|
1
|
Peng C, Zhang X, Zhou N, Hu T, Shen Y, Chen TJ, Liu Y, Cui H, Zhu S. Apigenin inhibits lipid metabolism of hepatocellular carcinoma cells by targeting the histone demethylase KDM1A. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 135:156024. [PMID: 39341125 DOI: 10.1016/j.phymed.2024.156024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 08/26/2024] [Accepted: 09/02/2024] [Indexed: 09/30/2024]
Abstract
BACKGROUND The development of cancer is accompanied by metabolic reprogramming, and the liver serves as a central hub for lipid transportation. Apigenin, a plant-derived flavonoid, demonstrates potent anticancer properties across various cancer types and exhibits promising potential as a therapeutic agent for cancer treatment. However, there are limited studies focusing on the downstream targets of apigenin. Moreover, there are few reports on the impact of apigenin in lipid metabolism within liver cancer cells. PURPOSE The objective is to elucidate the metabolic mechanism underlying the inhibitory effect of apigenin on liver cancer progression, search for downstream targets and provide reliable data support for the clinical trials of apigenin. METHODS Anticancer effects of apigenin were detected at cellular and molecular levels in vitro, and downstream targets of apigenin, especially metabolic pathway genes, were analyzed by transcriptome. Next, the downstream target of apigenin was verified and the biological function of the downstream target was examined. Finally, the downstream target of apigenin was further verified by restoring target gene expression. RESULTS Cellular molecular experiments showed that Apigenin inhibited the proliferation, migration, invasion and lipid metabolism of hepatocellular carcinoma (HCC) cells. Transcriptome analysis showed apigenin widely regulates histone demethylase, particularly histone H3K4 lysine demethylase 1A (KDM1A). Apigenin treatment inhibited the expression of KDM1A protein and mRNA levels in liver cancer cells, molecular docking predicted the interaction between apigenin and KDM1A. Furthermore, downregulation KDM1A inhibited the proliferation and lipid metabolism of HCC cells, in the same way, overexpressing KDM1A promoted proliferation of HCC cells. Finally, restoring KDM1A expression partially attenuated the effects of apigenin on lipid metabolism in HCC cells. CONCLUSION In conclusion, our study provides compelling evidence that apigenin inhibits liver cancer progression and elucidates its mechanism of action in regulating lipid metabolism. Specifically, we find that apigenin suppresses the progression of HCC cells by downregulating genes involved in lipid metabolism. Additionally, our results indicate that KDM1A acts as a downstream target of apigenin in the inhibition of lipid metabolism in HCC. These findings offer experimental support for the potential use of apigenin as a therapeutic agent for liver cancer, highlighting its relevance in future clinical applications.
Collapse
Affiliation(s)
- Cheng Peng
- School of Life Sciences, Southwest University, Beibei, Chongqing 400716, China
| | - Ximei Zhang
- School of Life Sciences, Southwest University, Beibei, Chongqing 400716, China; Chipscreen Biosciences Pharmaceutical Ltd, Chengdu, Sichuan 610041, China
| | - Nini Zhou
- School of Life Sciences, Southwest University, Beibei, Chongqing 400716, China
| | - Ting Hu
- School of Life Sciences, Southwest University, Beibei, Chongqing 400716, China
| | - Yang Shen
- State Key Laboratory of Resource Insects, Medical Research Institute, Southwest University, Chongqing 400715, China; Jinfeng Laboratory, Chongqing 401329, China
| | - Teng Jiang Chen
- School of Life Sciences, Southwest University, Beibei, Chongqing 400716, China
| | - Yan Liu
- School of Life Sciences, Southwest University, Beibei, Chongqing 400716, China
| | - Hongjuan Cui
- State Key Laboratory of Resource Insects, Medical Research Institute, Southwest University, Chongqing 400715, China; Jinfeng Laboratory, Chongqing 401329, China
| | - Shunqin Zhu
- School of Life Sciences, Southwest University, Beibei, Chongqing 400716, China; State Key Laboratory of Resource Insects, Medical Research Institute, Southwest University, Chongqing 400715, China; Jinfeng Laboratory, Chongqing 401329, China.
| |
Collapse
|
|
2
|
Kapoor A, Bayat Mokhtari R, Sonti SS, Patel R, George A, Attwood K, Iyer R, Chakraborty S. Circulatory Agrin Serves as a Prognostic Indicator for Hepatocellular Carcinoma. Cancers (Basel) 2024; 16:2719. [PMID: 39123447 PMCID: PMC11312157 DOI: 10.3390/cancers16152719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 07/26/2024] [Accepted: 07/30/2024] [Indexed: 08/12/2024] Open
Abstract
Hepatocellular carcinoma (HCC), the predominant form of liver cancer, is associated with high mortality rates both in the United States and globally. Despite current advances in immunotherapy regimens, there is a scarcity of biomarkers to guide therapy selection. Alpha-fetoprotein (AFP) and glypican-3 have been proposed as biomarkers for HCC, but they do not provide any prognostic benefit for modeling disease progression. Agrin, a secreted proteoglycan, is frequently overexpressed in HCC and plays prominent role(s) in the liver tumor microenvironment (TME) to promote hepatocarcinogenesis. Here we employed a pilot single-center retrospective investigation to assess the prognostic value of agrin in HCC. Our evidence suggests that elevated serum agrin levels are associated with poor prognosis and performance among HCC patients. Multivariate Cox regression models indicate that secreted agrin serves as a better prognostic indicator compared to AFP that is significantly correlated with other secreted biomarkers (e.g., IL6). Cumulatively, this work demonstrates a promising clinical value of agrin in the detection and prognosis of HCC.
Collapse
Affiliation(s)
- Ankita Kapoor
- Department of Hematology-Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (A.K.); (S.S.S.); (R.P.)
| | - Reza Bayat Mokhtari
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA;
| | - Sahithi Savithri Sonti
- Department of Hematology-Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (A.K.); (S.S.S.); (R.P.)
| | - Riya Patel
- Department of Hematology-Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (A.K.); (S.S.S.); (R.P.)
| | - Anthony George
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (A.G.); (K.A.)
| | - Kristopher Attwood
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (A.G.); (K.A.)
| | - Renuka Iyer
- Department of Hematology-Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (A.K.); (S.S.S.); (R.P.)
| | - Sayan Chakraborty
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA;
- Program of Developmental Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| |
Collapse
|
|
3
|
Forna L, Bozomitu L, Lupu VV, Lupu A, Trandafir LM, Adam Raileanu A, Cojocariu C, Anton C, Girleanu I, Muzica CM. Pediatric Perspectives on Liver Cirrhosis: Unravelling Clinical Patterns and Therapeutic Challenges. J Clin Med 2024; 13:4275. [PMID: 39064318 PMCID: PMC11278264 DOI: 10.3390/jcm13144275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Revised: 07/01/2024] [Accepted: 07/19/2024] [Indexed: 07/28/2024] Open
Abstract
Background: Liver cirrhosis presents significant challenges in the pediatric population due to a complex interplay of etiological factors, clinical manifestations, and limited therapeutic options. The leading contributors to cirrhosis among pediatric patients are chronic cholestasis, metabolic disorders present from birth, and long-term hepatitis. Materials and method: Our narrative review aimed to synthesize literature data on the etiology, clinical picture, diagnostic techniques, optimal management of complications, and timely transplantation. Results: The epidemiology of liver cirrhosis in pediatric patients is evolving. The introduction of a universal vaccination and effective long-term viral suppression in viral hepatitis have significantly decreased complications rates. Liver transplantation programs worldwide have also improved the management of cirrhosis complications. Conclusions: Early diagnosis, comprehensive management strategies, and advancements in treatment modalities are critical for improving outcomes. Understanding these differences is crucial in providing age-appropriate care and support for those affected by cirrhosis.
Collapse
Affiliation(s)
- Lorenza Forna
- Pediatrics—“Sf. Maria” Clinical Emergency Children’s Hospital, 700309 Iași, Romania; (L.F.); (V.V.L.); (A.L.); (L.M.T.); (A.A.R.)
- Faculty of General Medicine, University of Medicine and Pharmacy “Gr. T. Popa”, 700115 Iași, Romania; (C.C.); (C.A.); (I.G.); (C.M.M.)
| | - Laura Bozomitu
- Pediatrics—“Sf. Maria” Clinical Emergency Children’s Hospital, 700309 Iași, Romania; (L.F.); (V.V.L.); (A.L.); (L.M.T.); (A.A.R.)
- Faculty of General Medicine, University of Medicine and Pharmacy “Gr. T. Popa”, 700115 Iași, Romania; (C.C.); (C.A.); (I.G.); (C.M.M.)
| | - Vasile Valeriu Lupu
- Pediatrics—“Sf. Maria” Clinical Emergency Children’s Hospital, 700309 Iași, Romania; (L.F.); (V.V.L.); (A.L.); (L.M.T.); (A.A.R.)
- Faculty of General Medicine, University of Medicine and Pharmacy “Gr. T. Popa”, 700115 Iași, Romania; (C.C.); (C.A.); (I.G.); (C.M.M.)
| | - Ancuta Lupu
- Pediatrics—“Sf. Maria” Clinical Emergency Children’s Hospital, 700309 Iași, Romania; (L.F.); (V.V.L.); (A.L.); (L.M.T.); (A.A.R.)
- Faculty of General Medicine, University of Medicine and Pharmacy “Gr. T. Popa”, 700115 Iași, Romania; (C.C.); (C.A.); (I.G.); (C.M.M.)
| | - Laura Mihaela Trandafir
- Pediatrics—“Sf. Maria” Clinical Emergency Children’s Hospital, 700309 Iași, Romania; (L.F.); (V.V.L.); (A.L.); (L.M.T.); (A.A.R.)
- Faculty of General Medicine, University of Medicine and Pharmacy “Gr. T. Popa”, 700115 Iași, Romania; (C.C.); (C.A.); (I.G.); (C.M.M.)
| | - Anca Adam Raileanu
- Pediatrics—“Sf. Maria” Clinical Emergency Children’s Hospital, 700309 Iași, Romania; (L.F.); (V.V.L.); (A.L.); (L.M.T.); (A.A.R.)
- Faculty of General Medicine, University of Medicine and Pharmacy “Gr. T. Popa”, 700115 Iași, Romania; (C.C.); (C.A.); (I.G.); (C.M.M.)
| | - Camelia Cojocariu
- Faculty of General Medicine, University of Medicine and Pharmacy “Gr. T. Popa”, 700115 Iași, Romania; (C.C.); (C.A.); (I.G.); (C.M.M.)
- Department of Clinical Gastroenterology, “Sf. Spiridon” Clinical Emergency Hospital, 700111 Iași, Romania
| | - Carmen Anton
- Faculty of General Medicine, University of Medicine and Pharmacy “Gr. T. Popa”, 700115 Iași, Romania; (C.C.); (C.A.); (I.G.); (C.M.M.)
- Department of Clinical Gastroenterology, “Sf. Spiridon” Clinical Emergency Hospital, 700111 Iași, Romania
| | - Irina Girleanu
- Faculty of General Medicine, University of Medicine and Pharmacy “Gr. T. Popa”, 700115 Iași, Romania; (C.C.); (C.A.); (I.G.); (C.M.M.)
- Department of Clinical Gastroenterology, “Sf. Spiridon” Clinical Emergency Hospital, 700111 Iași, Romania
| | - Cristina Maria Muzica
- Faculty of General Medicine, University of Medicine and Pharmacy “Gr. T. Popa”, 700115 Iași, Romania; (C.C.); (C.A.); (I.G.); (C.M.M.)
- Department of Clinical Gastroenterology, “Sf. Spiridon” Clinical Emergency Hospital, 700111 Iași, Romania
| |
Collapse
|
|
4
|
Basthi Mohan P, Lochan R, Shetty S. Biomarker in Hepatocellular Carcinoma. Indian J Surg Oncol 2024; 15:261-268. [PMID: 38817995 PMCID: PMC11133295 DOI: 10.1007/s13193-023-01858-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Accepted: 11/29/2023] [Indexed: 06/01/2024] Open
Abstract
Liver cancer is one of the most prevalent types of cancer and a major contributor to the socioeconomic burden worldwide. The pathogenesis of hepatocellular carcinoma (HCC) is contributed by various etiological factors like virus infection, excessive alcohol consumption, exposure to toxins, or metabolic disorders. Majority of patients are diagnosed with late-stage HCC, which restricts its management to only palliative care. HCC, if diagnosed early, increases the survival and quality of life. Currently available biomarker (alpha-fetoproteins) have several limitations, that impede the early diagnosis and staging of cancer. This warrants the continous search in pursuit of a novel biomarker. Several research works in diverse areas have contributed to the identification of various novel biomarkers that have shown multifaceted application in early disease diagnosis, which further aid in targeted and effective therapy that can prevent cancer progression. This improves the overall health status of the patient along with significant reduction in caretaker's burden. With the aid of novel technologies, several biomarkers have been investigated and validated in mutliple preliminary research works. Therefore in this review, we have outlined various novel biomarkers that showed promising outcomes in their trials and we have highlighted the developing areas that act as game changers in cancer diagnosis and management.
Collapse
Affiliation(s)
- Pooja Basthi Mohan
- Department of Gastroenterology and Hepatology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, 576104 Karnataka India
| | - Rajiv Lochan
- Department of Gastroenterology and Hepatology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, 576104 Karnataka India
- Lead Consultant Surgeon - HPB and Liver transplantation Surgery, Manipal Hospital, Bengaluru, 560017 Karnataka India
| | - Shiran Shetty
- Department of Gastroenterology and Hepatology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, 576104 Karnataka India
| |
Collapse
|
|
5
|
Nenu I, Toadere TM, Topor I, Țichindeleanu A, Bondor DA, Trella ȘE, Sparchez Z, Filip GA. Interleukin-6 in Hepatocellular Carcinoma: A Dualistic Point of View. Biomedicines 2023; 11:2623. [PMID: 37892997 PMCID: PMC10603956 DOI: 10.3390/biomedicines11102623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Revised: 09/14/2023] [Accepted: 09/21/2023] [Indexed: 10/29/2023] Open
Abstract
Hepatocellular Carcinoma (HCC) is a pressing health concern, demanding a deep understanding of various mediators' roles in its development for therapeutic progress. Notably, interleukin-6 (IL-6) has taken center stage in investigations due to its intricate and context-dependent functions. This review delves into the dual nature of IL-6 in HCC, exploring its seemingly contradictory roles as both a promoter and an inhibitor of disease progression. We dissect the pro-tumorigenic effects of IL-6, including its impact on tumor growth, angiogenesis, and metastasis. Concurrently, we examine its anti-tumorigenic attributes, such as its role in immune response activation, cellular senescence induction, and tumor surveillance. Through a comprehensive exploration of the intricate interactions between IL-6 and the tumor microenvironment, this review highlights the need for a nuanced comprehension of IL-6 signaling in HCC. It underscores the importance of tailored therapeutic strategies that consider the dynamic stages and diverse surroundings within the tumor microenvironment. Future research directions aimed at unraveling the multifaceted mechanisms of IL-6 in HCC hold promise for developing more effective treatment strategies and improving patient outcomes.
