Some HCC subtypes as well as mimickers are associated with unacceptably high recurrence and poor outcome after transplant, and there remains limited data on the role and prognosis of liver transplantation for treatment of rare HCC subtypes. Other subtypes tend to recur later than classic HCC, potentially requiring a different follow-up scheme. This review will discuss the appearance of different HCC subtypes in relation to their histopathologic features. LEVEL OF EVIDENCE: 5 TECHNICAL EFFICACY: Stage 3.
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Affiliation(s)
- Hernan R Bello
- Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Zaid K Mahdi
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Shu K Lui
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Sadhna B Nandwana
- Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Peter A Harri
- Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Amir H Davarpanah
- Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, Georgia, USA
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5
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Suceveanu AI, Micu IS, Baltatescu GI, Petcu LC, Dobrin N, Brinzan C, Nitipir C, Mazilu L, Botea F, Herlea V, Voinea F, Suceveanu AP. Overexpression of Survivin-1, TAG-72 and HERC5 in patients diagnosed with hepatocellular carcinoma in the Black Sea coast geographical area. Exp Ther Med 2021; 21:284. [PMID: 33603891 PMCID: PMC7851649 DOI: 10.3892/etm.2021.9715] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Accepted: 11/26/2020] [Indexed: 11/06/2022] Open
Abstract
Epidemiological data regarding hepatocellular carcinoma (HCC) report unsatisfactory morbimortality rates despite the global efforts to decrease the incidence and prolong patient survival. Current guidelines lack diagnostic biomarkers to better characterize patients with HCC. We aimed to validate the overexpression of Survivin-1, tumor-associated glyocoprotein 72 (Tag-72), and HECT and RLD domain containing E3 ubiquitin protein ligase 5 (HERC5) as tissue biomarkers for HCC characterization in patients from our geographical area and to standardize a local biomarker panel to be introduced in the current management guideline. Thirty samples of histologically confirmed HCC were compared to an equal number of samples of benign tumors in terms of Survivin-1, TAG-72, and HERC5 overexpression. Student's t-test, Mann-Whitney U test and Chi-square test were used to find differences between the two studied groups and to compare the categorical variables. The discriminative power of Survivin-1, Tag-72, and HERC5 overexpression was assessed using ROC curves. The multivariate linear regression analysis revealed that Survivin, Tag-72, and HERC5 were significantly overexpressed in older male patients, with α-fetoprotein (AFP) >200 ng/dl, low serum albumin, as well as in patients with imaging features of portal thrombosis and ascites. The diagnostic performance of Survivin-1, Tag-72 and HERC5 tissue biomarkers for HCC characterization was superior to that of the gold-standard AFP. Our study results validate the overexpression of Survivin-1, Tag-72, and HERC5 as tissue biomarkers for HCC characterization in patients from our geographical region and could be standardized in the current HCC management guideline.
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Affiliation(s)
| | - Ioan Sergiu Micu
- Department of Gastroenterology, ‘Ovidius’ University, 900527 Constanta, Romania
| | - Gabriela-Izabela Baltatescu
- Research and Development Centre for The Morphologic and Genetic Study of Malignant Pathology, ‘Ovidius’ University, 900527 Constanta, Romania
| | - Lucian Cristian Petcu
- Dentistry Faculty, Biophysics and Biostatistics Disciplines, ‘Ovidius’ University, 900527 Constanta, Romania
| | - Nicolae Dobrin
- Research and Development Centre for The Morphologic and Genetic Study of Malignant Pathology, ‘Ovidius’ University, 900527 Constanta, Romania
| | - Costel Brinzan
- Doctoral School of Medicine, ‘Ovidius’ University, 900527 Constanta, Romania
| | - Cornelia Nitipir
- Department of Oncology, ‘Carol Davila’ University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Laura Mazilu
- Department of Oncology, ‘Ovidius’ University, 900527 Constanta, Romania
| | - Florin Botea
- Liver Transplant and General Surgery Centre, ‘Fundeni’ Institute, 022328 Bucharest, Romania
| | - Vlad Herlea
- Department of Pathology, ‘Fundeni’ Institute, 022328 Bucharest, Romania
| | - Felix Voinea
- Department of Urology, ‘Ovidius’ University, 900527 Constanta, Romania
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Zeyada MS, Abdel-Rahman N, El-Karef A, Yahia S, El-Sherbiny IM, Eissa LA. Niclosamide-loaded polymeric micelles ameliorate hepatocellular carcinoma in vivo through targeting Wnt and Notch pathways. Life Sci 2020; 261:118458. [PMID: 32961231 DOI: 10.1016/j.lfs.2020.118458] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Revised: 09/09/2020] [Accepted: 09/13/2020] [Indexed: 12/19/2022]
Abstract
AIM Niclosamide (NIC) is an anthelmintic agent repurposed as a potent anticancer agent. However, its use is hindered by its poor solubility. We investigated the underlying mechanisms of NIC anticancer activity employing a novel oral NIC pluronic-based nanoformulation and tested its effect in thioacetamide-induced hepatocellular carcinoma (HCC) in rats. We evaluated its antitumor effect through regulating Wnt/β-catenin and Notch signaling pathways and apoptosis. MAIN METHODS Niclosamide-loaded pluronic nanoparticles (NIC-NPs) were optimally developed and characterized with sustained release properties up to 7 days. Sixteen weeks after HCC induction, NIC (70 mg/kg) and an equivalent dose of NIC-NPs were administered orally for 3 consecutive weeks. Hepatocyte integrity was assessed by measuring serum levels of aminotransferases, ALP, GGT, bilirubin, albumin and total protein. HCC development was detected by measuring AFP expression. Necroinflammation and fibrosis were scored by histopathological examination. Wnt/β-catenin and Notch signaling were evaluated by measuring hepatic mRNA levels of Wnt3A, Lrp5 and Lrp6 Co-receptors, Dvl-2, Notch1 and Hes1 and β-catenin protein levels. Apoptosis was assessed by measuring mRNA and protein levels of cyclin D1 and caspase-3. KEY FINDING The novel NIC-NPs restored liver integrity, reduced AFP levels and showed improved anticancer and proapoptotic activities compared to drug alone. The inhibitory effect of NIC on Wnt/β-catenin and Notch signaling pathways was potentiated by the NIC-NPs formulation. SIGNIFICANCE We conclude that NIC acts by inhibiting Wnt/β-catenin and Notch signaling and inducing apoptosis in HCC. Developing pluronic-based nanoformulations may be a promising approach to improve NIC solubility and offer the possibility of controlled release.
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Affiliation(s)
- Menna S Zeyada
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Noha Abdel-Rahman
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Amro El-Karef
- Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Sarah Yahia
- Center for Materials Science, Zewail City of Science & Technology, 6th October City, 12578 Giza, Egypt
| | - Ibrahim M El-Sherbiny
- Center for Materials Science, Zewail City of Science & Technology, 6th October City, 12578 Giza, Egypt.
| | - Laila A Eissa
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
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7
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Stavropoulos A, Varras M, Vasilakaki T, Varra VK, Varra FN, Tsavari A, Nonni A, Kavantzas N, Lazaris AC. Expression of anti-apoptotic protein survivin in human endometrial carcinoma: Clinical and pathological associations as a separate factor and in combination with concomitant PTEN and p53 expression. Oncol Lett 2020; 20:1033-1054. [PMID: 32724342 PMCID: PMC7377108 DOI: 10.3892/ol.2020.11690] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Accepted: 04/21/2020] [Indexed: 12/12/2022] Open
Abstract
Endometrial carcinoma is one of the most common types of gynecological cancer. A total of 99 cases of primary endometrial carcinoma were investigated for survivin expression by immunohistochemistry. Furthermore, the association between concomitant survivin, PTEN and p53 expression, and clinicopathological parameters was examined. Immunopositivity for survivin was identified in 88% of cases. Concomitant survivin, PTEN and p53 expression (staining scores and intensity) was observed in 60% of endometrial adenocarcinomas. A significant association was identified between the sum of staining intensity and scores of survivin immunopositive cells, and patient age (P=0.028), histological grade (P<0.001), clinical stage (P=0.018) and fallopian tube and/or ovarian invasion (P=0.039). A negative tendency for correlation was observed between surivin and PTEN immunostaining scores (P=0.062; ρ=−0.238). Specimens with high scores of survivin expression tended to show decreased scores of PTEN immunostaining, and vice versa. However, in circumstances with an increased co-expression of survivin and PTEN, a statistically significant association with histological types was observed (P=0.020). A statistically significant positive correlation was identified between survivin and p53 sum co-expression (P=0.008; ρ=0.300). Furthermore, a significant association was identified between survivin and p53 concomitant sum expression and age of patients (P=0.001), histological type (P=0.020), clinical stage (P=0.037), histological differentiation (P=0.001) and presence of fallopian tube and/or ovarian invasion (P=0.026). The present findings suggested that survivin may be an indicator of unfavorable outcome in older patients with endometrial carcinoma, in specific circumstances that are dependent on different concomitant genetic alterations and different combinations of molecular signaling pathways. Increased expression levels of survivin and PTEN may serve a role in the development of more aggressive endometrial carcinoma during their interaction. In addition, protein expression levels of survivin and p53 are positively correlated and may share a common molecular pathway to promote endometrial carcinogenesis. These findings provided evidence that survivin and p53 combined may be useful markers for the prediction of tumor behavior and prognosis.