Collapse
Affiliation(s)
- Iuliana Nenu
- Department of Physiology, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400006 Cluj-Napoca, Romania; (I.N.); (T.M.T.); (A.Ț.); (D.A.B.); (Ș.E.T.); (G.A.F.)
- Department of Gastroenterology, “Prof. Dr. O. Fodor” Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania;
| | - Teodora Maria Toadere
- Department of Physiology, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400006 Cluj-Napoca, Romania; (I.N.); (T.M.T.); (A.Ț.); (D.A.B.); (Ș.E.T.); (G.A.F.)
| | - Ioan Topor
- Department of Physiology, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400006 Cluj-Napoca, Romania; (I.N.); (T.M.T.); (A.Ț.); (D.A.B.); (Ș.E.T.); (G.A.F.)
| | - Andra Țichindeleanu
- Department of Physiology, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400006 Cluj-Napoca, Romania; (I.N.); (T.M.T.); (A.Ț.); (D.A.B.); (Ș.E.T.); (G.A.F.)
| | - Daniela Andreea Bondor
- Department of Physiology, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400006 Cluj-Napoca, Romania; (I.N.); (T.M.T.); (A.Ț.); (D.A.B.); (Ș.E.T.); (G.A.F.)
| | - Șerban Ellias Trella
- Department of Physiology, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400006 Cluj-Napoca, Romania; (I.N.); (T.M.T.); (A.Ț.); (D.A.B.); (Ș.E.T.); (G.A.F.)
| | - Zeno Sparchez
- Department of Gastroenterology, “Prof. Dr. O. Fodor” Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania;
- Department of Internal Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400162 Cluj-Napoca, Romania
| | - Gabriela Adriana Filip
- Department of Physiology, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400006 Cluj-Napoca, Romania; (I.N.); (T.M.T.); (A.Ț.); (D.A.B.); (Ș.E.T.); (G.A.F.)
| |
Collapse
|
|
6
|
Inoue T, Tanaka Y. Noninvasive assessments of liver disease severity based on biomarkers. COMPREHENSIVE GUIDE TO HEPATITIS ADVANCES 2023:31-60. [DOI: 10.1016/b978-0-323-98368-6.00009-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
|
|
7
|
Schlosser S, Tümen D, Volz B, Neumeyer K, Egler N, Kunst C, Tews HC, Schmid S, Kandulski A, Müller M, Gülow K. HCC biomarkers - state of the old and outlook to future promising biomarkers and their potential in everyday clinical practice. Front Oncol 2022; 12:1016952. [PMID: 36518320 PMCID: PMC9742592 DOI: 10.3389/fonc.2022.1016952] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 11/04/2022] [Indexed: 08/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common and deadly tumors worldwide. Management of HCC depends on reliable biomarkers for screening, diagnosis, and monitoring of the disease, as well as predicting response towards therapy and safety. To date, imaging has been the established standard technique in the diagnosis and follow-up of HCC. However, imaging techniques have their limitations, especially in the early detection of HCC. Therefore, there is an urgent need for reliable, non/minimal invasive biomarkers. To date, alpha-fetoprotein (AFP) is the only serum biomarker used in clinical practice for the management of HCC. However, AFP is of relatively rather low quality in terms of specificity and sensitivity. Liquid biopsies as a source for biomarkers have become the focus of clinical research. Our review highlights alternative biomarkers derived from liquid biopsies, including circulating tumor cells, proteins, circulating nucleic acids, and exosomes, and their potential for clinical application. Using defined combinations of different biomarkers will open new perspectives for diagnosing, treating, and monitoring HCC.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Karsten Gülow
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases, University Hospital Regensburg, Regensburg, Germany
| |
Collapse
|
|
8
|
Tang Z, Zhang F, Wang Y, Zhang C, Li X, Yin M, Shu J, Yu H, Liu X, Guo Y, Li Z. Diagnosis of hepatocellular carcinoma based on salivary protein glycopatterns and machine learning algorithms. Clin Chem Lab Med 2022; 60:1963-1973. [PMID: 36113983 DOI: 10.1515/cclm-2022-0715] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 09/08/2022] [Indexed: 12/04/2024]
Abstract
OBJECTIVES Hepatocellular carcinoma (HCC) is difficult to diagnose early and progresses rapidly, making it one of the most deadly malignancies worldwide. This study aimed to evaluate whether salivary glycopattern changes combined with machine learning algorithms could help in the accurate diagnosis of HCC. METHODS Firstly, we detected the alteration of salivary glycopatterns by lectin microarrays in 118 saliva samples. Subsequently, we constructed diagnostic models for hepatic cirrhosis (HC) and HCC using three machine learning algorithms: Least Absolute Shrinkage and Selector Operation, Support Vector Machine (SVM), and Random Forest (RF). Finally, the performance of the diagnostic models was assessed in an independent validation cohort of 85 saliva samples by a series of evaluation metrics, including area under the receiver operator curve (AUC), accuracy, specificity, and sensitivity. RESULTS We identified alterations in the expression levels of salivary glycopatterns in patients with HC and HCC. The results revealed that the glycopatterns recognized by 22 lectins showed significant differences in the saliva of HC and HCC patients and healthy volunteers. In addition, after Boruta feature selection, the best predictive performance was obtained with the RF algorithm for the construction of models for HC and HCC. The AUCs of the RF-HC model and RF-HCC model in the validation cohort were 0.857 (95% confidence interval [CI]: 0.780-0.935) and 0.886 (95% CI: 0.814-0.957), respectively. CONCLUSIONS Detecting alterations in salivary protein glycopatterns with lectin microarrays combined with machine learning algorithms could be an effective strategy for diagnosing HCC in the future.
Collapse
Affiliation(s)
- Zhen Tang
- Laboratory for Functional Glycomics, College of Life Sciences, Northwest University, Xi'an, P.R. China
| | - Fan Zhang
- Laboratory for Functional Glycomics, College of Life Sciences, Northwest University, Xi'an, P.R. China
| | - Yuan Wang
- Department of Infectious Diseases, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, P.R. China
| | - Chen Zhang
- Laboratory for Functional Glycomics, College of Life Sciences, Northwest University, Xi'an, P.R. China
| | - Xia Li
- Laboratory for Functional Glycomics, College of Life Sciences, Northwest University, Xi'an, P.R. China
| | - Mengqi Yin
- Laboratory for Functional Glycomics, College of Life Sciences, Northwest University, Xi'an, P.R. China
| | - Jian Shu
- Laboratory for Functional Glycomics, College of Life Sciences, Northwest University, Xi'an, P.R. China
| | - Hanjie Yu
- Laboratory for Functional Glycomics, College of Life Sciences, Northwest University, Xi'an, P.R. China
| | - Xiawei Liu
- Laboratory for Functional Glycomics, College of Life Sciences, Northwest University, Xi'an, P.R. China
| | - Yonghong Guo
- The infectious disease department, Gongli Hospital, Pudong New Area, Shanghai, P.R. China
| | - Zheng Li
- Laboratory for Functional Glycomics, College of Life Sciences, Northwest University, Xi'an, P.R. China
| |
Collapse
|
|
9
|
Kim DS, Kim BK, Lee JS, Lee HW, Park JY, Kim DY, Ahn SH, Kim SU. Validation of Pre-/Post-TACE-Predict Models among Patients with Hepatocellular Carcinoma Receiving Transarterial Chemoembolization. Cancers (Basel) 2021; 14:67. [PMID: 35008231 PMCID: PMC8750487 DOI: 10.3390/cancers14010067] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 12/17/2021] [Accepted: 12/20/2021] [Indexed: 11/17/2022] Open
Abstract
This study attempted to validate the prognostic performance of the proposed Pre- and Post-TACE (transarterial chemoembolization)-Predict models, in comparison with other models for prognostication. One-hundred-and-eighty-seven patients with HCC who underwent TACE were recruited. Regarding overall survival (OS), the predictive performance of the Pre-TACE-Predict model (one-year integrated area under the curve (iAUC) 0.685 (95% confidence interval (CI) 0.593-0.772)) was better than that of the Post-TACE-Predict model (iAUC 0.659 (95% CI 0.580-0.742)). However, there was no significant statistical difference between two models at any time point. For comparison between models using pre-treatment factors, the modified hepatoma arterial embolization prognostic (mHAP)-II model demonstrated significantly better predictive performance at one year (iAUC 0.767 (95% CI 0.683-0.847)) compared with Pre-TACE-Predict. For comparison between models using first TACE response, the SNACOR model was significantly more predictive at one year (iAUC 0.778 (95% CI 0.687-0.866) vs. 0.659 (95% CI 0.580-0.742), respectively) and three years (iAUC 0.707 (95% CI 0.646-0.770) vs. 0.624 (95% CI 0.564-0.688), respectively) than the Post-TACE-Predict model. mHAP-II and SNACOR may be preferred over the Pre- and Post-TACE-Predict models, respectively, considering their similar or better performance and the ease of application.
Collapse
Affiliation(s)
- David Sooik Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea; (D.S.K.); (B.K.K.); (J.S.L.); (H.W.L.); (J.Y.P.); (D.Y.K.); (S.H.A.)
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea; (D.S.K.); (B.K.K.); (J.S.L.); (H.W.L.); (J.Y.P.); (D.Y.K.); (S.H.A.)
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Korea
- Yonsei Liver Center, Severance Hospital, Yonsei University Health System, Seoul 03722, Korea
| | - Jae Seung Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea; (D.S.K.); (B.K.K.); (J.S.L.); (H.W.L.); (J.Y.P.); (D.Y.K.); (S.H.A.)
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Korea
- Yonsei Liver Center, Severance Hospital, Yonsei University Health System, Seoul 03722, Korea
| | - Hye Won Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea; (D.S.K.); (B.K.K.); (J.S.L.); (H.W.L.); (J.Y.P.); (D.Y.K.); (S.H.A.)
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Korea
- Yonsei Liver Center, Severance Hospital, Yonsei University Health System, Seoul 03722, Korea
| | - Jun Yong Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea; (D.S.K.); (B.K.K.); (J.S.L.); (H.W.L.); (J.Y.P.); (D.Y.K.); (S.H.A.)
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Korea
- Yonsei Liver Center, Severance Hospital, Yonsei University Health System, Seoul 03722, Korea
| | - Do Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea; (D.S.K.); (B.K.K.); (J.S.L.); (H.W.L.); (J.Y.P.); (D.Y.K.); (S.H.A.)
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Korea
- Yonsei Liver Center, Severance Hospital, Yonsei University Health System, Seoul 03722, Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea; (D.S.K.); (B.K.K.); (J.S.L.); (H.W.L.); (J.Y.P.); (D.Y.K.); (S.H.A.)
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Korea
- Yonsei Liver Center, Severance Hospital, Yonsei University Health System, Seoul 03722, Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea; (D.S.K.); (B.K.K.); (J.S.L.); (H.W.L.); (J.Y.P.); (D.Y.K.); (S.H.A.)
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Korea
- Yonsei Liver Center, Severance Hospital, Yonsei University Health System, Seoul 03722, Korea
| |
Collapse
|
|
10
|
El Raziky M, Abdel Hafez H, Elsharkawy A, Moneer TA, EL-Sheikh SM, Maher RM, Sharaf SA. Serum level of cytokeratin 19 as a diagnostic and prognostic marker in patients with HCV-related hepatocellular carcinoma. EGYPTIAN LIVER JOURNAL 2021. [DOI: 10.1186/s43066-021-00125-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
The heterogeneous nature of human hepatocellular carcinoma (HCC) impedes both treatment strategies and prognostic predictions. Several markers have been proposed for the diagnosis of HCC. Cytoskeleton-associated proteins have been known as cellular integrators in neoplasm formation. Hepatic progenitor cells are thought to express alpha-fetoprotein (AFP) and hematopoietic as well as biliary markers such as cytokeratin 19 (CK 19) and cytokeratin 7. The aim of this study was to verify the role of serum CK 19 alone or in combination with AFP as a diagnostic marker of HCC and to assess the changes in its levels after ablation of HCV-related HCC to evaluate its role as a predictor marker for recurrence of HCC after ablation. The study was conducted on 102 HCV-related cirrhotic patients categorized into three different groups according to the clinical, laboratory, and radiological evaluation: group I—62 patients with early or intermediate HCC who underwent locoregional intervention, group II—20 patients with advanced HCC not fit for any intervention apart from best supportive treatment, and group III—20 cirrhotic patients with no evidence of HCC as proved by two imaging techniques.
Results
The mean serum levels of CK 19 were 6.5 ± 5.7, 10.5 ± 12.5, and 6.8 ± 2.8 ng/ml in groups I, II, and III, respectively, with no significant difference between groups. Sensitivity, specificity, positive, and negative predictive values of combined AFP and human CK 19 at cutoff levels of 25.5 ng/ml and 6.25 ng/ml were 93.9%, 45%, 87.5%, and 64.3%, respectively. In group I patients, CK 19 levels were comparable in patients with ablated focal lesion and those who did not at baseline; then, it was significantly higher in ablated patients than in patients with residual tumor 1 and 6 months after the intervention.
Conclusions
Combination of both AFP and CK 19 levels could increase the diagnostic accuracy of suspected HCCs. CK 19 levels are good predictors of ablation/recurrence in patients who underwent interventional procedures minimizing the need for follow-up imaging modalities.
Collapse
|
|
11
|
Zweerink S, Mesghenna S, Mueck V, Schulte S, Kuetting F, Quaas A, Goeser T, Nierhoff D. First evaluation of Neighbor of Punc E11 (NOPE) as a novel marker in human hepatocellular carcinoma. Cancer Biomark 2021; 30:75-83. [PMID: 32986656 DOI: 10.3233/cbm-190819] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the second most common cause of cancer death worldwide and the search for clinically useful biomarkers is ongoing. Neighbor of Punc E11 (NOPE) is an established biomarker of murine HCC that remains undetectable in normal liver and at preneoplastic stages. OBJECTIVE The aim of our study was to evaluate the presence of NOPE in human HCC. METHODS Histologically confirmed HCC and corresponding non-tumor liver samples from 20 patients were analyzed for expression of NOPE using qRT-PCR and mRNA-in-situ technology in a conserved tissue context. RESULTS In our cohort, 30% of HCC samples were expressing NOPE which proved particularly useful in non-cirrhotic HCC samples with up to 155-fold higher expression than in adult liver. Using mRNA-in-situ technology, NOPE was clearly identified within epithelial tumor cells of NOPE positive human HCCs. In our analyzed cohort, the combination of AFP with NOPE did not reach more than 40% sensitivity while GPC-3 and NOPE were complementary to each other reaching a combined sensitivity of 85.7%. CONCLUSIONS This is the first characterization of NOPE as a potential biomarker for human HCC. Our results underline the value of NOPE as a complementing biomarker for human HCC.
Collapse
Affiliation(s)
- Susanne Zweerink
- Department of Gastroenterology and Hepatology, Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany
| | - Senait Mesghenna
- Department of Internal Medicine, Donau-Ries Clinic Donauworth, Donauworth, Germany
| | - Vera Mueck
- Department of Gastroenterology and Hepatology, Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany
| | - Sigrid Schulte
- Department of Gastroenterology and Hepatology, Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany
| | - Fabian Kuetting
- Department of Gastroenterology and Hepatology, Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany
| | - Alexander Quaas
- Institute of Pathology, Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany.,Gastrointestinal Cancer Group Cologne (GCGC), Cologne, Germany
| | - Tobias Goeser
- Department of Gastroenterology and Hepatology, Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany
| | - Dirk Nierhoff
- Department of Gastroenterology and Hepatology, Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany
| |
Collapse
|
|
12
|
Gomaa SH, Abaza MM, Elattar HA, Amin GA, Elshahawy DM. Soluble cluster of differentiation 26/soluble dipeptidyl peptidase-4 and glypican-3 are promising serum biomarkers for the early detection of Hepatitis C virus related hepatocellular carcinoma in Egyptians. Arab J Gastroenterol 2020; 21:224-232. [PMID: 32891543 DOI: 10.1016/j.ajg.2020.04.016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Revised: 02/05/2020] [Accepted: 04/19/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND STUDY AIMS Many patients are diagnosed with hepatocellular carcinoma (HCC) in the late stage when it is already untreatable. Therefore, there is an increased need for sensitive biomarkers to detect HCC at an earlier stage in high risk patients with hepatitis C virus (HCV)-induced cirrhosis. This study aimed to evaluate the diagnostic performance of soluble cluster of differentiation 26/dipeptidyl peptidase 4 (sCD26/sDPP4) and glypican-3 (GPC3) as serum biomarkers for the early detection of HCV related HCC and compare it with that of the conventional tumor marker serum alpha fetoprotein (AFP). PATIENTS AND METHODS The study included 80 participants, 30 patients diagnosed with HCV infection without HCC (HCV group), 30 patients diagnosed with HCV- related HCC (HCV group), and 20 healthy volunteers (control group). The serum levels of GPC3 and sCD26 were measured using specific enzyme linked immunosorbant assay (ELISA) kits, whereas AFP levels were determined using chemiluminescence. RESULTS The serum levels of both sCD26 and GPC3 were found to be significantly higher in patients with early-stage HCC than in the HCV group, (1450 and 1.16 ng/mL, respectively). sCD26 at a cutoff value of > 1000 ng/ml, showed a high sensitivity (83.3%) and 63.3% specificity with an area under curve (AUC) of 0.811 and a 95% confidence interval (CI) of (0.682-0.94). While, the combination of GPC3 and sCD26 exhibited the best diagnostic performance for early-stage-HCC because it increased the sensitivity and specificity (85% and 93.3% respectively), with an AUC of 0.986 and a 95% CI of (0.899-1.00) compared to sCD26 alone. CONCLUSION We conclude that serum sCD26 could be a sensitive biomarker for the early detection of HCC among HCV patients. Moreover, the combination of sCD26 and GPC3 increases both the sensitivity and specificity for the early detection of HCV related HCC compared with AFP and could help in the monitoring of HCC in high risk patients with HCV induced cirrhosis.
Collapse
Affiliation(s)
- Salwa H Gomaa
- Department of Chemical Pathology, Medical Research Institute, Alexandria University, Egypt.
| | - Mona M Abaza
- Department of Chemical Pathology, Medical Research Institute, Alexandria University, Egypt
| | - Hoda A Elattar
- Department of Chemical Pathology, Medical Research Institute, Alexandria University, Egypt
| | - Gamal A Amin
- Department of Experimental and Internal Medicine, Medical Research Institute, Alexandria University, Egypt
| | | |
Collapse
|
|
13
|
Inoue T, Tanaka Y. Novel biomarkers for the management of chronic hepatitis B. Clin Mol Hepatol 2020; 26:261-279. [PMID: 32536045 PMCID: PMC7364351 DOI: 10.3350/cmh.2020.0032] [Citation(s) in RCA: 89] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 04/11/2020] [Accepted: 04/13/2020] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) cannot be eliminated completely from infected hepatocytes because of the presence of intrahepatic covalently closed circular DNA (cccDNA). As chronic hepatitis B (CHB) can progress to cirrhosis and hepatocellular carcinoma (HCC), it is important to manage CHB to prevent HCC development in high-risk patients with high viral replicative activity or advanced fibrosis. Serum biomarkers are noninvasive and valuable for the management of CHB. Hepatitis B core-related antigen (HBcrAg) correlates with serum HBV DNA and intrahepatic cccDNA. In CHB patients with undetectable serum HBV DNA or loss of HBsAg, HBcrAg still can be detected and the decrease in HBcrAg levels is significantly associated with hopeful outcomes. Therefore, HBcrAg can predict HCC occurrence or recurrence. Measurement of the Mac-2 binding protein glycosylation isomer (M2BPGi) has been introduced for the evaluation of liver fibrosis. Because elevated M2BPGi in CHB is related to liver fibrosis and the prediction of HCC development, monitoring its progression is essential. Because alpha fetoprotein (AFP) has insufficient sensitivity and specificity for early-stage HCC, a combination of AFP plus protein induced by vitamin K absence factor II, or AFP plus Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein might improve the diagnosis of HCC development. Additionally, Dickkopf-1 and circulating immunoglobulin G antibodies are the novel markers to diagnose HCC or assess HCC prognosis. This review provides an overview of novel HBV biomarkers used for the management of intrahepatic viral replicative activity, liver fibrosis, and HCC development.
Collapse
Affiliation(s)
- Takako Inoue
- Department of Clinical Laboratory Medicine, Nagoya City University Hospital, Nagoya, Japan
| | - Yasuhito Tanaka
- Department of Clinical Laboratory Medicine, Nagoya City University Hospital, Nagoya, Japan
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| |
Collapse
|
|
14
|
Zhang Y, Gao Y, Gao Y. Early changes in the urine proteome in a rat liver tumour model. PeerJ 2020; 8:e8462. [PMID: 32095334 PMCID: PMC7017802 DOI: 10.7717/peerj.8462] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Accepted: 12/26/2019] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Urine, as a potential biomarker source among body fluids, can accumulate many early changes in the body due to the lack of mechanisms to maintain a homeostatic state. This study aims to detect early changes in the urinary proteome in a rat liver tumour model. METHODS The tumour model was established with the Walker-256 carcinosarcoma cell line (W256). Urinary proteins at days 3, 5, 7 and 11 were profiled by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Compared with controls, differential proteins were selected. Associations of differential proteins with cancer were retrieved. RESULTS At days 3, 5, 7 and 11, five, fifteen, eleven and twelve differential proteins were identified, respectively. Some of the differential proteins were reported to be associated with liver cancer. This differential urinary protein pattern was different from the patterns in W256 subcutaneous, lung metastasis and intracerebral tumour models. CONCLUSIONS This study demonstrates that (1) early changes in urinary proteins can be found in the rat liver tumour model; (2) urinary proteins can be used to differentiate the same tumour cells grown in different organs.
Collapse
Affiliation(s)
- Yameng Zhang
- Department of Biochemistry and Molecular Biology, Beijing Normal University, Gene Engineering Drug and Biotechnology Beijing Key Laboratory, Beijing, China
| | - Yufei Gao
- College of Information Science and Technology, Beijing Normal University, Beijing, China
| | - Youhe Gao
- Department of Biochemistry and Molecular Biology, Beijing Normal University, Gene Engineering Drug and Biotechnology Beijing Key Laboratory, Beijing, China
| |
Collapse
|
|
15
|
Abou-Alfa GK, Jarnagin W, El Dika I, D'Angelica M, Lowery M, Brown K, Ludwig E, Kemeny N, Covey A, Crane CH, Harding J, Shia J, O'Reilly EM. Liver and Bile Duct Cancer. ABELOFF'S CLINICAL ONCOLOGY 2020:1314-1341.e11. [DOI: 10.1016/b978-0-323-47674-4.00077-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
|
16
|
Kim KH, Kim JY, Yoo JS. Mass spectrometry analysis of glycoprotein biomarkers in human blood of hepatocellular carcinoma. Expert Rev Proteomics 2019; 16:553-568. [PMID: 31145639 DOI: 10.1080/14789450.2019.1626235] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Kwang Hoe Kim
- Biomedical Omics Group, Korea Basic Science Institute, Cheongju, Republic of Korea
| | - Jin Young Kim
- Biomedical Omics Group, Korea Basic Science Institute, Cheongju, Republic of Korea
| | - Jong Shin Yoo
- Biomedical Omics Group, Korea Basic Science Institute, Cheongju, Republic of Korea
- Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, Republic of Korea
| |
Collapse
|
|
17
|
Gosain R, Anwar S, Miller A, Iyer R, Mukherjee S. Interleukin-6 as a biomarker in patients with hepatobiliary cancers. J Gastrointest Oncol 2019; 10:537-545. [PMID: 31183205 DOI: 10.21037/jgo.2019.01.09] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Background The role of inflammation has been well established in many cancers, including hepatobiliary cancers. Elevated levels of interleukin-6 (IL-6), a pro-inflammatory marker, are associated with poor overall survival (OS) in hepatocellular carcinoma (HCC) patients. Methods We performed a study to establish the role of IL-6 as a prognostic biomarker in both HCC and biliary cancer patients and further assessed the impact of IL-6 on pain score and performance status, two parameters that affect the quality of life. We evaluated 91 patients with newly diagnosed unresectable hepatobiliary cancer and compared them with age, gender and BMI matched healthy controls. Results We found that IL-6 levels were elevated in hepatobiliary cancer patients compared to healthy controls. Higher levels of IL-6 were associated with poor prognosis, elevated pain scores and poor performance status in patients. Interestingly, we found an association between elevated IL-6 levels and the presence of portal vein thrombosis (PVT) at the time of cancer diagnosis. Conclusions This study suggests that IL-6 is an important prognostic biomarker in hepatobiliary cancers, where elevated levels are not only associated with a worse survival but also linked to an inferior quality of life.
Collapse
Affiliation(s)
- Rohit Gosain
- Division of Hematology-Oncology, Roswell Park Comprehensive Cancer Center, University at Buffalo School of Medicine, Buffalo, New York, NY, USA
| | - Sidra Anwar
- Division of Hematology-Oncology, Roswell Park Comprehensive Cancer Center, University at Buffalo School of Medicine, Buffalo, New York, NY, USA
| | - Austin Miller
- Division of Hematology-Oncology, Roswell Park Comprehensive Cancer Center, University at Buffalo School of Medicine, Buffalo, New York, NY, USA
| | - Renuka Iyer
- Division of Hematology-Oncology, Roswell Park Comprehensive Cancer Center, University at Buffalo School of Medicine, Buffalo, New York, NY, USA
| | - Sarbajit Mukherjee
- Division of Hematology-Oncology, Roswell Park Comprehensive Cancer Center, University at Buffalo School of Medicine, Buffalo, New York, NY, USA.,Division of Hematology-Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| |
Collapse
|
|
18
|
Robinson JL, Feizi A, Uhlén M, Nielsen J. A Systematic Investigation of the Malignant Functions and Diagnostic Potential of the Cancer Secretome. Cell Rep 2019; 26:2622-2635.e5. [PMID: 30840886 PMCID: PMC6441842 DOI: 10.1016/j.celrep.2019.02.025] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Revised: 01/13/2019] [Accepted: 02/07/2019] [Indexed: 12/16/2022] Open
Abstract
The collection of proteins secreted from a cell-the secretome-is of particular interest in cancer pathophysiology due to its diagnostic potential and role in tumorigenesis. However, cancer secretome studies are often limited to one tissue or cancer type or focus on biomarker prediction without exploring the associated functions. We therefore conducted a pan-cancer analysis of secretome gene expression changes to identify candidate diagnostic biomarkers and to investigate the underlying biological function of these changes. Using transcriptomic data spanning 32 cancer types and 30 healthy tissues, we quantified the relative diagnostic potential of secretome proteins for each cancer. Furthermore, we offer a potential mechanism by which cancer cells relieve secretory pathway stress by decreasing the expression of tissue-specific genes, thereby facilitating the secretion of proteins promoting invasion and proliferation. These results provide a more systematic understanding of the cancer secretome, facilitating its use in diagnostics and its targeting for therapeutic development.
Collapse
Affiliation(s)
- Jonathan L Robinson
- Department of Biology and Biological Engineering, Chalmers University of Technology, Kemivägen 10, Gothenburg, Sweden; Wallenberg Centre for Protein Research, Chalmers University of Technology, Kemivägen 10, Gothenburg, Sweden
| | - Amir Feizi
- Department of Biology and Biological Engineering, Chalmers University of Technology, Kemivägen 10, Gothenburg, Sweden
| | - Mathias Uhlén
- Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden; Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, 2800 Kgs. Lyngby, Denmark
| | - Jens Nielsen
- Department of Biology and Biological Engineering, Chalmers University of Technology, Kemivägen 10, Gothenburg, Sweden; Wallenberg Centre for Protein Research, Chalmers University of Technology, Kemivägen 10, Gothenburg, Sweden; Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden; Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, 2800 Kgs. Lyngby, Denmark.
| |
Collapse
|
|
19
|
Han C, Gao L, Bai H, Dou X. Identification of a role for serum aldo-keto reductase family 1 member B10 in early detection of hepatocellular carcinoma. Oncol Lett 2018; 16:7123-7130. [PMID: 30546447 PMCID: PMC6256343 DOI: 10.3892/ol.2018.9547] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Accepted: 09/06/2018] [Indexed: 12/11/2022] Open
Abstract
Despite improved screening programs, the vast majority of patients with hepatocellular carcinoma (HCC) are diagnosed at an advanced stage. A lack of effective diagnosis methods for preclinical HCC has resulted in a low rate of early detection. Aldo-keto reductase family 1 member B10 (AKR1B10) is associated with several cancer types. However, to the best of our knowledge, the diagnostic value of AKR1B10 in early stage HCC is poorly understood. In the current study, the diagnostic performance of serum AKR1B10 in hepatitis B virus/hepatitis C virus (HBV/HCV)-related liver disorders was evaluated and the unique role of AKR1B10 in diagnosing HCC was assessed. Serum AKR1B10 was detected by sandwich ELISA in 84 patients with HBV/HCV-related HCC, 74 patients with liver cirrhosis, 29 patients with chronic hepatitis and 30 healthy controls. Serum AKR1B10 and α-fetoprotein (AFP) levels were analyzed and compared. Elevated levels of serum AKR1B10 were identified in patients with HCC compared with patients with other liver disorders (P<0.05). Compared with advanced and terminal stage HCC, a significant increase in AKR1B10 levels was primarily detected in early and intermediate stage HCC. The sensitivity (81.0%) and specificity (60.9%) for HCC diagnosis with AKR1B10 were high at a cutoff value of 1.51 ng/ml. Conversely, a prominent increase in AFP was observed in advanced and terminal stage HCC. Furthermore, concurrent measurement of serum AKR1B10 and AFP significantly increased sensitivity and negative predictive value for HCC diagnosis. The results presented in the current study strongly indicate AKR1B10 has a unique role as a biomarker for early stage HBV/HCV-related HCC. Compared with AFP alone, a combination of serum AKR1B10 and AFP increased the diagnostic performance in patients with HCC. In summary, the current results identify a unique role of AKR1B10 in HCC diagnosis.