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Affiliation(s)
- Aggelis Stavropoulos
- Forth Obstetrics and Gynecology Department, 'Elena Venizelou' General Hospital, Athens 11521, Greece
| | - Michail Varras
- Fifth Obstetrics and Gynecology Department, 'Elena Venizelou' General Hospital, Athens 11521, Greece
| | - Thivi Vasilakaki
- Department of Pathology, 'Tzaneio' General Hospital, Piraeus 18536, Greece
| | | | - Fani-Niki Varra
- Department of Pharmacy, Frederick University, Nicosia 1036, Cyprus
| | - Aikaterini Tsavari
- Department of Pathology, 'Tzaneio' General Hospital, Piraeus 18536, Greece
| | - Aphrodite Nonni
- First Pathology Department, Medical School, National Kapodistrian University, Athens 11527, Greece
| | - Nikolaos Kavantzas
- First Pathology Department, Medical School, National Kapodistrian University, Athens 11527, Greece
| | - Andreas C Lazaris
- First Pathology Department, Medical School, National Kapodistrian University, Athens 11527, Greece
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Ragab HM, Maksoud NAE, Elaziz WA, Halim MH, Kamel A, Abdulla NA. Combination of Serum Survivin and AFP as a Potential Marker in HCC Associated with Hepatitis C Viral Infection. JOURNAL OF APPLIED SCIENCES 2019; 19:295-302. [DOI: 10.3923/jas.2019.295.302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/01/2023]
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9
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Ebrahimiyan H, Rezaei N, Vojdanian M, Aslani S, Jamshidi A, Mahmoudi M. microRNA involvement in the regulation of survivin in peripheral blood mononuclear cells from rheumatoid arthritis patients. Int J Rheum Dis 2019; 22:1107-1114. [PMID: 30834699 DOI: 10.1111/1756-185x.13520] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Revised: 01/13/2019] [Accepted: 02/01/2019] [Indexed: 12/13/2022]
Abstract
AIM Impaired regulation of immune tolerance results in autoimmune diseases, such as rheumatoid arthritis (RA). Survivin is an anti-apoptotic protein and can induce cellular mitosis. In the current study, we assessed the transcript level of total survivin (survivin-TS) and its three major variants and evaluated the expression level of important micro RNAs (miRNAs) involved in survivin expression regulation in RA patients. METHOD Peripheral blood mononuclear cells (PBMCs) were isolated from 50 healthy controls and 50 RA-active patients. RNA extraction was performed and then single-strand complementary DNA was synthesized. Quantitative real-time polymerase chain reaction was used to assess the expression level of survivin-TS and its variants with effective miRNAs in PBMCs. RESULTS Overexpression of survivin-2B (fold change = 1.57, P = 0.005), survivn-ΔEx3 (fold change = 1.93, P = 0.009) and downregulation of survivin-WT (fold change = 0.64, P = 0.0002) were found in PBMCs of patients, while messenger RNA (mRNA) expression of survivin-TS had no significant difference between RA patients and controls. Expression levels of miR-335-5p, miR-485-5p, miR-16-5p, miR-150-5p, miR-34a-5p, and miR-203a-3p were significantly increased in PBMCs from patients compared with healthy controls. In a correlation study, dysregulation of these miRNAs were not correlated with mRNA expression level of survivin. CONCLUSION While survivin-TS was not differently expressed in RA patients, its variants had altered expression. Although miRNAs were aberrantly expressed in PBMCs from RA subjects, they did not regulate survivin-TS. miRNAs might be involved in RA pathogenesis, but not through controlling survivin.
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Affiliation(s)
| | - Nima Rezaei
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.,Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Sheffield, UK
| | - Mahdi Vojdanian
- Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Saeed Aslani
- Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran.,Rheumatology Expert Group (REG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Ahmadreza Jamshidi
- Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahdi Mahmoudi
- Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran.,Rheumatology Expert Group (REG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
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Abstract
Fibrolamellar carcinoma is a rare primary hepatocellular malignancy arising in noncirrhotic livers of young individuals. Patients commonly present with a large solitary liver mass and nonspecific symptoms. Characteristic histologic features include large polygonal cells with oncocytic cytoplasm and prominent nucleoli separated into trabeculae and cords by dense parallel bands of collagen. Important differential diagnoses include classical hepatocellular carcinoma and intrahepatic cholangiocarcinoma, which may be distinguished by a judicious panel of immunohistochemical studies, including cytokeratin 7, CD68, and hepatocyte paraffin 1 (HepPar-1). In addition, fibrolamellar carcinomas are characterized by activation of protein kinase A. Prognosis of fibrolamellar carcinoma is similar to classical hepatocellular carcinoma occurring in the absence of liver cirrhosis and is strongly correlated with tumor resectability. Other treatment options include liver transplant, chemotherapy, and hepatic artery embolization. In this article, we review the clinical features, gross and microscopic pathology, molecular genetics, differential diagnosis, treatment, and prognosis of this rare and interesting tumor.
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Affiliation(s)
| | - Hui-Min Yang
- From the Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York. Dr Hui-Min Yang is currently located in the Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
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11
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Li J, Ma R, Cao Z, Zhang D. Correlations of MRI manifestations with survivin gene expression in primary hepatic carcinoma. Cancer Biomark 2018; 23:45-51. [PMID: 30010107 DOI: 10.3233/cbm-181285] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Affiliation(s)
- Jian Li
- Department of Radiology, Jining No. 1 People’s Hospital, Jining, Shandong, China
- Department of Radiology, Jining No. 1 People’s Hospital, Jining, Shandong, China
| | - Rui Ma
- Department of Radiology, Jining No. 1 People’s Hospital, Jining, Shandong, China
- Department of Radiology, Jining No. 1 People’s Hospital, Jining, Shandong, China
| | - Zhenbin Cao
- Department of Radiology, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Dongmei Zhang
- Department of Radiology, Jining No. 1 People’s Hospital, Jining, Shandong, China
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12
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Liver Calcifications and Calcified Liver Masses: Pattern Recognition Approach on CT. AJR Am J Roentgenol 2018; 211:76-86. [DOI: 10.2214/ajr.18.19704] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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13
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Zaghloul RA, Elsherbiny NM, Kenawy HI, El-Karef A, Eissa LA, El-Shishtawy MM. Hepatoprotective effect of hesperidin in hepatocellular carcinoma: Involvement of Wnt signaling pathways. Life Sci 2017; 185:114-125. [PMID: 28754618 DOI: 10.1016/j.lfs.2017.07.026] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2017] [Revised: 07/18/2017] [Accepted: 07/23/2017] [Indexed: 02/07/2023]
Abstract
AIMS Wnt3a and Wnt5a are ligands orchestrating the canonical and non-canonical pathways, respectively, with involvement in hepatocellular carcinoma (HCC). Hesperidin (HP) is a natural product found in citrus fruits and reputed for its antitumor activity. The present study aims to investigate the potential hepatoprotective effect of HP against thioacetamide (TAA)-induced HCC focusing on its potential role on Wnt3a and Wnt5a signaling pathways. MAIN METHODS Forty rats were equally divided into groups; normal control, HP control (receiving HP, 150mg/kg/day), HCC (receiving TAA, 200mg/kg twice weekly for 14weeks) and HP-HCC (receiving HP and TAA). Gene expressions of Wnt3a, Wnt5a, β-catenin and Cyclin D1 were assessed by qPCR, while their protein levels, along with active caspase-3 level, were quantified by ELISA and immunohistochemistry. Liver functions, oxidative stress parameters and myeloperoxidase activity were measured. MTT assay of hepG2 cells treated with recombinant Wnt3a (10ng/ml) in presence or absence of HP (100μM) was performed. KEY FINDINGS HCC group exhibited a significant increase in Wnt3a, β-catenin, Cyclin D1 and Wnt5a gene expressions, as well as, their protein levels. HP significantly prevented TAA-activated Wnt3a/β-catenin and Wnt5a pathways. Moreover, HP exerted hepatoprotective effect by significantly improving the oxidative imbalance, inflammation and liver function parameters, serum ALT, AST activities, and albumin level. SIGNIFICANCE Our study is the first to report the possible role of Wnt3a/β-catenin and Wnt5a pathways in TAA-induced early HCC model in rats. HP has a prophylactic effect against hepatocarcinogenesis via preventing the induction of both canonical and non-canonical Wnt pathways.