Collapse
Affiliation(s)
- Chao Han
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110022, P.R. China
| | - Lanzhu Gao
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110022, P.R. China.,Department of Infectious Diseases, Tongliao Infectious Diseases Hospital, Tongliao, Inner Mongolia Autonomous Region 028000, P.R. China
| | - Han Bai
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110022, P.R. China
| | - Xiaoguang Dou
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110022, P.R. China
| |
Collapse
|
|
20
|
Jing R, Zhou X, Zhao J, Wei Y, Zuo B, You A, Rao Q, Gao X, Yang R, Chen L, Lu Z, Zhou Q, Zhang N, Yin H. Fluorescent peptide highlights micronodules in murine hepatocellular carcinoma models and humans in vitro. Hepatology 2018; 68:1391-1411. [PMID: 29405333 DOI: 10.1002/hep.29829] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Revised: 01/12/2018] [Accepted: 01/31/2018] [Indexed: 12/11/2022]
Abstract
UNLABELLED Early detection and clear delineation of microscopic lesions during surgery are critical to the prognosis and survival of patients with hepatocellular carcinoma (HCC), a devastating malignancy without effective treatments except for resection. Tools to specifically identify and differentiate micronodules from normal tissue in HCC patients can have a positive impact on survival. Here, we discovered a peptide that preferentially binds to HCC cells through phage display. Significant accumulation of the fluorescence-labeled peptide in tumor from ectopic and orthotopic HCC mice was observed within 2 hours of systemic injection. Contrast between tumor and surrounding liver is up to 6.5-fold, and useful contrast lasts for 30 hours. Micronodules (0.03 cm in diameter) in liver and lung can clearly be distinguished from normal tissue with this fluorescence-labeled peptide in orthotopic HCC mice and HCC patients. Compared to indocyanine green, a Food and Drug Administration-approved imaging contrast agent, an up to 8.7-fold higher differentiation ratio of tumor to fibrosis is achieved with this fluorescence-labeled peptide. Importantly, this peptide enables up to 10-fold differentiation between HCC and peritumoral tissue in human tissues and the complete removal of tumor in HCC mice with surgical navigation. No abnormalities in behavior or activity are observed after systemic treatment, indicating the absence of overt toxicity. The peptide is metabolized with a half-life of approximately 4 hours in serum. CONCLUSION Our findings demonstrate that micronodules can be specifically differentiated with high sensitivity from surrounding tissue with this molecule, opening clinical possibilities for early detection and precise surgery of HCC. (Hepatology 2018).
Collapse
Affiliation(s)
- Renwei Jing
- Department of Cell Biology and Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Medical University, Tianjin, China
| | - Xiaoli Zhou
- Department of Cell Biology and Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Medical University, Tianjin, China
| | - Jingwen Zhao
- Department of Cell Biology and Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Medical University, Tianjin, China
| | - Yushuang Wei
- Department of Nanomedicine and Biopharmaceuticals, National Engineering Research Center for Nanomedicine, Huazhong University of Science and Technology, Wuhan, China
| | - Bingfeng Zuo
- Department of Cell Biology and Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Medical University, Tianjin, China
| | - Abin You
- Department of Cell Biology and Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Medical University, Tianjin, China
| | - Quan Rao
- Department of Cell Biology and Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Medical University, Tianjin, China
| | - Xianjun Gao
- Department of Cell Biology and Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Medical University, Tianjin, China
| | - Rong Yang
- Department of Nanomedicine and Biopharmaceuticals, National Engineering Research Center for Nanomedicine, Huazhong University of Science and Technology, Wuhan, China
| | - Lu Chen
- Department of Genetics and Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China
| | - Zhen Lu
- Department of Cell Biology and Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Medical University, Tianjin, China
| | - Qibing Zhou
- Department of Nanomedicine and Biopharmaceuticals, National Engineering Research Center for Nanomedicine, Huazhong University of Science and Technology, Wuhan, China
| | - Ning Zhang
- Department of Genetics and Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China
| | - HaiFang Yin
- Department of Cell Biology and Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Medical University, Tianjin, China
| |
Collapse
|
|
21
|
Singh AK, Kumar R, Pandey AK. Hepatocellular Carcinoma: Causes, Mechanism of Progression and Biomarkers. Curr Chem Genom Transl Med 2018; 12:9-26. [PMID: 30069430 PMCID: PMC6047212 DOI: 10.2174/2213988501812010009] [Citation(s) in RCA: 107] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Revised: 05/15/2018] [Accepted: 05/20/2018] [Indexed: 01/18/2023] Open
Abstract
Hepatocellular Carcinoma (HCC) is one of the most common malignant tumours in the world. It is a heterogeneous group of a tumour that vary in risk factor and genetic and epigenetic alteration event. Mortality due to HCC in last fifteen years has increased. Multiple factors including viruses, chemicals, and inborn and acquired metabolic diseases are responsible for its development. HCC is closely associated with hepatitis B virus, and at least in some regions of the world with hepatitis C virus. Liver injury caused by viral factor affects many cellular processes such as cell signalling, apoptosis, transcription, DNA repair which in turn induce important effects on cell survival, growth, transformation and maintenance. Molecular mechanisms of hepatocellular carcinogenesis may vary depending on different factors and this is probably why a large set of mechanisms have been associated with these tumours. Various biomarkers including α-fetoprotein, des-γ-carboxyprothrombin, glypican-3, golgi protein-73, squamous cell carcinoma antigen, circulating miRNAs and altered DNA methylation pattern have shown diagnostic significance. This review article covers up key molecular pathway alterations, biomarkers for diagnosis of HCC, anti-HCC drugs and relevance of key molecule/pathway/receptor as a drug target.
Collapse
Affiliation(s)
| | | | - Abhay K. Pandey
- Department of Biochemistry, University of Allahabad, Allahabad 211002, India
| |
Collapse
|
|
22
|
Liu H, Wang X, Feng B, Tang L, Li W, Zheng X, Liu Y, Peng Y, Zheng G, He Q. Golgi phosphoprotein 3 (GOLPH3) promotes hepatocellular carcinoma progression by activating mTOR signaling pathway. BMC Cancer 2018; 18:661. [PMID: 29914442 PMCID: PMC6006993 DOI: 10.1186/s12885-018-4458-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Accepted: 04/30/2018] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the sixth most common cancer and the second leading cause of cancer-related deaths worldwide. Despite new technologies in diagnosis and treatment, the incidence and mortality of HCC continue rising. And its pathogenesis is still unclear. As a highly conserved protein of the Golgi apparatus, Golgi phosphoprotein 3 (GOLPH3) has been shown to be involved in tumorigenesis of HCC. This study aimed to explore the exact oncogenic mechanism of GOLPH3 and provide a novel diagnose biomarker and therapeutic strategy for patients with HCC. METHODS Firstly, the expression of GOLPH3 was detected in the HCC tissue specimens and HCC cell lines. Secondly, RNA interference was used for GOLPH3 gene inhibition. Thirdly, cell proliferation was analyzed by MTT; cell apoptosis was analyzed by Annexin-V/PI staining, Hoechst 33,342 staining and caspase 3/7 activity assay. Fourthly, xenograft tumor model was used to study the function of GOLPH3 in tumor growth in vivo. Finally, western blotting and immunohistochemistry were used to investigate the role of GOLHP3 in the mTOR signaling pathway. RESULTS Data showed that the mRNA and protein expression of GOLPH3 were up-regulated in HCC tumor tissue and cell lines compared with those of control (P < 0.05). Correlation analyses showed that GOLPH3 expression was positively correlated with serum alpha-fetoprotein level (AFP, P = 0.006). Knockdown GOLPH3 expression inhibited proliferation and promoted apoptosis in HCC cell lines. What's more, knockdown GOLPH3 expression led to tumor growth restriction in xenograft tumor model. The expression of phosphorylated mTOR, AKT and S6 K1 were significantly higher in HCC tumor tissue and cell lines compared with those in normal liver tissues (p < 0.05). While the phosphorylated mTOR, AKT and S6 K1 were much lower when diminished GOLPH3 expression in HCC cell lines both in vitro and in vivo. CONCLUSION The current study suggests that GOLPH3 contributes to the tumorigenesis of HCC by activating mTOR signaling pathway. GOLPH3 is a promising diagnose biomarker and therapeutic target for HCC. Our study may provide a scientific basis for developing effective approaches to treat the HCC patients with GOLPH3 overexpression.
Collapse
Affiliation(s)
- Hongying Liu
- Department of Pathology, The Second Clinical College of Guangzhou University of Chinese Medicine,Guangdong Provincial Hospital of Chinese Medicine, 111 Dade Road, Guangzhou, 510120, Guangdong, China
| | - Xieqi Wang
- Guangzhou University of Chinese Medicine, 232 Waihuan East Road, Guangzhou, 510006, China
| | - Bing Feng
- Department of Pharmacology of Traditional Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine,Guangdong Provincial Hospital of Chinese Medicine, 111 Dade Road, Guangzhou, 510120, Guangdong, China
| | - Lipeng Tang
- Department of Pharmacology of Traditional Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine,Guangdong Provincial Hospital of Chinese Medicine, 111 Dade Road, Guangzhou, 510120, Guangdong, China
| | - Weiping Li
- Department of Pathology, The Second Clinical College of Guangzhou University of Chinese Medicine,Guangdong Provincial Hospital of Chinese Medicine, 111 Dade Road, Guangzhou, 510120, Guangdong, China
| | - Xirun Zheng
- Department of Pathology, The Second Clinical College of Guangzhou University of Chinese Medicine,Guangdong Provincial Hospital of Chinese Medicine, 111 Dade Road, Guangzhou, 510120, Guangdong, China
| | - Ying Liu
- Department of Pathology, The Second Clinical College of Guangzhou University of Chinese Medicine,Guangdong Provincial Hospital of Chinese Medicine, 111 Dade Road, Guangzhou, 510120, Guangdong, China
| | - Yan Peng
- Department of Pathology, The Second Clinical College of Guangzhou University of Chinese Medicine,Guangdong Provincial Hospital of Chinese Medicine, 111 Dade Road, Guangzhou, 510120, Guangdong, China
| | - Guangjuan Zheng
- Department of Pathology, The Second Clinical College of Guangzhou University of Chinese Medicine,Guangdong Provincial Hospital of Chinese Medicine, 111 Dade Road, Guangzhou, 510120, Guangdong, China. .,Department of Pharmacology of Traditional Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine,Guangdong Provincial Hospital of Chinese Medicine, 111 Dade Road, Guangzhou, 510120, Guangdong, China.
| | - Qinglian He
- Department of Pathology, The Second Clinical College of Guangzhou University of Chinese Medicine,Guangdong Provincial Hospital of Chinese Medicine, 111 Dade Road, Guangzhou, 510120, Guangdong, China.
| |
Collapse
|
|
23
|
Ram AK, Pottakat B, Vairappan B. Increased systemic zonula occludens 1 associated with inflammation and independent biomarker in patients with hepatocellular carcinoma. BMC Cancer 2018; 18:572. [PMID: 29776350 PMCID: PMC5960107 DOI: 10.1186/s12885-018-4484-5] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2017] [Accepted: 05/08/2018] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a frequent type of primary liver cancer, and its prevalence is increasing worldwide. Indeed, the underlying molecular mechanism is not well understood. Previous studies have shown evidence that tight junction (TJ) components were correlated with carcinogenesis and tumor development. Our aims were to determine the serum levels of tight junction protein Zonula Occludens (ZO)-1 and an inflammatory marker such as high-sensitive C-reactive protein (hs-CRP) in HCC patients compared to healthy volunteers and also to identify the association between ZO-1 and inflammation in HCC. METHODS Thirty HCC patients and 30 healthy volunteers were recruited in the current study. Clinical data regarding child class, BCLC staging, the number of lesions, tumor size, absence or presence of metastasis, cirrhosis and hepatitis infection were also collected in HCC patients. Plasma ZO-1 and serum hsCRP were analyzed by EIA and ELISA respectively and biochemical parameters by autoanalyser (AU680 Beckman Coulter, USA). Furthermore, hepatic ZO-1 protein expression and tissue localization were examined. RESULTS Compared to healthy individuals, the serum levels of bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyltransferase (GGT) and alkaline phosphatase (ALP) were elevated significantly (P < 0.0001) whilst serum albumin level was significantly (P < 0.0001) decreased in HCC patients. Furthermore, tight junction protein ZO-1 concentration was significantly elevated in HCC patients compared to control subjects (648 ± 183.8 vs. 396.4 ± 135.8 pg/ml, respectively; P < 0.0001). Serum hsCRP level was also significantly increased in HCC patients compared to control subjects (17.25 ± 3.57 vs. 5.54 ± 2.62 mg/L, respectively; P < 0.0001). Moreover, decreased protein expression of ZO-1 was found in liver tissue obtained from HCC patients. CONCLUSION Our findings show for the first time that the systemic concentration of ZO-1 was significantly elevated in HCC patients and is positively correlated with inflammatory markers. Thus, the current study showing evidence that inflammation promotes plasma ZO-1 concentration and raises the possibility that it could be used as a potential diagnostic biomarker for HCC progression.
Collapse
Affiliation(s)
- Amit Kumar Ram
- Liver Diseases Research Lab, Department of Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Dhanvantari Nagar, Puducherry, 605006 India
| | - Biju Pottakat
- Department of Surgical Gastroenterology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, 605006 India
| | - Balasubramaniyan Vairappan
- Liver Diseases Research Lab, Department of Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Dhanvantari Nagar, Puducherry, 605006 India
| |
Collapse
|
|
24
|
Braunwarth E, Stättner S, Fodor M, Cardini B, Resch T, Oberhuber R, Putzer D, Bale R, Maglione M, Margreiter C, Schneeberger S, Öfner D, Primavesi F. Surgical techniques and strategies for the treatment of primary liver tumours: hepatocellular and cholangiocellular carcinoma. Eur Surg 2018; 50:100-112. [PMID: 29875798 PMCID: PMC5968076 DOI: 10.1007/s10353-018-0537-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2018] [Accepted: 05/02/2018] [Indexed: 12/14/2022]
Abstract
Background Owing to remarkable improvements of surgical techniques and associated specialities, liver surgery has become the standard of care for hepatocellular carcinoma and cholangiocarcinoma. Although applied with much greater safety, hepatic resections for primary liver tumours remain challenging and need to be integrated in a complex multidisciplinary treatment approach. Methods This literature review gives an update on the recent developments regarding basics of open and laparoscopic liver surgery and surgical strategies for primary liver tumours. Results Single-centre reports and multicentre registries mainly from Asia and Europe dominate the surgical literature on primary liver tumours, but the numbers of randomized trials are slowly increasing. Perioperative outcomes of open liver surgery for hepatocellular and cholangiocellular carcinoma have vastly improved over the last decades, accompanied by some progress in terms of oncological outcome. The laparoscopic approach is increasingly being applied in many centres, even for patients with underlying liver disease, and may result in decreased morbidity. Liver transplantation represents a cornerstone in the treatment of early hepatocellular carcinoma and is indispensable to achieve long-term survival. In contrast, resection remains the gold standard for cholangiocarcinoma in most countries, but interventional techniques are on the rise. Conclusion Liver surgery for primary tumours is complex, with a need for high expertise in a multidisciplinary team to achieve acceptable outcomes. Technical developments and clinical stratification tools have optimized individual care, but further improvements in oncological survival will likely require enhanced pre- and postoperative systemic and local treatment options.
Collapse
Affiliation(s)
- Eva Braunwarth
- Department of Visceral, Transplantation and Thoracic Surgery, Medical University of Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria
| | - Stefan Stättner
- Department of Visceral, Transplantation and Thoracic Surgery, Medical University of Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria
| | - Margot Fodor
- Department of Visceral, Transplantation and Thoracic Surgery, Medical University of Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria
| | - Benno Cardini
- Department of Visceral, Transplantation and Thoracic Surgery, Medical University of Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria
| | - Thomas Resch
- Department of Visceral, Transplantation and Thoracic Surgery, Medical University of Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria
| | - Rupert Oberhuber
- Department of Visceral, Transplantation and Thoracic Surgery, Medical University of Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria
| | - Daniel Putzer
- Department of Radiology, Medical University of Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria
| | - Reto Bale
- Department of Radiology, Medical University of Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria
| | - Manuel Maglione
- Department of Visceral, Transplantation and Thoracic Surgery, Medical University of Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria
| | - Christian Margreiter
- Department of Visceral, Transplantation and Thoracic Surgery, Medical University of Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria
| | - Stefan Schneeberger
- Department of Visceral, Transplantation and Thoracic Surgery, Medical University of Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria
| | - Dietmar Öfner
- Department of Visceral, Transplantation and Thoracic Surgery, Medical University of Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria
| | - Florian Primavesi
- Department of Visceral, Transplantation and Thoracic Surgery, Medical University of Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria
| |
Collapse
|
|
25
|
El-Saadany S, El-Demerdash T, Helmy A, Mayah WW, El-Sayed Hussein B, Hassanien M, Elmashad N, Fouad MA, Basha EA. Diagnostic Value of Glypican-3 for Hepatocellular Carcinomas. Asian Pac J Cancer Prev 2018; 19:811-817. [PMID: 29582639 PMCID: PMC5980860 DOI: 10.22034/apjcp.2018.19.3.811] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/16/2017] [Indexed: 12/12/2022] Open
Abstract
Background: Hepatocellular carcinoma (HCC) is a common and dangerous malignancy in many parts of the world, and especially in Egypt. Early diagnosis is the most important step in successful HCC management. However most cases are detected at late stage making effective intervention impossible. Aim: The aim of this study was to evaluate the potential of Glypican-3 (GPC-3) to aid in diagnosis of HCC, especially in patients with low serum alpha-fetoprotein (AFP). Subjects and methods: Serum GPC-3 was assessed by flow-cytometry and serum AFP by enzyme-linked immunosorbent assay (ELISA) in 40 HCC patients with AFP< 400ug\l. (GI), 40 HCC patients with AFP> 400ug\l. (GII) and 20 healthy controls (GIII). Results: GPC-3 was found to be significantly elevated in HCC as compared to healthy subjects (GI 38.2±22. 5, GII 50.2±22.6, and GIII 2.24±1.19), with sensitivities of 85% for GI and 84% for GII and specificities of 95% for GI and 92% for GII. AFP showed respective sensitivities of 50% and 79%, and specificities of 80% and 90%, for HCC diagnosis. The combination of GPC-3 with AFP achieved the highest sensitivity (98.5%) and specificity (97.8%). Conclusion: Serum GPC-3 has a better sensitivity than AFP for the diagnosis of HCC. Combination of two markers appears warranted for greatest accuracy.
Collapse
Affiliation(s)
- Sherif El-Saadany
- Department of Tropical Medicine and Infectious Diseases, Faculty of Medicine, University of Tanta, Egypt
- Fakeeh College for Medical Sciences, Jeddah, Saudi Arabia
| | | | | | | | | | | | | | | | | |
Collapse
|
|
26
|
Poddar S, Loh PS, Ooi ZH, Osman F, Eul J, Patzel V. RNA Structure Design Improves Activity and Specificity of trans-Splicing-Triggered Cell Death in a Suicide Gene Therapy Approach. MOLECULAR THERAPY-NUCLEIC ACIDS 2018; 11:41-56. [PMID: 29858076 PMCID: PMC5849863 DOI: 10.1016/j.omtn.2018.01.006] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Revised: 01/17/2018] [Accepted: 01/17/2018] [Indexed: 01/20/2023]
Abstract
Spliceosome-mediated RNA trans-splicing enables correction or labeling of pre-mRNA, but therapeutic applications are hampered by issues related to the activity and target specificity of trans-splicing RNA (tsRNA). We employed computational RNA structure design to improve both on-target activity and specificity of tsRNA in a herpes simplex virus thymidine kinase/ganciclovir suicide gene therapy approach targeting alpha fetoprotein (AFP), a marker of hepatocellular carcinoma (HCC) or human papillomavirus type 16 (HPV-16) pre-mRNA. While unstructured, mismatched target binding domains significantly improved 3′ exon replacement (3’ER), 5′ exon replacement (5’ER) correlated with the thermodynamic stability of the tsRNA 3′ end. Alternative on-target trans-splicing was found to be a prevalent event. The specificity of trans-splicing with the intended target splice site was improved 10-fold by designing tsRNA that harbors secondary target binding domains shielding alternative on-target and blinding off-target splicing events. Such rationally designed suicide RNAs efficiently triggered death of HPV-16-transduced or hepatoblastoma-derived human tissue culture cells without evidence for off-target cell killing. Highest cell death activities were observed with novel dual-targeting tsRNAs programmed for trans-splicing toward AFP and a second HCC pre-mRNA biomarker. Our observations suggest trans-splicing represents a promising approach to suicide gene therapy.
Collapse
Affiliation(s)
- Sushmita Poddar
- Department of Microbiology & Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Block MD4, Level 5, 5 Science Drive 2, Singapore 117597, Singapore
| | - Pei She Loh
- Department of Microbiology & Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Block MD4, Level 5, 5 Science Drive 2, Singapore 117597, Singapore
| | - Zi Hao Ooi
- Department of Microbiology & Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Block MD4, Level 5, 5 Science Drive 2, Singapore 117597, Singapore
| | - Farhana Osman
- Department of Microbiology & Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Block MD4, Level 5, 5 Science Drive 2, Singapore 117597, Singapore
| | - Joachim Eul
- INEIDFO GmbH, Weserstrasse 23, 12045 Berlin, Germany
| | - Volker Patzel
- Department of Microbiology & Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Block MD4, Level 5, 5 Science Drive 2, Singapore 117597, Singapore; Department of Medicine, Division of Infectious Diseases, University of Cambridge, Addenbrooke's Hospital, Level 5, Hills Road, Cambridge CB2 0QQ, UK.
| |
Collapse
|
|
27
|
Wu J, Zhu P, Zhang Z, Zhang B, Shu C, Chen L, Feng R, Mba'nbo Koumpa AA, Li G, Ge Q. A new tumor-associated antigen prognostic scoring system for spontaneous ruptured hepatocellular carcinoma after partial hepatectomy. Cancer Biol Med 2018; 15:415-424. [PMID: 30766751 PMCID: PMC6372911 DOI: 10.20892/j.issn.2095-3941.2018.0095] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Objective: Spontaneous hepatocellular carcinoma (HCC) rupture can be fatal, and hepatic resection could achieve a favorable long-term survival among all strategies of tumor rupture. However, there is no available prognostic scoring system for patients with ruptured HCC who underwent partial hepatectomy. Methods: From January 2005 to May 2015, 129 patients with spontaneous HCC rupture underwent partial hepatectomy. Preoperative clinical data were collected and analyzed. Independent risk factors affecting overall survival (OS) were used to develop the new scoring system. Harrell’s C statistics, Akaike information criterion (AIC), the relative likelihood, and the log likelihood ratio were calculated to measure the homogeneity and discriminatory ability of a prognostic system. Results: In the multivariable Cox regression analysis, three factors, including tumor size, preoperative α-fetoprotein level, and alkaline phosphatase level, were chosen for the new tumor-associated antigen (TAA) prognostic scoring system. The 1-year OS rates were 88.1%, 43.2%, and 30.2% for TAA scores of 0–5 points (low-risk group), 6–9 points (moderate-risk group), and 10–13 points (high-risk group), respectively. The TAA scoring system had superior homogeneity and discriminatory ability (Harrell’s C statistics, 0.693 vs. 0.627 and 0.634; AIC, 794.79 vs. 817.23 and 820.16; relative likelihood, both < 0.001; and log likelihood ratio, 45.21 vs. 22.77 and 21.84) than the Barcelona Clinic Liver Cancer staging system and the Cancer of the Liver Italian Program in predicting OS. Similar results were found while predicting disease-free survival (DFS).
Conclusions: The new prognostic scoring system is simple and effective in predicting both OS and DFS of patients with spontaneous ruptured HCC.
Collapse
Affiliation(s)
| | - Peng Zhu
- Department of Hepatic Surgery Center
| | | | | | - Chang Shu
- Department of Hepatic Surgery Center
| | - Lin Chen
- Department of Hepatic Surgery Center
| | - Renjie Feng
- Department of Neurology, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430030, China
| | | | - Ganxun Li
- Department of Hepatic Surgery Center
| | | |
Collapse
|
|
28
|
Lou J, Zhang L, Lv S, Zhang C, Jiang S. Biomarkers for Hepatocellular Carcinoma. BIOMARKERS IN CANCER 2017; 9:1-9. [PMID: 28469485 PMCID: PMC5345949 DOI: 10.1177/1179299x16684640] [Citation(s) in RCA: 79] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/20/2016] [Accepted: 11/26/2016] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide. The HCC diagnosis is usually achieved by biomarkers, which can also help in prognosis prediction. Furthermore, it might represent certain therapeutic interventions through some combinations of biomarkers. Here, we review on our current understanding of HCC biomarkers.
Collapse
Affiliation(s)
- Jiatao Lou
- Department of Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - LingFei Zhang
- Center for RNA Research, State Key Laboratory of Molecular Biology, Chinese Academy of Sciences (CAS), Shanghai, China.,Department of Anatomy, Histology & Embryology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Shaogang Lv
- Department of Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Chenzi Zhang
- Department of Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Shuai Jiang
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
| |
Collapse
|
|
29
|
Higher Ratio of Serum Alpha-Fetoprotein Could Predict Outcomes in Patients with Hepatitis B Virus-Associated Hepatocellular Carcinoma and Normal Alanine Aminotransferase. PLoS One 2016; 11:e0157299. [PMID: 27304617 PMCID: PMC4909194 DOI: 10.1371/journal.pone.0157299] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Accepted: 05/26/2016] [Indexed: 12/14/2022] Open
Abstract
Background The role of serum alpha-fetoprotein (AFP) levels in the surveillance and diagnosis of hepatocellular carcinoma (HCC) is controversial. The aim of this study was to investigate the value of serially measured serum AFP levels in HCC progression or recurrence after initial treatment. Methods A total of 722 consecutive patients newly diagnosed with HCC and treated at the National Cancer Center, Korea, between January 2004 and December 2009 were enrolled. The AFP ratios between 4–8 weeks post-treatment and those at the time of HCC progression or recurrence were obtained. Multivariate logistic regression analysis was performed to correlate the post-treatment AFP ratios with the presence of HCC progression or recurrence. Results The etiology of HCC was related to chronic hepatitis B virus (HBV) infection in 562 patients (77.8%), chronic hepatitis C virus (HCV) infection in 74 (10.2%), and non-viral cause in 86 (11.9%). There was a significant decrease in serum AFP levels from the baseline to 4 to 8 weeks after treatment (median AFP, 319.6 ng/mL vs. 49.6 ng/mL; p< 0.001). Multivariate analysis showed that an AFP ratio > 1.0 was an independently associated with HCC progression or recurrence. Among the different causes of HCC analyzed, this association was significant only for HCC related to chronic hepatitis B (p< 0.001) and non-viral causes (p<0.05), and limited only to patients who had normal alanine aminotransferase (ALT) levels. Conclusion Serial measurements of serum AFP ratios could be helpful in detecting progression or recurrence in treated patients with HBV-HCC and normal ALT.