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Affiliation(s)
- Randa A Zaghloul
- Dept. of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
| | - Nehal M Elsherbiny
- Dept. of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Hany I Kenawy
- Dept. of Microbiology and Immunology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Amr El-Karef
- Dept. of Pathology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Laila A Eissa
- Dept. of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
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15
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Sorenson EC, Khanin R, Bamboat ZM, Cavnar MJ, Kim TS, Sadot E, Zeng S, Greer JB, Seifert AM, Cohen NA, Crawley MH, Green BL, Klimstra DS, DeMatteo RP. Genome and transcriptome profiling of fibrolamellar hepatocellular carcinoma demonstrates p53 and IGF2BP1 dysregulation. PLoS One 2017; 12:e0176562. [PMID: 28486549 PMCID: PMC5423588 DOI: 10.1371/journal.pone.0176562] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Accepted: 04/12/2017] [Indexed: 01/17/2023] Open
Abstract
Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare variant of HCC that most frequently affects young adults. Because of its rarity and an absence of preclinical models, our understanding of FL-HCC is limited. Our objective was to analyze chromosomal alterations and dysregulated gene expression in tumor specimens collected at a single center during two decades of experience with FL-HCC. We analyzed 38 specimens from 26 patients by array comparative genomic hybridiziation (aCGH) and 35 specimens from 15 patients by transcriptome sequencing (RNA-seq). All tumor specimens exhibited genomic instability, with a higher frequency of genomic amplifications or deletions in metastatic tumors. The regions encoding 71 microRNAs (miRs) were deleted in at least 25% of tumor specimens. Five of these recurrently deleted miRs targeted the insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) gene product, and a correlating 100-fold upregulation of IGF2BP1 mRNA was seen in tumor specimens. Transcriptome analysis demonstrated intrapatient tumor similarity, independent of recurrence site or time. The p53 tumor suppressor pathway was downregulated as demonstrated by both aCGH and RNA-seq analysis. Notch, EGFR, NRAS, and RB1 pathways were also significantly dysregulated in tumors compared with normal liver tissue. The findings illuminate the genomic and transcriptomic landscape of this rare disease and provide insight into dysregulated oncogenic pathways and potential therapeutic targets in FL-HCC.
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Affiliation(s)
- Eric C. Sorenson
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
| | - Raya Khanin
- Department of Computational Biology and Bioinformatics Core, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
| | - Zubin M. Bamboat
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
| | - Michael J. Cavnar
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
| | - Teresa S. Kim
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
| | - Eran Sadot
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
| | - Shan Zeng
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
| | - Jonathan B. Greer
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
| | - Adrian M. Seifert
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
| | - Noah A. Cohen
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
| | - Megan H. Crawley
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
| | - Benjamin L. Green
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
| | - David S. Klimstra
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
| | - Ronald P. DeMatteo
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
- * E-mail:
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16
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Yang XP, Liu SL, Xu JF, Cao SG, Li Y, Zhou YB. Pancreatic stellate cells increase pancreatic cancer cells invasion through the hepatocyte growth factor /c-Met/survivin regulated by P53/P21. Exp Cell Res 2017; 357:79-87. [PMID: 28461158 DOI: 10.1016/j.yexcr.2017.04.027] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Revised: 04/24/2017] [Accepted: 04/25/2017] [Indexed: 02/07/2023]
Abstract
Pancreatic stellate cells (PSCs) are a key cellular component of the pancreatic tumor microenvironment and are considered to contribute to tumor invasion and metastasis. Multiple cytokines and growth factors derived from PSCs are involved in malignant cancer progression, including hepatocyte growth factor (HGF). However, the molecular mechanisms by which HGF regulates cancer invasion and metastasis have not been completely elucidated. Here, we report that two pancreatic cancer (PC) cell lines, Panc-1 and SW1990, displayed different invasive and migratory abilities after treatment with HGF secreted by PSCs. We found that HGF enhanced the invasive and migratory capacity of Panc-1 cells because of P53 deficiency, leading to overexpression of c-Met, which was regulated through P21. Additionally, our data showed that HGF/c-Met-mediated invasion and migration required the upregulation of survivin expression. In conclusion, PSCs promote PC cells invasion and migration via the HGF/c-Met/survivin pathway, which is negatively regulated by P53/P21.
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Affiliation(s)
- Xiao-Peng Yang
- Department of Clinical Medicine, Medical College, Qingdao University, Qingdao, Shandong, China
| | - Shang-Long Liu
- Department of General Surgery, Affiliated Hospital of Qingdao University, 16 Jiang-Su Street, Qingdao, Shandong, China
| | - Jian-Fei Xu
- Department of Clinical Medicine, Medical College, Qingdao University, Qingdao, Shandong, China
| | - Shou-Gen Cao
- Department of General Surgery, Affiliated Hospital of Qingdao University, 16 Jiang-Su Street, Qingdao, Shandong, China
| | - Yu Li
- Department of General Surgery, Affiliated Hospital of Qingdao University, 16 Jiang-Su Street, Qingdao, Shandong, China
| | - Yan-Bing Zhou
- Department of Clinical Medicine, Medical College, Qingdao University, Qingdao, Shandong, China; Department of General Surgery, Affiliated Hospital of Qingdao University, 16 Jiang-Su Street, Qingdao, Shandong, China.
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17
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El Zeneini E, Kamel S, El-Meteini M, Amleh A. Knockdown of COBRA1 decreases the proliferation and migration of hepatocellular carcinoma cells. Oncol Rep 2017; 37:1896-1906. [PMID: 28112367 DOI: 10.3892/or.2017.5390] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Accepted: 12/27/2016] [Indexed: 11/06/2022] Open
Abstract
Cofactor of BRCA1 (COBRA1) is one of the four subunits that make up the negative elongation factor (NELF) complex that is involved in the stalling of RNA polymerase II early during transcription elongation. As such, it regulates the expression of a substantial number of genes involved in cell cycle control, cellular metabolism and DNA repair. With no DNA binding domain, its capacity to modulate gene expression occurs via its ability to interact with different transcription factors. In the field of cancer, its role is not yet fully understood. In this study, we demonstrate the frequent overexpression of COBRA1 along with the remaining NELF subunits in hepatocellular carcinoma (HCC) tissues relative to non-cancerous liver tissues. To elucidate its biological significance in HCC, RNA interference was utilized to silence COBRA1 expression in the HCC cell line, HepG2. Interestingly, COBRA1 knockdown resulted in a significant decrease in cell proliferation and migration, accompanied by a concomitant reduction in the expression of the proliferation marker, Ki-67. Survivin, a proto-oncogene that is commonly upregulated in almost all human malignancies including HCC, was also significantly downregulated following COBRA1 silencing. This suggests that it might be one of the mechanisms by which COBRA1 mediates its role in HCC. Taken together, our data findings collectively highlight an important role for COBRA1 in supporting HCC proliferation and migration.
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Affiliation(s)
- Eman El Zeneini
- Biotechnology Department, The American University in Cairo, New Cairo 11835, Egypt
| | - Sarah Kamel
- Biotechnology Department, The American University in Cairo, New Cairo 11835, Egypt
| | - Mahmoud El-Meteini
- HPB and Liver Transplant Surgical Department, Faculty of Medicine, Ain Shams University, Cairo 11341, Egypt
| | - Asma Amleh
- Biotechnology Department, The American University in Cairo, New Cairo 11835, Egypt
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18
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Ma C, Lu B, Sun E. Clinicopathological and prognostic significance of survivin expression in renal cancer patients: a meta-analysis. Postgrad Med J 2016; 93:186-192. [PMID: 27489375 DOI: 10.1136/postgradmedj-2016-134105] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2016] [Revised: 07/05/2016] [Accepted: 07/12/2016] [Indexed: 12/31/2022]
Abstract
BACKGROUND Survivin has been reported to play a role in the diagnosis and prognosis of renal cell carcinoma (RCC); however, published data on this subject are conflicting. AIM To conduct a meta-analysis to evaluate the impact of survivin as a prognostic marker and its association with clinicopathological variables in patients with RCC. METHOD Comprehensive searches of electronic databases (PubMed, ISI Web of Knowledge Embase, Google Scholar Web and the Cochrane Library) were updated to June 2016 to retrieve eligible studies. The association strength was measured with relative risks (RRs) and pooled HRs with 95% CIs, which were extracted and pooled to determine the association between survivin expression and patient survival and clinicopathological features. RESULTS Ten studies with 1063 cases of RCC were included. Positive survivin expression in RCC was associated with the TNM stage (pooled RR 1.49; 95% CI 1.07 to 2.07) or Fuhrman grade (pooled RR 1.63; 95% CI 1.15 to 2.32) in patients. The correlation between survivin expression and gender was not significant (pooled RR 0.97; 95% CI 0.83 to 1.15). In addition, a considerable association was found between survivin expression and overall survival for patients with RCC (pooled HR 1.94; 95% CI 1.24 to 3.05 (multivariate model) and 5.41; 95% CI 4.08 to 7.17 (univariate model)). CONCLUSIONS Our results indicate that survivin is of prognostic significance in patients with RCC.