Collapse
|
|
30
|
Omran MM, Emran TM, Farid K, Eltaweel FM, Omar MA, Bazeed FB. An Easy and Useful Noninvasive Score Based on α-1-acid Glycoprotein and C-Reactive Protein for Diagnosis of Patients with Hepatocellular Carcinoma Associated with Hepatitis C Virus Infection. J Immunoassay Immunochem 2016; 37:273-288. [PMID: 26685049 DOI: 10.1080/15321819.2015.1132229] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
This study aimed to evaluate the diagnostic value of α-1-acid glycoprotein (AGP) and C-reactive protein (CRP) and develop a predictive score to improve the diagnosis of hepatocellular carcinoma (HCC). AGP and CRP were measured in serum of 53 HCC patients and 20 liver cirrhosis (LC) patients, in addition to 15 healthy individuals. Area under receiver-operating characteristic curves (AUCs) was used to create a predictive score comprising AGP, CRP, alpha fetoprotein, and albumin. The diagnostic performances of score was determined and compared with AFP alone for the diagnosis of HCC. The combination of AGP, albumin, CRP, and AFP had AUC 0.92 and sensitivity 85% which was higher than AFP alone. The odds ratio of having HCC was 8.4 for AGP, 5.8 for CRP, 12.5 for AFP and 6.5 for albumin. Our score predicted HCC with an OR of 50.6 for HCC. The AUC of score in HCC with single tumor, absent vascular invasion and CLIP score (0-1) were 0.9, 0.9, 0.82, respectively, compared with 0.71, 0.71, 0.68, respectively, for AFP. In conclusion, a non-invasive and simple score based on AGP, CRP, AFP, and albumin could improve the accuracy of HCC diagnosis.
Collapse
Affiliation(s)
| | - Tarek M Emran
- b Clinical Pathology Department , Al-Azhar University , New Damietta , Egypt
| | - Khaled Farid
- c Tropical Medicine Department, Faculty of Medicine , Mansoura University , Mansoura , Egypt
| | | | - Mona A Omar
- d Chemistry Department , Damietta University , Egypt
| | - Fagr B Bazeed
- e Medical Biochemistry Department , Mansoura University , Egypt
| |
Collapse
|
|
31
|
Tsuchiya N, Sawada Y, Endo I, Saito K, Uemura Y, Nakatsura T. Biomarkers for the early diagnosis of hepatocellular carcinoma. World J Gastroenterol 2015; 21:10573-10583. [PMID: 26457017 PMCID: PMC4588079 DOI: 10.3748/wjg.v21.i37.10573] [Citation(s) in RCA: 372] [Impact Index Per Article: 37.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2015] [Revised: 05/21/2015] [Accepted: 08/31/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second leading cause of cancer-related deaths worldwide. Although the prognosis of patients with HCC is generally poor, the 5-year survival rate is > 70% if patients are diagnosed at an early stage. However, early diagnosis of HCC is complicated by the coexistence of inflammation and cirrhosis. Thus, novel biomarkers for the early diagnosis of HCC are required. Currently, the diagnosis of HCC without pathological correlation is achieved by analyzing serum α-fetoprotein levels combined with imaging techniques. Advances in genomics and proteomics platforms and biomarker assay techniques over the last decade have resulted in the identification of numerous novel biomarkers and have improved the diagnosis of HCC. The most promising biomarkers, such as glypican-3, osteopontin, Golgi protein-73 and nucleic acids including microRNAs, are most likely to become clinically validated in the near future. These biomarkers are not only useful for early diagnosis of HCC, but also provide insight into the mechanisms driving oncogenesis. In addition, such molecular insight creates the basis for the development of potentially more effective treatment strategies. In this article, we provide an overview of the biomarkers that are currently used for the early diagnosis of HCC.
Collapse
|
|
32
|
Sadeghi M, Lahdou I, Oweira H, Daniel V, Terness P, Schmidt J, Weiss KH, Longerich T, Schemmer P, Opelz G, Mehrabi A. Serum levels of chemokines CCL4 and CCL5 in cirrhotic patients indicate the presence of hepatocellular carcinoma. Br J Cancer 2015; 113:756-762. [PMID: 26270232 PMCID: PMC4559820 DOI: 10.1038/bjc.2015.227] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Revised: 03/03/2015] [Accepted: 05/13/2015] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Most hepatocellular carcinomas (HCCs) are diagnosed at an advanced stage. The prognostic value of serum tumour markers alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) is limited. The aim of our study is to evaluate the diagnostic value of serum growth factors, apoptotic and inflammatory mediators of cirrhotic patients with and without HCC. METHODS Serum samples were collected from cirrhotic potential liver transplant patients (LTx) with (n=61) and without HCC (n=78) as well as from healthy controls (HCs; n=39). Serum concentrations of CRP, neopterin and IL-6 as markers of inflammation and thrombopoietin (TPO), GCSF, FGF basic and VEGF, HMGB1, CK-18 (M65) and CK18 fragment (M30) and a panel of proinflammatory chemokines (CCL2, CCL3, CCL4, CCL5, CXCL5 and IL-8) were measured. Chi square, Fisher exact, Mann-Whitney U-tests, ROC curve analysis and forward stepwise logistic regression analyses were applied. RESULTS Patients with HCC had higher serum TPO and chemokines (P<0.001 for TPO, CCL4, CCL5 and CXCL5) and lower CCL2 (P=0.008) levels than cirrhotic patients without HCC. Multivariate forward stepwise regression analysis for significant parameters showed that among the studied parameters CCL4 and CCL5 (P=0.001) are diagnostic markers of HCC. Serum levels of TPO and chemokines were lower, whereas M30 was significantly higher in cirrhotic patients than in HCs. CONCLUSIONS High serum levels of inflammatory chemokines such as CCL4 and CCL5 in the serum of cirrhotic patients indicate the presence of HCC.
Collapse
Affiliation(s)
- M Sadeghi
- Department of General, Visceral and Transplant Surgery, University of Heidelberg, Heidelberg, Germany
| | - I Lahdou
- Department of Transplantation Immunology, University of Heidelberg, Heidelberg, Germany
| | - H Oweira
- Department of General, Visceral and Transplant Surgery, University of Heidelberg, Heidelberg, Germany
- Vascular and Visceral Surgery, Zürich Surgical Center, Kappelistr. 7, Zürich CH-8002, Switzerland
| | - V Daniel
- Department of Transplantation Immunology, University of Heidelberg, Heidelberg, Germany
| | - P Terness
- Department of Transplantation Immunology, University of Heidelberg, Heidelberg, Germany
| | - J Schmidt
- Department of General, Visceral and Transplant Surgery, University of Heidelberg, Heidelberg, Germany
- Vascular and Visceral Surgery, Zürich Surgical Center, Kappelistr. 7, Zürich CH-8002, Switzerland
| | - K-H Weiss
- Department of Internal Medicine IV, University of Heidelberg, Heidelberg, Germany
| | - T Longerich
- Department of Pathology, University of Heidelberg, Heidelberg, Germany
| | - P Schemmer
- Department of General, Visceral and Transplant Surgery, University of Heidelberg, Heidelberg, Germany
| | - G Opelz
- Department of Transplantation Immunology, University of Heidelberg, Heidelberg, Germany
| | - A Mehrabi
- Department of General, Visceral and Transplant Surgery, University of Heidelberg, Heidelberg, Germany
| |
Collapse
|
|
33
|
Lee KA, Ahn JY, Lee SH, Singh Sekhon S, Kim DG, Min J, Kim YH. Aptamer-based Sandwich Assay and its Clinical Outlooks for Detecting Lipocalin-2 in Hepatocellular Carcinoma (HCC). Sci Rep 2015; 5:10897. [PMID: 26039737 PMCID: PMC4454046 DOI: 10.1038/srep10897] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2014] [Accepted: 04/20/2015] [Indexed: 01/15/2023] Open
Abstract
We validated a single-stranded, DNA aptamer-based, diagnostic method capable of detecting Lipocalin-2 (LCN2), a biomarker from clinically relevant hepatocellular carcinoma (HCC) patient serum, in the sandwich assay format. Nine aptamers (LCN2_apta1 to LCN2_apta9) for LCN2 were screened with SELEX processes, and a sandwich pair (LCN2_apta2 and LCN2_apta4) was finally chosen using surface plasmon resonance (SPR) and dot blotting analysis. The result of the proposed aptamer sandwich construction shows that LCN2 was sensitively detected in the concentration range of 2.5–500 ng mL−1 with a limit of detection of 0.6 ng mL−1. Quantitative measurement tests in HCC patients were run on straight serum and were compared with the performance of the conventional antibody-based ELISA kit. The aptamer sandwich assay demonstrated an excellent dynamic range for LCN2 at clinically relevant serum levels, covering sub-nanogram per mL concentrations. The new approach offers a simple and robust method for detecting serum biomarkers that have low and moderate abundance. It consists of functionalization, hybridization and signal read-out, and no dilution is required. The results of the study demonstrate the capability of the aptamer sandwich assay platform for diagnosing HCC and its potential applicability to the point-of-care testing (POCT) system.
Collapse
Affiliation(s)
- Kyeong-Ah Lee
- Department of Microbiology, Chungbuk National University, 1 Chungdae-Ro, Seowon-Gu, Cheongju 362-763, South Korea
| | - Ji-Young Ahn
- Department of Microbiology, Chungbuk National University, 1 Chungdae-Ro, Seowon-Gu, Cheongju 362-763, South Korea
| | - Sang-Hee Lee
- Department of Microbiology, Chungbuk National University, 1 Chungdae-Ro, Seowon-Gu, Cheongju 362-763, South Korea
| | - Simranjeet Singh Sekhon
- Department of Microbiology, Chungbuk National University, 1 Chungdae-Ro, Seowon-Gu, Cheongju 362-763, South Korea
| | - Dae-Ghon Kim
- Division of Gastroenterology and Hepatology, Research Institute of Clinical Medicine, Department of Internal Medicine, Chonbuk National University, Medical School and Hospital, Jeonju, 561-756, South Korea
| | - Jiho Min
- Graduate School of Semiconductor and Chemical Engineering, Chonbuk National University, 567 Baekje-daero, Deokjin-Gu, Jeonju, 561-756, South Korea
| | - Yang-Hoon Kim
- Department of Microbiology, Chungbuk National University, 1 Chungdae-Ro, Seowon-Gu, Cheongju 362-763, South Korea
| |
Collapse
|
|
34
|
JIA XIAOBO, GAO YINGTANG, ZHAI DAOKUAN, LIU JIAO, WANG YAJIE, JING LI, DU ZHI. Survivin is not a promising serological maker for the diagnosis of hepatocellular carcinoma. Oncol Lett 2015; 9:2347-2352. [PMID: 26137069 PMCID: PMC4467326 DOI: 10.3892/ol.2015.3050] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2014] [Accepted: 02/23/2015] [Indexed: 12/25/2022] Open
Abstract
Survivin expression in the serum of patients with hepatocellular carcinoma (HCC) and nonmalignant chronic liver diseases remain to be elucidated. The aims of the present study were to evaluate the diagnostic role of survivin in the serum of patients with HCC and identify which ELISA kit performed best in detecting the levels of serum survivin. In total, 80 patients were included in the present study, including 20 patients with HCC, 20 patients with liver cirrhosis, 20 patients with chronic hepatitis B virus infection and 20 healthy volunteers. The levels of survivin protein in the serum were detected using two different ELISA kits (R&D and Abnova). The positive ratios of serum survivin detected by the R&D ELISA kit in all the cases were 8.75% (7/80; median, 0 pg/ml; range, 0-39.8 pg/ml) and in HCC patients were 5% (1/20; median, 0 pg/ml; range, 0-39.8 pg/ml). For the same samples analyzed using the Abnova ELISA kit, the positive ratios of serum survivin in all the cases were 22.5% (18/80; median, 0 pg/ml; range, 0-553.5 pg/ml) and in HCC patients were 25% (5/20; median, 0 pg/ml; range, 0-93.5 pg/ml). The results obtained by the different ELISA kits demonstrated no statistically significant differences in the level of survivin between HCC patients and healthy controls. The correlation coefficient was 0.0064 (P=0.481) when analyzing the same serum samples with the different ELISA kits. In addition, the highest positive ratio of serum survivin was observed using the Abnova kit. A statistically significant difference in the results was observed between the R&D and Abnova kits. In general, the levels and positive ratios of serum survivin in the patients with HCC were significantly low. Furthermore, no difference was observed between HCC patients and controls in regard to the levels of serum survivin detected by the R&D and Abnova ELISA kits. In conclusion, survivin is unlikely to be a promising serological maker for the diagnosis of HCC.
Collapse
Affiliation(s)
- XIAOBO JIA
- Third Central Clinical College, Tianjin Medical University, Tianjin 300170, P.R. China
| | - YINGTANG GAO
- Key Laboratory of Artificial Cell, Institute of Hepatobiliary Disease, Tianjin Third Central Hospital, Tianjin Medical University, Tianjin 300170, P.R. China
| | - DAOKUAN ZHAI
- Key Laboratory of Artificial Cell, Institute of Hepatobiliary Disease, Tianjin Third Central Hospital, Tianjin Medical University, Tianjin 300170, P.R. China
| | - JIAO LIU
- Key Laboratory of Artificial Cell, Institute of Hepatobiliary Disease, Tianjin Third Central Hospital, Tianjin Medical University, Tianjin 300170, P.R. China
| | - YAJIE WANG
- Key Laboratory of Artificial Cell, Institute of Hepatobiliary Disease, Tianjin Third Central Hospital, Tianjin Medical University, Tianjin 300170, P.R. China
| | - LI JING
- Key Laboratory of Artificial Cell, Institute of Hepatobiliary Disease, Tianjin Third Central Hospital, Tianjin Medical University, Tianjin 300170, P.R. China
| | - ZHI DU
- Key Laboratory of Artificial Cell, Institute of Hepatobiliary Disease, Tianjin Third Central Hospital, Tianjin Medical University, Tianjin 300170, P.R. China
- Department of Hepatobiliary Surgery, Tianjin Third Central Hospital, Tianjin Medical University, Tianjin 300170, P.R. China
| |
Collapse
|
|
35
|
Liu J, Gao Y, Yang B, Jia X, Zhai D, Li S, Zhang Q, Jing L, Wang Y, Du Z, Wang Y. Overexpression of squamous cell carcinoma antigen 1 is associated with the onset and progression of human hepatocellular carcinoma. Arch Med Res 2015; 46:133-141. [PMID: 25819271 DOI: 10.1016/j.arcmed.2015.03.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2014] [Accepted: 03/12/2015] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND AIMS Previous studies indicated Squamous Cell Carcinoma Antigen 1 (SCCA1) may be involved in tumorigenesis and progress of various human malignancies by inhibiting cell apoptosis and promoting cell proliferative activity. The aim of the study was to further investigate SCCA1 expression in different extent of liver diseases and evaluate the clinical significance and prognostic value in HCC. METHODS Eighty nine patient-matched tumors and peritumoral surgical specimens and 56 liver biopsies specimens from 23 patients with chronic hepatitis B (CHB), 19 with dysplastic nodule (DN), and 14 with HCC were enrolled. An additional four normal liver (NL) samples were used as controls. SCCA1 expression in liver tissue was measured by immunochemistry. Another 28 HCC specimens and paired non-tumor tissues were used for SCCA1 detection by Western blot. The prognostic value of SCCA1 expression in HCC was evaluated by the Cox proportional hazards regression model analysis. RESULTS Western blot analysis showed SCCA1 positive rate in HCC was higher than the matched adjacent noncancerous tissues (p <0.001). Immunohistochemistry revealed that SCCA1-positive rate increased gradually from NL, CHB, PNT to DN and HCC (p <0.05). Clinicopathological analysis showed that SCCA1 expression was positively associated with tumor differentiation (p = 0.043) and patients' Child-Pugh score (p = 0.021). The SCCA1-poistive group showed better overall survival than the negative group (p = 0.029). Importantly, SCCA1 expression was an independent prognostic factor for the overall survival of HCC patients (hazard ratio = 3.757, p <0.001). CONCLUSION SCCA1 expression pattern may relate to the progression of chronic liver diseases. Furthermore, our study supports a potential association of negative SCCA1 expression with poor outcome in HCC.