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Affiliation(s)
- Chengquan Ma
- Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Bingxin Lu
- Department of Urology, Tianjin Nankai hospital, Tianjin, China
| | - Erlin Sun
- Tianjin institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China
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19
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Sarvagalla S, Cheung CHA, Tsai JY, Hsieh HP, Coumar MS. Disruption of protein–protein interactions: hot spot detection, structure-based virtual screening and in vitro testing for the anti-cancer drug target – survivin. RSC Adv 2016. [DOI: 10.1039/c5ra22927h] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Hot spot detection at the protein–protein interaction interface using computational tools helped to identify indinavir as survivin inhibitor.
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Affiliation(s)
- Sailu Sarvagalla
- Centre for Bioinformatics
- School of Life Sciences
- Pondicherry University
- Puducherry 605014
- India
| | - Chun Hei Antonio Cheung
- Department of Pharmacology
- College of Medicine
- National Cheng Kung University
- Tainan
- Republic of China
| | - Ju-Ya Tsai
- Department of Pharmacology
- College of Medicine
- National Cheng Kung University
- Tainan
- Republic of China
| | - Hsing Pang Hsieh
- Institute of Biotechnology and Pharmaceutical Research
- National Health Research Institutes
- Miaoli County 350
- Republic of China
| | - Mohane Selvaraj Coumar
- Centre for Bioinformatics
- School of Life Sciences
- Pondicherry University
- Puducherry 605014
- India
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Tumour antigen expression in hepatocellular carcinoma in a low-endemic western area. Br J Cancer 2015; 112:1911-20. [PMID: 26057582 PMCID: PMC4580401 DOI: 10.1038/bjc.2015.92] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2014] [Revised: 01/21/2015] [Accepted: 02/12/2015] [Indexed: 02/06/2023] Open
Abstract
Background: Identification of tumour antigens is crucial for the development of
vaccination strategies against hepatocellular carcinoma (HCC). Most studies
come from eastern-Asia, where hepatitis-B is the main cause of HCC. However,
tumour antigen expression is poorly studied in low-endemic, western areas
where the aetiology of HCC differs. Methods: We constructed tissue microarrays from resected HCC tissue of 133 patients.
Expression of a comprehensive panel of cancer-testis (MAGE-A1,
MAGE-A3/4, MAGE-A10, MAGE-C1, MAGE-C2, NY-ESO-1, SSX-2, sperm protein
17), onco-fetal (AFP, Glypican-3) and overexpressed tumour antigens
(Annexin-A2, Wilms tumor-1, Survivin, Midkine, MUC-1) was determined by
immunohistochemistry. Results: A higher prevalence of MAGE antigens was observed in patients with
hepatitis-B. Patients with expression of more tumour antigens in general had
better HCC-specific survival (P=0.022). The four tumour
antigens with high expression in HCC and no, or weak, expression in
surrounding tumour-free-liver tissue, were Annexin-A2, GPC-3, MAGE-C1 and
MAGE-C2, expressed in 90, 39, 17 and 20% of HCCs, respectively.
Ninety-five percent of HCCs expressed at least one of these four tumour
antigens. Interestingly, GPC-3 was associated with SALL-4 expression
(P=0.001), an oncofetal transcription factor highly
expressed in embryonal stem cells. SALL-4 and GPC-3 expression levels were
correlated with vascular invasion, poor differentiation and higher AFP
levels before surgery. Moreover, patients who co-expressed higher levels of
both GPC-3 and SALL-4 had worse HCC-specific survival
(P=0.018). Conclusions: We describe a panel of four tumour antigens with excellent coverage and good
tumour specificity in a western area, low-endemic for hepatitis-B. The
association between GPC-3 and SALL-4 is a novel finding and suggests that
GPC-3 targeting may specifically attack the tumour stem-cell
compartment.
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21
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Jebar AH, Vile RG, Melcher AA, Griffin S, Selby PJ, Errington-Mais F. Progress in clinical oncolytic virus-based therapy for hepatocellular carcinoma. J Gen Virol 2015; 96:1533-50. [DOI: 10.1099/vir.0.000098] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
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Ganeshan D, Szklaruk J, Kundra V, Kaseb A, Rashid A, Elsayes KM. Imaging features of fibrolamellar hepatocellular carcinoma. AJR Am J Roentgenol 2014; 202:544-552. [PMID: 24555590 DOI: 10.2214/ajr.13.11117] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
OBJECTIVE Fibrolamellar hepatocellular carcinoma (HCC) is a rare primary liver tumor, which significantly differs from conventional HCC. This article reviews the molecular cytogenetics, pathology, imaging features, and management of this relatively rare tumor. CONCLUSION Fibrolamellar HCC predominantly occurs in young patients without underlying hepatitis or cirrhosis. Serum α-fetoproteins are not elevated in most cases, and hence imaging plays an important role in diagnosis, staging, and surveillance.
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Affiliation(s)
- Dhakshinamoorthy Ganeshan
- 1 Division of Diagnostic Imaging, Body Imaging Section, Unit 1473, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030-4009
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23
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Torbenson M. Fibrolamellar carcinoma: 2012 update. SCIENTIFICA 2012; 2012:743790. [PMID: 24278737 PMCID: PMC3820672 DOI: 10.6064/2012/743790] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/26/2012] [Accepted: 08/22/2012] [Indexed: 06/02/2023]
Abstract
Fibrolamellar carcinomas are a unique type of primary liver cancer. They occur most commonly in children and young adults. Their etiology remains a mystery, as they are not associated with chronic liver disease. Fibrolamellar carcinomas are not indolent tumors, but have an overall better prognosis than typical hepatocellular carcinomas, in part because of the younger age at presentation and the lack of cirrhosis. The most important prognostic feature is whether the tumor is resectable. Histologically, the tumor is made up of large cells that contain abundant mitochondria. The nuclei of the tumor cells have prominent nucleoli. The tumor cells induce the formation of extensive intratumoral fibrosis, which often grows in parallel, or lamellar bands. The tumor cells clearly show hepatocellular features but are also unique in showing both biliary and neuroendocrine differentiation. The uniqueness of fibrolamellar carcinoma extends to their molecular findings. While the genetic abnormalities that lead to fibrolamellar carcinomas are not yet known, studies have shown that they lack mutations in the genes most commonly mutated in typical hepatocellular carcinoma (TP53 and CTNNB1). In this paper, the clinical, pathological, and basic science literature on fibrolamellar carcinoma is comprehensively reviewed. Key areas of needed research are also discussed.
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Affiliation(s)
- Michael Torbenson
- Department of Pathology, The Johns Hopkins University School of Medicine, Room B314, 1503 E. Jefferson, Bond Street Building, Baltimore, MD 21231, USA
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Epstein-Barr virus oncoprotein LMP1 mediates survivin upregulation by p53 contributing to G1/S cell cycle progression in nasopharyngeal carcinoma. Int J Mol Med 2012; 29:574-80. [PMID: 22266808 PMCID: PMC3573768 DOI: 10.3892/ijmm.2012.889] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2011] [Accepted: 12/05/2011] [Indexed: 01/04/2023] Open
Abstract
Latent membrane protein 1 (LMP1) is an important oncogenic protein encoded by Epstein-Barr virus (EBV) and plays an important role in the development of nasopharyngeal carcinoma (NPC). Our previous study has shown that p53 protein was accumulated and phosphorylated in NPC, implying its transcription factor activity in NPC tumorigenesis. However, the biological function and potential downstream target of p53 mediated by LMP1 in NPC remain unknown. In this study, we found that LMP1 simultaneously induced upregulation of both p53 and survivin at the protein level, as well as their phosphorylation. Knockdown of p53 by siRNA revealed that LMP1 increased survivin expression by p53 directly. Furthermore, we found that LMP1 upregulated survivin by p53 at the transcriptional level by increasing p53-mediated survivin promoter activity and DNA binding activity. Moreover, LMP1 induced the co-localization of p53 and survivin in the nucleus, conferring to their related functions in NPC tumorigenesis. We further found that p53 promoted G1/S cell cycle progression, but did not induce apoptosis in LMP1-positive NPC cells. Collectively, these findings suggest that p53 acting as a transcription factor promotes the transcriptional activity of survivin, and further increases its protein expression and phosphorylation in the regulation of LMP1, thus, leading to G1/S cell cycle progression with no effect on apoptosis in NPC tumorigenesis.
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Jiang J, Slivova V, Jedinak A, Sliva D. Gossypol inhibits growth, invasiveness, and angiogenesis in human prostate cancer cells by modulating NF-κB/AP-1 dependent- and independent-signaling. Clin Exp Metastasis 2011; 29:165-78. [DOI: 10.1007/s10585-011-9439-z] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2010] [Accepted: 02/23/2011] [Indexed: 01/06/2023]
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Hmeljak J, Erčulj N, Dolžan V, Kern I, Cör A. BIRC5 promoter SNPs do not affect nuclear survivin expression and survival of malignant pleural mesothelioma patients. J Cancer Res Clin Oncol 2011; 137:1641-51. [PMID: 21861135 DOI: 10.1007/s00432-011-1030-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2011] [Accepted: 07/29/2011] [Indexed: 10/17/2022]
Abstract
PURPOSE Malignant pleural mesothelioma is an incurable, asbestos-associated cancer. Its incidence is rapidly increasing and survival remains short. Apoptosis deregulation is an important feature of cancer and survivin, a member of the inhibitor-of-apoptosis-protein family encoded by the BIRC5 gene, has been suggested to have a role in the development and progression of several cancers. Genetic variability, in particular single nucleotide polymorphisms in the BIRC5 promoter, may affect the protein's expression levels. The aim of our study was to elucidate the effects of BIRC5 promoter single nucleotide polymorphisms on survivin expression, patient survival and age at diagnosis in malignant pleural mesothelioma. METHODS Archival mesothelioma samples from 101 Slovenian patients were immunohistochemically analysed for survivin expression. DNA was extracted from tumour samples and genotyped for three BIRC5 promoter single nucleotide polymorphisms (-31G > C, -241C > T and -625G > C). Genotypes were associated with nuclear survivin expression. Nuclear survivin expression, genotypes, haplotypes, histological type, gender and asbestos exposure were included in univariate Cox survival analyses. RESULTS Survivin expression was detected in both tumour cell nuclei and cytoplasms in all analysed samples. No association between BIRC5 promoter polymorphism genotypes or haplotypes and nuclear survivin expression was found. Polymorphism -241C > T affected patients' age at diagnosis. Survival analysis confirmed that younger age at diagnosis and epitheloid histological type improved survival, but no significant effects of nuclear survivin expression or genotype/haplotype on overall survival were observed. CONCLUSION Our findings indicate no relationship between BIRC5 genotypes and survivin expression or overall survival in mesothelioma patients. We observed that BIRC5 -241C > T polymorphism had a significant effect on patient age at diagnosis.
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Affiliation(s)
- Julija Hmeljak
- College of Health Care Izola, University of Primorska, Polje 42, 6310 Izola, Slovenia.
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Baytekin F, Tuna B, Mungan U, Aslan G, Yorukoglu K. Significance of P-glycoprotein, p53, and survivin expression in renal cell carcinoma. Urol Oncol 2011; 29:502-7. [DOI: 10.1016/j.urolonc.2009.09.001] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2009] [Revised: 08/31/2009] [Accepted: 09/03/2009] [Indexed: 11/16/2022]
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Antonacopoulou AG, Floratou K, Bravou V, Kottorou A, Dimitrakopoulos FI, Marousi S, Stavropoulos M, Koutras AK, Scopa CD, Kalofonos HP. The survivin -31 snp in human colorectal cancer correlates with survivin splice variant expression and improved overall survival. Cell Oncol (Dordr) 2011; 34:381-91. [PMID: 21538024 DOI: 10.1007/s13402-011-0038-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/09/2010] [Indexed: 10/18/2022] Open
Abstract
BACKGROUND Survivin is involved in the regulation of cell division and survival, two key processes in cancer. The majority of studies on survivin in colorectal cancer (CRC) have focused on protein expression and less is known about the expression of survivin splicing variants or survivin gene polymorphisms in CRC. In the present study, the mRNA levels of the five known isoforms of survivin as well as survivin protein were assessed in matched normal and neoplastic colorectal tissue. Moreover, the 9386 C/T and -31 G/C polymorphisms were investigated. METHODS Quantitative RT-PCR was used to assess mRNA levels in fresh/frozen tissue samples. Protein levels were immunohistochemically evaluated on formalin-fixed paraffin-embedded tissue sections. Individuals were genotyped using real time PCR. RESULTS Expression of all 5 survivin splice variants as well as survivin protein was elevated in colorectal carcinomas compared to normal tissue. Specific splice variant expression differentially correlated with clinicopathological parameters. Furthermore, both snps correlated with splice variant levels or their ratios in colorectal carcinomas while the -31 G/C snp may be related to CRC development and improved overall survival. CONCLUSION Our results support a role of survivin in colorectal carcinogenesis while the -31 G/C snp may constitute a marker of survival.
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Stefano JT, de Oliveira CPMS, Corrêa-Giannella ML, Soares IC, Kubrusly MS, Bellodi-Privato M, de Mello ES, de Lima VMR, Carrilho FJ, Alves VAF. Decreased immunoexpression of survivin could be a potential marker in human non-alcoholic fatty liver disease progression? Liver Int 2011; 31:377-385. [PMID: 21108736 DOI: 10.1111/j.1478-3231.2010.02370.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
BACKGROUND/AIM Regulation of apoptosis in non-alcoholic fatty liver disease (NAFLD) has been a theme of growing debate. Although no other study assessed the role of survivin in NAFLD, its expression has been reported in hepatic carcinogenesis because of other aetiological factors with relevant discrepancies. The aim of this study was to assess the pattern of survivin immunoexpression by tissue microarray along the whole spectrum of NAFLD, including non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC). METHODS Liver biopsies from 56 patients with NAFLD were evaluated: 18 with steatosis, 21 non-cirrhotic NASH, 10 NASH-related cirrhosis, seven NASH-related HCC, as compared with 71 HCC related to other causes and with 12 normal livers. RESULTS Survivin immunoexpression in NAFLD was restricted to cytoplasm and was found to be progressively lower in advanced stages, including cirrhosis and HCC: steatosis vs NASH-related cirrhosis (P=0.0243); steatosis vs NASH-related HCC (P=0.0010); NASH vs NASH-related cirrhosis (P=0.0318); and NASH vs NASH-related HCC (P=0.0007), thus suggesting a deregulation of apoptosis from NAFLD towards HCC. Interestingly, survivin immunoreactivity in NASH-related HCC was also found to be significantly lower than in HCC related to other causes (P<0.05). Remarkably, nuclear staining for survivin was not detected in any case of NAFLD, contrasting to its presence in all other cases of HCC. CONCLUSIONS Survivin immunoexpression in NASH-related HCC is herein originally found substantially different than in HCC related to other causes, thus requiring further studies to elucidate the role of survivin in human NAFLD progression.
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Affiliation(s)
- José T Stefano
- Department of Gastroenterology (LIM-07 and 37), University of São Paulo School of Medicine, Sao Paulo, SP, Brazil
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Abstract
Fibrolamellar hepatocellular carcinoma (FHLCC) generally occurs in young individuals lacking a background of chronic liver disease and other risk factors for hepatocellular carcinoma. The clinical presentations of FLHCC are generally nonspecific, and the alpha-fetoprotein level is typically within the normal range in most cases. Imaging studies have a major role in clinical diagnosis, but pathology is the gold standard in confirming diagnosis. Pathological characteristics of FLHCC include the presence of tumor cells with a deeply eosinophilic cytoplasm and macronucleoli surrounded by abundant fibrous bands. The most effective treatment for FLHCC is aggressive surgical resection. This comprehensive literature review gives a full account of the clinical, pathological, and molecular features of FLHCC.
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Shen Y, Lv B, Ding Y. Role of survivin in hepatocellular carcinoma and its clinical applications. Shijie Huaren Xiaohua Zazhi 2009; 17:1273-1278. [DOI: 10.11569/wcjd.v17.i13.1273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Survivin is a new family member of inhibitor of apoptosis proteins, which has the function of inhibiting apoptosis, inducing proliferation, and regulating caryocinesis and angiogenesis. It expresses highly and specifically in malignant tumors, and closely relates to development, metastasis, prognosis and recurrence of tumors. The gene therapy targeting survivin has been showing its clinical potential increasingly. This review summarizes the role of survivin in the occurrence and development of hepatocellular carcinoma as well as its clinical applications.