Collapse
Affiliation(s)
- Jiao Liu
- Third Central Clinical College of Tianjin Medical University, Tianjin, China
| | - Yingtang Gao
- Key Laboratory of Artificial Cell, Institute for Hepatobiliary Disease, Third Central Hospital of Tianjin, Tianjin, China
| | - Bin Yang
- Key Laboratory of Artificial Cell, Institute for Hepatobiliary Disease, Third Central Hospital of Tianjin, Tianjin, China
| | - Xiaobo Jia
- Third Central Clinical College of Tianjin Medical University, Tianjin, China
| | - Daokuan Zhai
- Department of Science and Education, Third Central Hospital of Tianjin, Tianjin, China
| | - Shilei Li
- Deparment of Hepatobiliary, Shengli Oilfield Central Hospital, Dongying, Shangdong, China
| | - Qin Zhang
- Department of Pathology, Third Central Hospital of Tianjin, Tianjin, China
| | - Li Jing
- Key Laboratory of Artificial Cell, Institute for Hepatobiliary Disease, Third Central Hospital of Tianjin, Tianjin, China
| | - Yajie Wang
- Third Central Clinical College of Tianjin Medical University, Tianjin, China
| | - Zhi Du
- Key Laboratory of Artificial Cell, Institute for Hepatobiliary Disease, Third Central Hospital of Tianjin, Tianjin, China; Department of Hepatobiliary Surgery, Third Central Hospital of Tianjin, Tianjin, China
| | - Yijun Wang
- Department of Hepatobiliary Surgery, Third Central Hospital of Tianjin, Tianjin, China.
| |
Collapse
|
|
36
|
Chimparlee N, Chuaypen N, Khlaiphuengsin A, Pinjaroen N, Payungporn S, Poovorawan Y, Tangkijvanich P. Diagnostic and Prognostic Roles of Serum Osteopontin and Osteopontin Promoter Polymorphisms in Hepatitis B-related Hepatocellular Carcinoma. Asian Pac J Cancer Prev 2015; 16:7211-7217. [PMID: 26514514 DOI: 10.7314/apjcp.2015.16.16.7211] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/21/2025] Open
Abstract
BACKGROUND The aims of this study were to evaluate the diagnostic and prognostic roles of serum osteopontin (OPN) and single nucleotide polymorphisms (SNPs) in the OPN promoter in patients with hepatitis B-related hepatocellular carcinoma (HCC). MATERIALS AND METHODS Four groups were studied, which included 157 patients with HCC, 73 with liver cirrhosis (LC) and 97 with chronic hepatitis (CH), along with 80 healthy subjects. Serum OPN and alpha-fetoprotein (AFP) levels were measured. The SNPs -66 T/G, -156 G/δG and -433 C/T within the OPN promoter were determined by direct sequencing. RESULTS Serum OPN levels were significantly higher in patients with HCC than in the other groups. Area under receiver operating characteristics curves in distinguishing HCC from chronic liver disease (CLD; CH and LC) were 0.782 (95% CI; 0.729-0.834) for OPN and 0.888 (95% CI; 0.850-0.927) for AFP. Using the optimal cut-off value (70 ng/mL), OPN had sensitivity and specificity of 72% and 71%, respectively. Serum OPN was superior to AFP in detecting early-stage HCC (68% vs. 46%). A combination of both markers yielded an improved sensitivity for detecting early HCC to 82%. A high OPN level was significantly correlated with advanced BCLC stage and was an independent prognostic factor for HCC. The SNPs -156 and -443 were associated with susceptibility to HCC, but were not related to overall survival. CONCLUSIONS Serum OPN is a useful diagnostic and prognostic marker for HCC. The combined use of serum OPN and AFP improved the diagnosis of early HCC. Genetic variation in the OPN promoter is associated with the risk, but not the prognosis of HCC.
Collapse
Affiliation(s)
- Nitinan Chimparlee
- Research Unit of Hepatitis and Liver Cancer, Department of Biochemistry, Chulalongkorn University, Bangkok, Thailand E-mail :
| | | | | | | | | | | | | |
Collapse
|
|
37
|
Consenso mexicano de diagnóstico y manejo del carcinoma hepatocelular. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2014; 79:250-62. [DOI: 10.1016/j.rgmx.2014.09.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/08/2013] [Revised: 07/07/2014] [Accepted: 09/08/2014] [Indexed: 02/08/2023]
|
|
38
|
Jia X, Liu J, Gao Y, Huang Y, Du Z. Diagnosis accuracy of serum glypican-3 in patients with hepatocellular carcinoma: a systematic review with meta-analysis. Arch Med Res 2014; 45:580-588. [PMID: 25446613 DOI: 10.1016/j.arcmed.2014.11.002] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2014] [Accepted: 08/31/2014] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS The diagnostic value of serum GPC3 in patients with hepatocellular carcinoma (HCC) remains controversial. Thus, we performed a systematic review and meta-analysis to assess the diagnostic accuracy of serum GPC3 for HCC. METHODS A systematic search was performed for the related studies. Sensitivity, specificity and other measures regarding the accuracy of serum GPC3 and alpha-fetoprotein (AFP) in the diagnosis of HCC were pooled using random-effects models. Summary receiver operating characteristic curve (sROC) analysis was used to summarize the overall test performance. RESULTS Nineteen studies were included in this meta-analysis. Pooled sensitivity, specificity and 95% confidence interval (CI) of serum GPC3 for the diagnosis of HCC were 55.2% (52.9-57.4%) and 84.2% (82.2-86.0%), respectively. When combining GPC3 with AFP, pooled sensitivity, specificity, and 95% CI were 75.7% (71.8-79.4%) and 83.3% (79.6-86.6%), respectively. The area under sROC (AUC) and 95% CI for AFP combined with GPC3 were 0.762 (0.649-0.875). For diagnosis of early HCC, pooled sensitivity and specificity of serum GPC3 were 55.1% (47.9-66.2%) and 97.0% (95.2-98.2%), respectively. The AUC of GPC3 for early HCC was 0.793 (0.668-0.917). CONCLUSIONS This meta-analysis indicates that serum GPC3 has a comparable accuracy to AFP for the diagnosis of HCC, and there is an elevation in the sensitivity of diagnosis when GPC3 was combined with AFP. Diagnostic accuracy of serum GPC3 for early HCC is still unsatisfactory.
Collapse
Affiliation(s)
- Xiaobo Jia
- Third Central Clinical College of Tianjin Medical University, Tianjin, China
| | - Jiao Liu
- Third Central Clinical College of Tianjin Medical University, Tianjin, China
| | - Yingtang Gao
- Key Laboratory of Artificial Cell, Institute of Hepatobiliary Disease, Tianjin Third Central Hospital Jintang Road, Hedong District, Tianjin, China
| | - Yong Huang
- Third Central Clinical College of Tianjin Medical University, Tianjin, China
| | - Zhi Du
- Department of Hepatobiliary Surgery, Tianjin Third Central Hospital, Tianjin, China.
| |
Collapse
|
|
39
|
Mexican consensus on the diagnosis and management of hepatocellular carcinoma. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO (ENGLISH EDITION) 2014. [DOI: 10.1016/j.rgmxen.2014.12.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
|
|
40
|
Meng FL, Wang W, Jia WD. Diagnostic and prognostic significance of serum miR-24-3p in HBV-related hepatocellular carcinoma. Med Oncol 2014; 31:177. [PMID: 25129312 DOI: 10.1007/s12032-014-0177-3] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2014] [Accepted: 08/09/2014] [Indexed: 12/14/2022]
Abstract
The aim of this study was to explore the diagnostic and prognostic value of serum microRNAs (miRNAs) in hepatitis B viral (HBV)-related hepatocellular carcinoma (HCC). We retrospectively analyzed clinical data of 84 consecutive patients with HBV-related HCC who underwent curative resection. Additionally, we enrolled 46 healthy controls and 31 patients with chronic liver disease (CLD). Serum levels of miR-155-5p, miR-24-3p, miR-490-3p, miR-210-3p, and miR-335-5p were measured. Associations of serum miRNAs with clinicopathological factors were evaluated. Receiver operating characteristic curves were established for discriminating HCC patients from CLD patients, and the area under the curve (AUC) was calculated. Overall survival (OS) and disease-free survival (DFS) were examined by the Kaplan-Meier method. Prognostic factors were determined by multivariate Cox analysis. Consequently, serum miR-24-3p levels were significantly greater in HCC patients than healthy controls and CLD patients. Serum miR-24-3p was significantly associated with vascular invasion in HCC patients. Serum miR-24-3p discriminated HCC patients from CLD, with an AUC of 0.636 [95 % confidence interval (CI) 0.524-0.748]. Combined serum alpha-fetoprotein (AFP) and miR-24-3p had an increased AUC of 0.834 (95 % CI 0.745-0.923; P < 0.001). Elevated serum miR-24-3p was an independent poor prognostic factor for OS and DFS of HCC patients. In conclusion, the combination of serum miR-24-3p and AFP improves the diagnostic accuracy for HCC prediction compared to each biomarker alone. High serum miR-24-3p level is an independent predictor of poor OS and DFS in patients with HBV-related HCC.
Collapse
Affiliation(s)
- Fan-Long Meng
- Department of Hepatic Surgery, Anhui Provincial Hospital, Anhui Medical University, Hefei, 230001, People's Republic of China
| | | | | |
Collapse
|
|
41
|
Squires RH, Ng V, Romero R, Ekong U, Hardikar W, Emre S, Mazariegos GV. Evaluation of the pediatric patient for liver transplantation: 2014 practice guideline by the American Association for the Study of Liver Diseases, American Society of Transplantation and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. Hepatology 2014; 60:362-98. [PMID: 24782219 DOI: 10.1002/hep.27191] [Citation(s) in RCA: 142] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2014] [Accepted: 04/22/2014] [Indexed: 12/16/2022]
Affiliation(s)
- Robert H Squires
- Department of Pediatrics, University of Pittsburgh School of Medicine; Division of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA
| | | | | | | | | | | | | |
Collapse
|
|
42
|
Shen P, Si J, Li QW, Qu LL, Li LR, Yan XL, Ji GZ. Human des-γ-carboxy prothrombin: Cloning, expression and monoclonal antibody preparation. Shijie Huaren Xiaohua Zazhi 2013; 21:3932-3939. [DOI: 10.11569/wcjd.v21.i35.3932] [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
AIM: To clone and express human des-γ-carboxy prothrombin (DCP), a valuable serum marker for hepatocellular carcinoma (HCC), and to prepare the monoclonal antibody (mAb) against DCP.
METHODS: The DCP gene was cloned into the prokaryotic expression vector pCold II. The recombinant construct was expressed in BL21 Escherichia coli strain, and the recombinant protein with an N-terminal 6-His tag was purified by nickel chelate-nitrilotriacetic-acid (Ni-NTA) affinity chromatography. The purified protein was used to immunize the Balb/c mice for mAb preparation. The sensitivity and specificity of the mAb were assessed by indirect enzyme-linked immunosorbent assay (ELISA), Western blot and immunohistochemistry.
RESULTS: The recombinant DCP protein was successfully expressed and purified, and its molecular weight was approximately 23 kDa. One hybridoma cell line stably secreting anti-DCP monoclonal antibody named 3B5 was obtained. Western blot analysis and immunohistochemistry indicated that the DCP mAb showed specific combination with DCP. ELISA detection indicated that the titer of the mAb was 1:2.43 × 105. The immunoglobulin isotype of the mAb was identified as IgG2a.
CONCLUSION: The successful preparation of DCP mAb may lay a solid foundation for the research of the use of DCP in early diagnosis of HCC.
Collapse
|
|
43
|
Salem M, Atti SA, Raziky ME, Darweesh SK, Sharkawy ME. Clinical Significance of Plasma Osteopontin Level as a Biomarker of Hepatocellular Carcinoma. Gastroenterology Res 2013; 6:191-199. [PMID: 27785253 PMCID: PMC5051095 DOI: 10.4021/gr499w] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/13/2012] [Indexed: 12/28/2022] Open
Abstract
Background Biomarkers of hepatocellular carcinoma (HCC) are helpful in screening, diagnosis and follow up of cases. Osteopontin (OPN) is a glycoprotein secreted by osteoblasts, osteoclasts, macrophages and T cells, and is over-expressed in a variety of tumors, including carcinomas of liver, stomach, breast, lung, colon, and prostate. So, the aim of this study was to verify the possibility of using the plasma Osteopontin level as a biomarker for diagnosis of HCC. Methods The study included 70 subjects divided into three groups: group I had 30 patients with HCC (proved by histopathology or combined spiral CT and elevated alpha-fetoprotein) on top of HCV, group II had 30 patients with HCV infection and group III had 10 healthy subjects serving as control. Osteopontin level was measured in plasma of the studied subjects by ELISA, serum alpha fetoprotein (AFP) level was also measured by EIA. Results Osteopontin levels were significantly elevated in patients with HCC and in HCV patients in comparison to control group (P: 0.005). There was significant correlation between OPN and AFP levels (P: 0.00). The sensitivity and specificity of OPN for selective detection of HCC group over the non-HCC group (HCV group and healthy control group) were73% and 54%, respectively, at a cut-off value of 128.5 ng/mL. Plasma OPN levels directly correlated with the tumor number but not with the size of the tumor (P: 0.00). Conclusion Plasma OPN level appears to be an additional biomarker for HCC detection.
Collapse
Affiliation(s)
- Mona Salem
- Clinical Pathology Dept., Faculty Of Medicine, Cairo University, Cairo, Egypt
| | - Sahar Abdel Atti
- Clinical Pathology Dept., Faculty Of Medicine, Cairo University, Cairo, Egypt
| | - Maisa El Raziky
- Tropical Medicine and Hepatology Dept., Faculty Of Medicine, Cairo University, Cairo, Egypt
| | - Samar Kamal Darweesh
- Tropical Medicine and Hepatology Dept., Faculty Of Medicine, Cairo University, Cairo, Egypt
| | - Marwa El Sharkawy
- Clinical Pathology Dept., Faculty Of Medicine, Cairo University, Cairo, Egypt
| |
Collapse
|
|
44
|
Lv Y, Wang W, Jia WD, Sun QK, Huang M, Zhou HC, Xia HH, Liu WB, Chen H, Sun SN, Xu GL. High preoparative levels of serum periostin are associated with poor prognosis in patients with hepatocellular carcinoma after hepatectomy. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2013; 39:1129-35. [PMID: 23916473 DOI: 10.1016/j.ejso.2013.06.023] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2012] [Revised: 05/07/2013] [Accepted: 06/17/2013] [Indexed: 01/06/2023]
Abstract
AIMS Periostin (POSTN) is implicated in cancer development and progression. The aim of this study was to evaluate the diagnostic and prognostic significance of serum POSTN in patients with hepatocellular carcinoma (HCC) receiving curative surgery. METHODS Enzyme-linked immunosorbent assay was performed to determine serum POSTN levels in 69 healthy volunteers, 30 patients with hepatolithiasis, 27 patients with cirrhosis, and 56 HCC patients. The relationships between serum POSTN and clinicopathologic features were analyzed. Receiver operating characteristics analysis was used to calculate diagnostic accuracy of serum POSTN, serum alpha-fetoprotein (AFP), and their combination. The prognostic impact of serum POSTN on overall survival (OS) and relapse-free survival (RFS) was also investigated. RESULTS The median serum POSTN level was significantly (P < 0.05) increased in HCC patients, compared to healthy controls, patients with hepatolithiasis, and patients with liver cirrhosis. Elevated serum POSTN was only significantly associated with Edmondson grade (P = 0.007). The combination of serum POSTN and AFP had a markedly higher area under the curve (0.805 (95% confidence interval [CI]: 0.677-0.932)) than POSTN (0.582 (95% CI: 0.427-0.736)) or AFP (0.655 (95% CI: 0.504-0.806)) alone. Kaplan-Meier analysis indicated that elevated serum POSTN was associated with OS (P = 0.031) and RFS (P = 0.027). Moreover, multivariate analysis revealed elevated serum POSTN as an independent poor prognostic marker for OS and RFS. CONCLUSIONS Preoperative serum POSTN has limited diagnostic value in distinguishing HCC from non-malignant liver diseases, but serves as independent prognostic biomarker in HCC patients.
Collapse
Affiliation(s)
- Y Lv
- Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Anhui Provincial Hospital, Hefei 230001, PR China; Department of Plastic Surgery, The Second Hospital of Anhui Medical University, Hefei 230601, PR China
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
45
|
Abstract
Alpha-fetoprotein (AFP) is a major mammalian embryo-specific and tumor-associated protein that is also present in small quantities in adults at normal conditions. Discovery of the phenomenon of AFP biosynthesis in carcinogenesis by G. Abelev and Yu. Tatarinov 50 years ago, in 1963, provoked intensive studies of this protein. AFPs of some mammalian species were isolated, purified and physico-chemically and immunochemically characterized. Despite the significant success in study of AFP, its three-dimensional structure, mechanisms of receptor binding along with a structure of the receptor itself and, what is the most important, its biological role in embryo- and carcinogenesis remain still obscure. Due to difficulties linked with methodological limitations, research of AFP was to some extent extinguished by the 1990 s. However, over the last decade a growing number of investigations of AFP and its usage as a tumor-specific biomarker have been observed. This was caused by the use of new technologies, primarily, computer-based and genetic engineering approaches in studying of this very important oncodevelopmental protein. Our review summarizes efforts of different scientific groups throughout the world in studying AFP for 50 years with emphasis on detailed description of recent achievements in this field.
Collapse
|
|
46
|
Tung EKK, Ng IOL. Significance of serum DKK1 as a diagnostic biomarker in hepatocellular carcinoma. Future Oncol 2013; 8:1525-8. [PMID: 23231514 DOI: 10.2217/fon.12.147] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Hyperactivation of the Wnt/β-catenin signaling pathway has been implicated in cancers, including hepatocellular carcinoma (HCC). Dickkopf-1 (DKK1) is a secretory antagonist of the Wnt/β-catenin signaling pathway and has been found to be upregulated in many cancer types. The functional role of DKK1 in cancer progression has been revealed in several studies but there is controversy with regard to its antitumor function; its oncogenic role seems to be context-dependent. Nevertheless, DKK1 has been proposed to be a potential new biomarker in several types of cancers. The paper by Shen et al. revealed the diagnostic accuracy of DKK1 as a serum biomarker for HCC in a large-scale, multicenter study. Their study demonstrated that serum DKK1 was high in both sensitivity and specificity in diagnosing HCC, especially early-stage HCC and α-fetoprotein-negative HCCs. The authors also demonstrated that combination of serum α-fetoprotein with serum DKK1 could further improve the diagnostic accuracy. Overall, their findings revealed the importance and significance of DKK1 in HCC diagnosis.
Collapse
Affiliation(s)
- Edmund Kwok-Kwan Tung
- Department of Pathology & State Key Laboratory for Liver Research, The University of Hong Kong, Pokfulam, Hong Kong
| | | |
Collapse
|
|
47
|
Lo RCL, Ng IOL. Hepatocellular tumors: immunohistochemical analyses for classification and prognostication. Chin J Cancer Res 2013; 23:245-53. [PMID: 23359751 DOI: 10.1007/s11670-011-0245-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2011] [Accepted: 09/22/2009] [Indexed: 12/11/2022] Open
Abstract
Following the classification of hepatocellular nodules by the International Working Party in 1995 and further elaboration by the International Consensus Group for Hepatocellular Neoplasia in 2009, entities under the spectrum of hepatocellular nodules have been better characterized. Research work hence has been done to answer questions such as distinguishing high-grade dysplastic nodules from early hepatocellular carcinoma (HCC), delineating the tumor cell origin of HCC, identifying its prognostic markers, and subtyping hepatocellular adenomas. As a result, a copious amount of data at immunohistochemical and molecular levels has emerged. A panel of immunohistochemical markers including glypican-3, heat shock protein 70 and glutamine synthetase has been found to be of use in the diagnosis of small, well differentiated hepatocellular tumors and particularly of HCC. The use of liver fatty acid binding protein (L-FABP), β-catenin, glutamine synthetase, serum amyloid protein and C-reactive protein is found to be helpful in the subtyping of hepatocellular adenomas. The role of tissue biomarkers for prognostication in HCC and the use of biomarkers in subclassifying HCC based on tumor cell origin are also discussed.
Collapse
Affiliation(s)
- Regina Cheuk-Lam Lo
- Department of Pathology and State Key Laboratory for Liver Research, the University of Hong Kong, Hong Kong, China
| | | |
Collapse
|
|
48
|
Liao R, Sun J, Wu H, Yi Y, Wang JX, He HW, Cai XY, Zhou J, Cheng YF, Fan J, Qiu SJ. High expression of IL-17 and IL-17RE associate with poor prognosis of hepatocellular carcinoma. J Exp Clin Cancer Res 2013; 32:3. [PMID: 23305119 PMCID: PMC3621615 DOI: 10.1186/1756-9966-32-3] [Citation(s) in RCA: 119] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2012] [Accepted: 01/07/2013] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a typical malignancy in a background of chronic inflammation. Th17 cells (a major source of IL-17) constitute crucial components of infiltrating inflammatory/immune cells in HCC and can amplify inflammatory response via binding to interleukin-17 receptor (IL-17R). Thus, we investigated the expression and clinical significance of IL-17 and IL-17 receptor family cytokines in HCC. METHODS The expression and prognostic value of IL-17 and IL-17R (A-E) were examined in 300 HCC patients after resection. Six Th17 associated cytokines in serum (n = 111) were quantified using enzyme-linked immunosorbent assays. Phenotypic features of IL-17+ CD4+ T cells were determined by flow cytometry analysis. RESULTS High expression of intratumoral IL-17 and IL1-7RE were significantly associated with poorer survival (p = 0.016 and <0.001, respectively) and increased recurrence (both P < 0.001) of HCC patients. Moreover, intratumoral IL-17, individually or synergistically with IL-17RE, could predict HCC early recurrence and late recurrence. Also, peritumoral IL-17RE showed the prognostic ability in HCC (P < 0.001 for OS/TTR). Furthermore, expression levels of Th17 associated cytokines including IL-6, -22, -17R and TNF-α were increased in serum of HCC patients compared to haemangioma patients. Importantly, activated human hepatic stellate cells induced in vitro expansion of IL-17+ CD4+ T cells. CONCLUSIONS High expression of IL-17 and IL-17RE were promising predictors for poor outcome of HCC patients. The protumor power of IL-17 producing CD4+ T cells was probably involved in the crosstalk with different types of inflammatory/immune cells in HCC.
Collapse
Affiliation(s)
- Rui Liao
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Rd, Shanghai 200032, China
- Key Laboratory of Carcinogenesis and Cancer Invasion, the Chinese Ministry of Education, Shanghai, China
| | - Jian Sun
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Rd, Shanghai 200032, China
- Key Laboratory of Carcinogenesis and Cancer Invasion, the Chinese Ministry of Education, Shanghai, China
| | - Han Wu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Rd, Shanghai 200032, China
- Key Laboratory of Carcinogenesis and Cancer Invasion, the Chinese Ministry of Education, Shanghai, China
| | - Yong Yi
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Rd, Shanghai 200032, China
- Key Laboratory of Carcinogenesis and Cancer Invasion, the Chinese Ministry of Education, Shanghai, China
| | - Jia-Xing Wang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Rd, Shanghai 200032, China
- Key Laboratory of Carcinogenesis and Cancer Invasion, the Chinese Ministry of Education, Shanghai, China
| | - Hong-Wei He
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Rd, Shanghai 200032, China
- Key Laboratory of Carcinogenesis and Cancer Invasion, the Chinese Ministry of Education, Shanghai, China
| | - Xiao-Yan Cai
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Rd, Shanghai 200032, China
- Key Laboratory of Carcinogenesis and Cancer Invasion, the Chinese Ministry of Education, Shanghai, China
| | - Jian Zhou
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Rd, Shanghai 200032, China
- Key Laboratory of Carcinogenesis and Cancer Invasion, the Chinese Ministry of Education, Shanghai, China
| | - Yun-Feng Cheng
- Biomedical Research Center, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jia Fan
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Rd, Shanghai 200032, China
- Key Laboratory of Carcinogenesis and Cancer Invasion, the Chinese Ministry of Education, Shanghai, China
| | - Shuang-Jian Qiu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Rd, Shanghai 200032, China
- Key Laboratory of Carcinogenesis and Cancer Invasion, the Chinese Ministry of Education, Shanghai, China
- Biomedical Research Center, Zhongshan Hospital, Fudan University, Shanghai, China
| |
Collapse
|
|
49
|
Bertino G, Ardiri A, Malaguarnera M, Malaguarnera G, Bertino N, Calvagno GS. Hepatocellualar carcinoma serum markers. Semin Oncol 2012; 39:410-33. [PMID: 22846859 DOI: 10.1053/j.seminoncol.2012.05.001] [Citation(s) in RCA: 121] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in some areas of the world. In most cases, HCC is diagnosed at a late stage. Therefore, the prognosis of patients with HCC is generally poor. The recommended screening strategy for patients with cirrhosis includes the determination of serum α-fetoprotein (AFP) levels and an abdominal ultrasound every 6 months to detect HCC at an earlier stage. AFP, however, is a marker characterized by poor sensitivity and specificity, and abdominal ultrasound is highly dependent on the operator's experience. In addition to AFP, Lens culinaris agglutinin-reactive AFP (AFP-L3), des-γ-carboxy prothrombin (DCP), glypican-3 (GPC-3), osteopontin (OPN), and several other biomarkers (such as squamous cell carcinoma antigen-immunoglobulin M complexes [SCCA-IgM], alpha-1-fucosidase [AFU], chromogranin A [CgA], human hepatocyte growth factor, insulin-like growth factor) have been proposed as markers for the early detection of HCC. For these markers, we describe the mechanisms of production, and their diagnostic and prognosis roles. None of them is optimal; however, when used together, their sensitivity in detecting HCC is increased. Recent research has shown that some biomarkers have mitogenic and migratory activities in the angiogenesis of HCC and are a factor of tumor growth.
Collapse
Affiliation(s)
- Gaetano Bertino
- Hepatology Unit, Department of Medical and Pediatric Sciences, Policlinic of Catania, University of Catania, Catania, Italy.
| | | | | | | | | | | |
Collapse
|
|
50
|
Comparative analysis of SV40 17kT and LT function in vivo demonstrates that LT's C-terminus re-programs hepatic gene expression and is necessary for tumorigenesis in the liver. Oncogenesis 2012; 1:e28. [PMID: 23552841 PMCID: PMC3503294 DOI: 10.1038/oncsis.2012.27] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Transformation by Simian Virus 40 (SV40) large T antigen (LT) is mediated in large part by its interaction with a variety of cellular proteins at distinct binding domains within LT. While the interaction of LT's N-terminus with the tumor suppressor Rb is absolutely required for LT-dependent transformation, the requirement for the interaction of LT's C-terminus with p53 is less clear and cell- and context-dependent. Here, we report a line of transgenic mice expressing a doxycycline-inducible liver-specific viral transcript that produces abundant 17kT, a naturally occurring SV40 early product that is co-linear with LT for the first 131 amino acids and that binds to Rb, but not p53. Comparative analysis of livers of transgenic mice expressing either 17kT or full length LT demonstrates that 17kT stimulates cell proliferation and induces hepatic hyperplasia but is incapable of inducing hepatic dysplasia or promoting hepatocarcinogenesis. Gene expression profiling demonstrates that 17kT and LT invoke a set of shared molecular signatures consistent with the action of LT's N-terminus on Rb-E2F-mediated control of hepatocyte transcription. However, 17kT also induces a unique set of genes, many of which are known transcriptional targets of p53, while LT actively suppresses them. LT also uniquely deregulates the expression of a subset of genes within the imprinted network and rapidly re-programs hepatocyte gene expression to a more fetal-like state. Finally, we provide evidence that the LT/p53 complex provides a gain-of-function for LT-dependent transformation in the liver, and confirm the absolute requirement for LT's C-terminus for liver tumor development by demonstrating that phosphatase and tensin homolog (PTEN)-deficiency readily cooperates with LT, but not 17kT, for tumorigenesis. These results confirm independent and inter-dependent functions for LT's N- and C-terminus and emphasize differences in the requirements for LT's C-terminus in cell-type dependent transformation.
Collapse
|