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Augello C, Caruso L, Maggioni M, Donadon M, Montorsi M, Santambrogio R, Torzilli G, Vaira V, Pellegrini C, Roncalli M, Coggi G, Bosari S. Inhibitors of apoptosis proteins (IAPs) expression and their prognostic significance in hepatocellular carcinoma. BMC Cancer 2009; 9:125. [PMID: 19397802 PMCID: PMC2680906 DOI: 10.1186/1471-2407-9-125] [Citation(s) in RCA: 118] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2008] [Accepted: 04/27/2009] [Indexed: 02/07/2023] Open
Abstract
Background Similarly to other tumor types, an imbalance between unrestrained cell proliferation and impaired apoptosis appears to be a major unfavorable feature of hepatocellular carcinoma (HCC). The members of IAP family are key regulators of apoptosis, cytokinesis and signal transduction. IAP survival action is antagonized by specific binding of Smac/DIABLO and XAF1. This study aimed to investigate the gene and protein expression pattern of IAP family members and their antagonists in a series of human HCCs and to assess their clinical significance. Methods Relative quantification of IAPs and their antagonist genes was assessed by quantitative Real Time RT-PCR (qPCR) in 80 patients who underwent surgical resection for HCC. The expression ratios of XIAP/XAF1 and of XIAP/Smac were also evaluated. Survivin, XIAP and XAF1 protein expression were investigated by immunohistochemistry. Correlations between mRNA levels, protein expression and clinicopathological features were assessed. Follow-up data were available for 69 HCC patients. The overall survival analysis was estimated according to the Kaplan-Meier method. Results Survivin and Livin/ML-IAP mRNAs were significantly over-expressed in cancer tissues compared to non-neoplastic counterparts. Although Survivin immunoreactivity did not correlate with qPCR data, a significant relation was found between higher Survivin mRNA level and tumor stage, tumor grade and vascular invasion. The mRNA ratio XIAP/XAF1 was significantly higher in HCCs than in cirrhotic tissues. Moreover, high XIAP/XAF1 ratio was an indicator of poor prognosis when overall survival was estimated and elevated XIAP immunoreactivity was significantly associated with shorter survival. Conclusion Our study demonstrates that alterations in the expression of IAP family members, including Survivin and Livin/ML-IAP, are frequent in HCCs. Of interest, we could determine that an imbalance in XIAP/XAF1 mRNA expression levels correlated to overall patient survival, and that high XIAP immunoreactivity was a poor prognostic factor.
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Affiliation(s)
- Claudia Augello
- Department of Medicine, Surgery and Dentistry, Division of Pathology, University of Milan, AO S Paolo e Fondazione IRCCS Ospedale Maggiore Policlinico, Regina Elena e Mangiagalli, Milan, Italy.
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Matar P, Alaniz L, Rozados V, Aquino JB, Malvicini M, Atorrasagasti C, Gidekel M, Silva M, Scharovsky OG, Mazzolini G. Immunotherapy for liver tumors: present status and future prospects. J Biomed Sci 2009; 16:30. [PMID: 19272130 PMCID: PMC2662798 DOI: 10.1186/1423-0127-16-30] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2008] [Accepted: 03/06/2009] [Indexed: 12/22/2022] Open
Abstract
Increasing evidence suggests that immune responses are involved in the control of cancer and that the immune system can be manipulated in different ways to recognize and attack tumors. Progress in immune-based strategies has opened new therapeutic avenues using a number of techniques destined to eliminate malignant cells. In the present review, we overview current knowledge on the importance, successes and difficulties of immunotherapy in liver tumors, including preclinical data available in animal models and information from clinical trials carried out during the lasts years. This review shows that new options for the treatment of advanced liver tumors are urgently needed and that there is a ground for future advances in the field.
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Affiliation(s)
- Pablo Matar
- Institute of Experimental Genetics, School of Medical Sciences, National University of Rosario, Santa Fe 3100, (2000) Rosario, Argentina.
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Vivekanandan P, Torbenson M. Epigenetic instability is rare in fibrolamellar carcinomas but common in viral-associated hepatocellular carcinomas. Mod Pathol 2008; 21:670-5. [PMID: 18264082 DOI: 10.1038/modpathol.2008.32] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Fibrolamellar carcinomas have a unique predilection for younger individuals and arise in livers without recognizable liver disease. In contrast to typical hepatocellular carcinomas, fibrolamellar carcinomas show few chromosomal changes and lack mutation in key genes such as TP53 and CTNNB1. Epigenetic instability, manifesting as methylation of important tumor suppressor gene promoters, has not been investigated in fibrolamellar carcinomas. Thus, the methylation status of 11 tumor suppressor gene promoters was investigated using methylation-specific PCR: RASSF1, CDH1, CDKN2B, HPP1, CDKN2A, GSTP1, P16, RARA, FLJ13081, SOCS1, and TP53. Nine fibrolamellar carcinomas were studied including primary tumors (N=5) and metastatic deposits (N=4) along with control groups of typical hepatocellular carcinoma arising in livers with (N=21) and without cirrhosis (N=10). In fibrolamellar carcinomas, RASSF1A and CDH1 (e-cadherin) were the most commonly methylated genes with 80-100% of tumors methylated. However, overall fibrolamellar carcinomas showed low levels of methylation with no differences between fibrolamellar carcinomas and their paired normal livers. However, fibrolamellar carcinomas showed significantly less methylation than hepatocellular carcinomas that arose in the background of viral cirrhosis. Overall, methylation was most strongly linked to viral cirrhosis. In conclusion, fibrolamellar carcinoma shows low levels of methylation. In contrast, higher levels of promoter methylation are associated with hepatocellular carcinomas that arise in the setting of viral induced cirrhosis.
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Affiliation(s)
- Perumal Vivekanandan
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
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35
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Rekha RD, Amali AA, Her GM, Yeh YH, Gong HY, Hu SY, Lin GH, Wu JL. Thioacetamide accelerates steatohepatitis, cirrhosis and HCC by expressing HCV core protein in transgenic zebrafish Danio rerio. Toxicology 2007; 243:11-22. [PMID: 17997003 DOI: 10.1016/j.tox.2007.09.007] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2007] [Revised: 09/03/2007] [Accepted: 09/03/2007] [Indexed: 12/19/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the common cancers worldwide, caused by Hepatitis C virus (HCV) and hepatotoxins. Here we report the development of HCC in wild type as well as HCV core protein (HCP)-transgenic zebrafish upon treatment with a hepatotoxin, thioacetamide (TAA). Two-fold accelerated HCC development could be achieved in the TAA-treated transgenic fish, that is, the progression of the disease in TAA-treated wild type zebrafish developed HCC in 12 weeks whereas that of HCP-transgenic zebrafish shortened the HCC progression to 6 weeks. Histopathological observation showed the specific pathological features of HCC. The HCC progression was confirmed through RT-PCR that revealed an up and down regulation of different marker genes at various stages of HCC progression such as, steatohepatitis, fibrosis and HCC. Moreover, HCV core protein expressed in the HCP-transgenic zebrafish and TAA synergistically accelerate the HCC development. It must be mentioned that, this is the first report revealing HCV core protein along with TAA to induce HCC in zebrafish, particularly, in a short period of time comparing to mice model. As zebrafish has already been considered as a good human disease model and in this context, this HCC-zebrafish model may serve as a powerful preclinical platform to study the molecular events in hepatocarcinogenesis, therapeutic strategies and for evaluating chemoprevention strategies in HCC.
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Affiliation(s)
- Ravikumar Deepa Rekha
- Laboratory of Marine Molecular Biology and Biotechnology, Institute of Cellular and Organismic Biology, Academia Sinica, NanKang, Taipei 11529, Taiwan
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36
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Chau GY, Lee AFY, Tsay SH, Ke YR, Kao HL, Wong FH, Tsou AP, Chau YP. Clinicopathological significance of survivin expression in patients with hepatocellular carcinoma. Histopathology 2007; 51:204-18. [PMID: 17559540 DOI: 10.1111/j.1365-2559.2007.02738.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
AIMS Survivin, a newly discovered member of the inhibitor of apoptosis protein family, is suggested to be involved in liver carcinogenesis. The aim was to investigate the clinical significance of survivin expression in resected hepatocellular carcinoma (HCC) and paired adjacent non-tumour tissue. METHODS AND RESULTS Immunohistochemistry, reverse transcriptase-polymerase chain reaction and Western blots were used to examine survivin mRNA and protein levels in 94 specimens of HCC tissues at different TNM stages and the data were correlated with the clinicopathological profiles. Patients were categorized into those with high tumour survivin protein levels (T-N >or= -1) and those with low levels (T-N < -1). Follow-up data were collected prospectively. mRNA levels of survivin and its splice variants in tumour tissue were significantly higher than in paired non-tumour tissue. However, survivin protein levels in paired non-tumour tissue were significantly higher than in tumour tissue from all three TNM stages. Additionally, high tumour survivin protein levels (T-N >or= -1) correlated with a better prognosis and low levels (T-N < -1) with a worse survival rate. CONCLUSIONS High cytoplasmic survivin protein levels in HCC tissues seem to be an indicator of better prognosis in HCC patients after resection.
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MESH Headings
- Alternative Splicing
- Antibody Specificity
- Base Sequence
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Cell Line, Tumor
- DNA Primers/genetics
- Female
- Humans
- Immunohistochemistry
- Inhibitor of Apoptosis Proteins
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Male
- Microtubule-Associated Proteins/genetics
- Microtubule-Associated Proteins/immunology
- Microtubule-Associated Proteins/metabolism
- Neoplasm Proteins/genetics
- Neoplasm Proteins/immunology
- Neoplasm Proteins/metabolism
- Neoplasm Staging
- Prognosis
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- RNA, Neoplasm/genetics
- RNA, Neoplasm/metabolism
- Reverse Transcriptase Polymerase Chain Reaction
- Survivin
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Affiliation(s)
- G-Y Chau
- Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan, ROC.
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37
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Abstract
Since its first description 50 years ago, fibrolamellar carcinomas (FLCs) have been recognized as a unique type of primary liver cancer. FLCs occur principally in children and young adults and are not associated with chronic liver disease. Their etiology is unknown. The tumor is made up of large polygonal cells containing abundant eosinophilic cytoplasm, large vesiculated nuclei, and large nucleoli, with tumor cells that are embedded in lamellar bands of fibrosis. Although rare, the most common variant of FLC shows areas of glandular type differentiation with mucin production. The uniqueness of FLC extends to their molecular findings, as they show no evidence for involvement by many of the major pathways and genes that are dysregulated in typical hepatocellular carcinoma, including alpha-fetoprotein, TP53 mutations, and beta catenin mutations. FLCs are not indolent tumors, but have an overall better prognosis than hepatocellular carcinomas of the usual sort because of the younger age at presentation and lack of cirrhosis. The most important prognostic feature is resectability. Although their morphologic appearance on routine stains is well defined, their etiology is still unknown and much of their molecular biology remains poorly described and awaits future investigation.
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Affiliation(s)
- Michael Torbenson
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
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D'Alessandro N, Poma P, Montalto G. Multifactorial nature of hepatocellular carcinoma drug resistance: could plant polyphenols be helpful? World J Gastroenterol 2007; 13:2037-43. [PMID: 17465444 PMCID: PMC4319121 DOI: 10.3748/wjg.v13.i14.2037] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2006] [Revised: 12/01/2006] [Accepted: 12/08/2006] [Indexed: 02/07/2023] Open
Abstract
Primary hepatocellular carcinoma (HCC) is a quite frequent tumor which results in high mortality and most often exhibits a poor response to present drug therapies. Clearly, a thorough understanding of the biological bases of this malignancy might suggest new strategies for its treatment. Here we examine the evidences that both "pharmacological" mechanisms (e.g. drug transporter or detoxification enzyme over-expression) and alterations in other critical factors, including the IAPs (Inhibitory of Apoptosis Proteins), involved in enhancement of cell survival and proliferation may determine the therapeutic resistance of HCC; we also underline the possible role in the process of the activation of transcription factors, like NF-kappaB, capable of contemporaneously up-regulating the mechanisms discussed. On this basis, we finally comment on the possible use of natural multi-targeted antitumoral agents like plant polyphenols to achieve sensitization to treatments in HCC.
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Affiliation(s)
- Natale D'Alessandro
- Department of Pharmacological Sciences, University of Palermo, Via del Vespro 129, Palermo 90127, Italy.
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Guan YS, La Z, Yang L, He Q, Li P. p53 gene in treatment of hepatic carcinoma: status quo. World J Gastroenterol 2007; 13:985-992. [PMID: 17373730 PMCID: PMC4146884 DOI: 10.3748/wjg.v13.i7.985] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2006] [Revised: 12/12/2006] [Accepted: 01/16/2007] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the 10 most common cancers worldwide. There is no ideal treatment for HCC yet and many researchers are trying to improve the effects of treatment by changing therapeutic strategies. As the majority of human cancers seem to exhibit either abnormal p53 gene or disrupted p53 gene activation pathways, intervention to restore wild-type p53 (wt-p53) activities is an attractive anti-cancer therapy including HCC. Abnormalities of p53 are also considered a predisposition factor for hepatocarcinogenesis. p53 is frequently mutated in HCC. Most HCCs have defects in the p53-mediated apoptotic pathway although they carry wt-p53. High expression of p53 in vivo may exert therapeutic effects on HCC in two aspects: (1) High expression of exogenous p53 protein induces apoptosis of tumor cells by inhibiting proliferation of cells through several biologic pathways and (2) Exogenous p53 renders HCC more sensitive to some chemotherapeutic agents. Several approaches have been designed for the treatment of HCC via the p53 pathway by restoring the tumor suppression function from inactivation, rescuing the mutated p53 gene from instability, or delivering therapeutic exogenous p53. Products with p53 status as the target have been studied extensively in vitro and in vivo. This review elaborates some therapeutic mechanisms and advances in using recombinant human adenovirus p53 and oncolytic virus products for the treatment of HCC.
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Affiliation(s)
- Yong-Song Guan
- Department of Radiology and Oncology, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China.
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40
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Zhang JF, Liu PQ, Chen GH, Lu MQ, Cai CJ, Yang Y, Li H. Ponicidin inhibits cell growth on hepatocellular carcinoma cells by induction of apoptosis. Dig Liver Dis 2007; 39:160-6. [PMID: 17049940 DOI: 10.1016/j.dld.2006.09.011] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2006] [Revised: 09/06/2006] [Accepted: 09/12/2006] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIM Ponicidin is recently reported to have anti-tumour effects on a large variety of cancers. The present study was undertaken to investigate the anti-proliferation effects of ponicidin on hepatocellular carcinoma cells and its mechanism. METHODS Two hepatocellular carcinoma cell lines, QGY-7701 and HepG-2 cells, were used. Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell apoptosis was assessed by flow cytometry and deoxyribonucleic acid fragmentation analysis. Cell morphology was observed by Hoechst 33258 staining. Reverse transcriptase-polymerase chain reaction and Western blot analysis were used to detect Survivin as well as Bax and Bcl-2 expressions. RESULTS Ponicidin could inhibit the growth of QGY-7701 and HepG-2 cells significantly by induction of apoptosis. Marked morphological changes of apoptosis were observed clearly. Both Survivin and Bcl-2 expressions were down-regulated remarkably while Bax expression up-regulated when apoptosis occurred. CONCLUSIONS Ponicidin has significant anti-proliferation effects by inducing apoptosis on hepatocellular carcinoma cells in vitro, down regulation of Survivin and Bcl-2 as well as upregualation of Bax expressions may be the important apoptotic inducing mechanisms.
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Affiliation(s)
- J-F Zhang
- Department of Liver Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, P.R. China
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41
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Sun Y, Lin R, Dai J, Jin D, Wang SQ. Suppression of tumor growth using antisense oligonucleotide against survivin in an orthotopic transplant model of human hepatocellular carcinoma in nude mice. Oligonucleotides 2007; 16:365-74. [PMID: 17155911 DOI: 10.1089/oli.2006.16.365] [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] [Indexed: 12/20/2022]
Abstract
Survivin, an inhibitor of apoptosis protein, deserves attention as a selective target for cancer therapy because it is overexpressed in many cancers, including human hepatocellular carcinoma (HCC). Here, we report a novel antisense oligonucleotide (ASO) against survivin for its effectiveness against tumor growth both in vitro and in vivo, and providing evidence in treatment for HCC. Initially, transfection of liver tumor cells HepG2 with ASO resulted in significant cells growth inhibition and reduction expression of survivin mRNA and protein, in a dose-dependent manner. Using caspase-3 protease activation assays, we observed that ASO has induced significantly greater apoptosis rate compared to control oligonucleotides. Furthermore, we used an orthotopic transplant model of HCC in nude mice to investigate the effect of ASO on tumor growth in vivo, and ASO reagents were delivered by intravenous injection. Interestingly, this systemic treatment also resulted in significant inhibition in tumor growth. Tumor growth in mice treated with ASO (50 and 75 mg/kg per day) was significantly inhibited (45.31% and 60.94%, respectively) compared with saline-injected group (p < 0.01), in a dose-dependent manner, and the effect of ASO on tumor growth was associated with downregulation of survivin in tumor xenografts. Moreover, the level of serum alpha-fetoprotein in ASO-treated groups was also decreased in a dose-dependent manner. Taken together, these data suggest that the usefulness of survivin ASO could potentially be a promising gene therapy approach to treatment of HCC.
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MESH Headings
- Animals
- Base Sequence
- Caspase 3/metabolism
- Cell Division/drug effects
- Cell Line, Tumor
- Enzyme Activation/drug effects
- Genetic Therapy/methods
- Humans
- Inhibitor of Apoptosis Proteins
- Liver Neoplasms, Experimental/genetics
- Liver Neoplasms, Experimental/metabolism
- Liver Neoplasms, Experimental/pathology
- Liver Neoplasms, Experimental/therapy
- Mice
- Mice, Nude
- Microtubule-Associated Proteins/antagonists & inhibitors
- Microtubule-Associated Proteins/genetics
- Neoplasm Proteins/antagonists & inhibitors
- Neoplasm Proteins/genetics
- Neoplasm Transplantation
- Oligodeoxyribonucleotides, Antisense/genetics
- Oligodeoxyribonucleotides, Antisense/therapeutic use
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- RNA, Neoplasm/genetics
- RNA, Neoplasm/metabolism
- Survivin
- Transfection
- Transplantation, Heterologous
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Affiliation(s)
- Yuning Sun
- Beijing Institute of Radiation Medicine, Beijing 100850, PR China
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42
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Llovet JM, Chen Y, Wurmbach E, Roayaie S, Fiel MI, Schwartz M, Thung SN, Khitrov G, Zhang W, Villanueva A, Battiston C, Mazzaferro V, Bruix J, Waxman S, Friedman SL. A molecular signature to discriminate dysplastic nodules from early hepatocellular carcinoma in HCV cirrhosis. Gastroenterology 2006; 131:1758-67. [PMID: 17087938 DOI: 10.1053/j.gastro.2006.09.014] [Citation(s) in RCA: 267] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2006] [Accepted: 09/07/2006] [Indexed: 12/02/2022]
Abstract
BACKGROUND & AIMS Small liver nodules approximately 2 cm are difficult to characterize by radiologic or pathologic examination. Our aim was to identify a molecular signature to diagnose early hepatocellular carcinoma (HCC). METHODS The transcriptional profiles of 55 candidate genes were assessed by quantitative real-time reverse-transcription polymerase chain reaction (RT-PCR) in 17 dysplastic nodules (diameter, 10 mm) and 20 early HCC (diameter, 18 mm) from HCV cirrhotic patients undergoing resection/transplantation and 10 nontumoral cirrhotic tissues and 10 normal liver tissues. Candidate genes were confirmed by quantitative RT-PCR in 20 advanced HCCs and by immunohistochemistry in 75 samples and validated in an independent set of 29 samples (dysplastic nodules [10] and small HCC [19; diameter, 20 mm]). RESULTS Twelve genes were significantly, differentially expressed in early HCCs compared with dysplastic nodules (>2-fold change; area under the receiver operating characteristic curve > or =0.8): this included TERT, GPC3, gankyrin, survivin, TOP2A, LYVE1, E-cadherin, IGFBP3, PDGFRA, TGFA, cyclin D1, and HGF. Logistic regression analysis identified a 3-gene set including GPC3 (18-fold increase in HCC, P = .01), LYVE1 (12-fold decrease in HCC, P = .0001), and survivin (2.2-fold increase in HCC, P = .02), which had a discriminative accuracy of 94%. The validity of the gene signature was confirmed in a prospective testing set. GPC3 immunostaining was positive in all HCCs and negative in dysplastic nodules (22/22 vs 0/14, respectively, P < .001). Nuclear staining for survivin was positive in 12 of 13 advanced HCC cases and in 1 of 9 early tumors. CONCLUSIONS Molecular data based on gene transcriptional profiles of a 3-gene set allow a reliable diagnosis of early HCC. Immunostaining of GPC3 confirms the diagnosis of HCC.
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Affiliation(s)
- Josep M Llovet
- Mount Sinai Liver Cancer Program, Department of Medicine, Mount Sinai School of Medicine, New York 10029, USA.
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El Far MA, Atwa MA, Yahya RS, El Basuni MA. Evaluation of serum levels of p53 in hepatocellular carcinoma in Egypt. Clin Chem Lab Med 2006; 44:653-6. [PMID: 16681440 DOI: 10.1515/cclm.2006.091] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-induced death. Somatic mutation of the p53 gene is the most common genetic abnormality so far described in human cancer and there is evidence that supports a high level of p53 alterations in HCC. The aim of this study was to investigate serum levels of p53 in Egyptian patients with HCC, and its relation to other prognostic factors such as tumor grade, alpha-fetoprotein (AFP), and liver function tests in an attempt to clarify their significance in the pathogenesis of the disease. Liver function tests were carried out and AFP and p53 levels were measured for all individuals studied. Our results show that detection of p53 increased the frequency of HCC prediction from 79.5% to 86.3%. Moreover, significant positive correlation between p53 and tumor size (cm) for tumor grade II and III was identified. In conclusion, serum concentration of p53 protein may be a convenient and useful non-invasive screening test for prediction of HCC.
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Affiliation(s)
- Mohamed A El Far
- Division of Biochemistry, Faculty of Sciences, Mansoura University, Mansoura, Egypt.
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44
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Guo RP, Zhong C, Shi M, Zhang CQ, Wei W, Zhang YQ, Li JQ. Clinical value of apoptosis and angiogenesis factors in estimating the prognosis of hepatocellular carcinoma. J Cancer Res Clin Oncol 2006; 132:547-55. [PMID: 16763805 DOI: 10.1007/s00432-006-0097-5] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2005] [Accepted: 03/10/2006] [Indexed: 12/11/2022]
Abstract
PURPOSE Whereas some studies have indicated that the prognosis of hepatocellular carcinoma (HCC) was correlated to some apoptosis and angiogenesis factors: p53, survivin, matrix metalloproteinases (MMPs, including MMP-2 and MMP-9) and vascular endothelial growth factor (VEGF), other studies have failed to confirm this. The aim of the present study is to investigate the expression of p53, survivin, MMPs and VEGF in HCC and the relationship between these factors and the prognosis of HCC patients. METHODS The expression of p53, survivin, MMP-2, MMP-9 and VEGF was measured by immunohistochemical assays in the liver resection specimens of 90 patients with HCC. RESULTS The positive rate of p53, survivin, MMP-2, MMP-9 and VEGF was 33.3, 51.1, 60.0, 37.8 and 76.7%, respectively. The expression of MMP-2, MMP-9 and VEGF was correlated to the recurrence of HCC patients, respectively (P < 0.01). No correlation was found between the expression of apoptosis factors (p53 and survivin) and the recurrence of HCC patients, respectively (P > 0.05). The positive correlations were found between MMP-2 and VEGF (r = 0.32, P < 0.01), MMP-9 and VEGF (r = 0.24, P < 0.05). Significant differences of disease-free survival rates occurred among subgroups according to the expression of MMP-2, MMP-9 and VEGF (P < 0.01). Multivariate analysis revealed that macroscopically disseminated nodules, tumor micrometastasis, high serum alpha-fetoprotein level, positive expression of MMP-9 and VEGF were independent recurrence risk factors. CONCLUSIONS Our investigation revealed that p53 and survivin could not estimate the prognosis of HCC patients. Angiogenesis factors (MMPs and VEGF) positively correlated to the prognosis of HCC patients. The expression of MMPs and VEGF in HCC tissues could be regarded as a valuable indicator in estimating the prognosis of HCC patients.
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Affiliation(s)
- Rong-Ping Guo
- State Key Laboratory of Oncology in Southern China, 651 Dongfeng Road East, Guangzhou, 510060, China.
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Cho-Rok J, Yoo J, Jang YJ, Kim S, Chu IS, Yeom YI, Choi JY, Im DS. Adenovirus-mediated transfer of siRNA against PTTG1 inhibits liver cancer cell growth in vitro and in vivo. Hepatology 2006; 43:1042-52. [PMID: 16628636 DOI: 10.1002/hep.21137] [Citation(s) in RCA: 93] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The pituitary tumor transforming (PTTG) gene family comprises PTTG1, 2, and 3. Forced expression of PTTG1 (securin) induces cellular transformation and promotes tumor development in animal models. PTTG1 is overexpressed in various human cancers. However, the expression and pathogenic implications of the PTTG gene family in hepatocellular carcinoma are largely unknown. Gene silencing using short interfering RNA (siRNA) has become an efficient means to study the functions of genes and has been increasingly used for cancer gene therapy approaches. We report that PTTG1, but not PTTG2 and 3, was highly and frequently expressed in liver cancer tissues from patients and highly in SH-J1, SK-Hep1, and Huh-7 hepatoma cell lines. Adenoviral vector encoding siRNA against PTTG1 (Ad.PTTG1-siRNA) depleted PTTG1 specifically and efficiently in SH-J1 hepatoma cells, which resulted in activation of p53 that led to increased p21 expression and induction of apoptosis. The depletion of PTTG1 in HCT116 colorectal cancer cells exhibited a cytotoxic effect in a p53-dependent manner. Ad.PTTG1-siRNA-mediated cytotoxic effect was dependent on expression levels of PTTG1 and p53 in hepatoma cell lines. Huh-7 hepatoma cells, once transduced with Ad.PTTG1-siRNA, displayed markedly attenuated growth potential in nude mice. Intra-tumor delivery of Ad.PTTG1-siRNA led to significant inhibition of tumor growth in SH-J1 tumor xenograft established in nude mice. In conclusion, PTTG1 overexpressed in hepatoma cell lines negatively regulates the ability of p53 to induce apoptosis. PTIG1 gene silencing using siRNA may be an effective modality to treat liver cancer, in which PTTG1 is abundantly expressed. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/ suppmat/index.html).
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Affiliation(s)
- Jung Cho-Rok
- Gene Therapy Research Unit, Korea Research Institute of Bioscience and Biotechnology, Yusong Daejeon, Republic of Korea
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