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Liu A, Zhang J, Li T, Zheng D, Ling Y, Lu L, Zhang Y, Cai J. Explainable attention-enhanced heuristic paradigm for multi-view prognostic risk score development in hepatocellular carcinoma. Hepatol Int 2025:10.1007/s12072-025-10793-8. [PMID: 40089963 DOI: 10.1007/s12072-025-10793-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Accepted: 02/07/2025] [Indexed: 03/18/2025]
Abstract
PURPOSE Existing prognostic staging systems depend on expensive manual extraction by pathologists, potentially overlooking latent patterns critical for prognosis, or use black-box deep learning models, limiting clinical acceptance. This study introduces a novel deep learning-assisted paradigm that complements existing approaches by generating interpretable, multi-view risk scores to stratify prognostic risk in hepatocellular carcinoma (HCC) patients. METHODS 510 HCC patients were enrolled in an internal dataset (SYSUCC) as training and validation cohorts to develop the Hybrid Deep Score (HDS). The Attention Activator (ATAT) was designed to heuristically identify tissues with high prognostic risk, and a multi-view risk-scoring system based on ATAT established HDS from microscopic to macroscopic levels. HDS was also validated on an external testing cohort (TCGA-LIHC) with 341 HCC patients. We assessed prognostic significance using Cox regression and the concordance index (c-index). RESULTS The ATAT first heuristically identified regions where necrosis, lymphocytes, and tumor tissues converge, particularly focusing on their junctions in high-risk patients. From this, this study developed three independent risk factors: microscopic morphological, co-localization, and deep global indicators, which were concatenated and then input into a neural network to generate the final HDS for each patient. The HDS demonstrated competitive results with hazard ratios (HR) (HR 3.24, 95% confidence interval (CI) 1.91-5.43 in SYSUCC; HR 2.34, 95% CI 1.58-3.47 in TCGA-LIHC) and c-index values (0.751 in SYSUCC; 0.729 in TCGA-LIHC) for Disease-Free Survival (DFS). Furthermore, integrating HDS into existing clinical staging systems allows for more refined stratification, which enables the identification of potential high-risk patients within low-risk groups. CONCLUSION This novel paradigm, from identifying high-risk tissues to constructing prognostic risk scores, offers fresh insights into HCC research. Additionally, the integration of HDS complements the existing clinical staging system by facilitating more detailed stratification in DFS and Overall Survival (OS).
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Affiliation(s)
- Anran Liu
- Department of Health Technology and Informatics, Hong Kong Polytechnic University, 11 Yuk Choi Road, Hong Kong SAR, China
| | - Jiang Zhang
- Department of Health Technology and Informatics, Hong Kong Polytechnic University, 11 Yuk Choi Road, Hong Kong SAR, China
| | - Tong Li
- Division of Computational & Data Sciences, Washington University in St. Louis, One Brookings Drive, St. Louis, MO, 63130, USA
| | - Danyang Zheng
- Department of Anesthesiology, First Affiliated Hospital of Sun Yat-sen University, No. 58 Zhongshan Road 2, Guangzhou, 510060, Guangdong, China
| | - Yihong Ling
- Department of Pathology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, 651 Dongfeng East Road, Guangzhou, 510060, Guangdong, China
| | - Lianghe Lu
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, 651 Dongfeng East Road, Guangzhou, 510060, Guangdong, China
| | - Yuanpeng Zhang
- Department of Health Technology and Informatics, Hong Kong Polytechnic University, 11 Yuk Choi Road, Hong Kong SAR, China
| | - Jing Cai
- Department of Health Technology and Informatics, Hong Kong Polytechnic University, 11 Yuk Choi Road, Hong Kong SAR, China.
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Liang L, Pang JS, Gao RZ, Que Q, Wu YQ, Peng JB, Bai XM, Qin Q, Tang QQ, Li LP, He Y, Yang H. Development and validation of a combined radiomic and clinical model based on contrast-enhanced ultrasound for preoperative prediction of CK19-positive hepatocellular carcinoma. Abdom Radiol (NY) 2025:10.1007/s00261-025-04799-x. [PMID: 39907719 DOI: 10.1007/s00261-025-04799-x] [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: 11/23/2024] [Revised: 12/31/2024] [Accepted: 01/03/2025] [Indexed: 02/06/2025]
Abstract
PURPOSE We aimed to develop and validate a combined model integrating radiomic features derived from Contrast-Enhanced Ultrasound (CEUS) images and clinical parameters for preoperative prediction of CK19-positive status in hepatocellular carcinoma (HCC). METHODS A total of 434 patients who underwent CEUS and surgical resection from January 2020 to December 2023 were included. Patients were randomly divided into a training cohort (n = 304) and a validation cohort (n = 130). Radiomic features were extracted from multiphase CEUS images, including two-dimensional ultrasound (US), arterial, portal venous, and delayed phases, and combined to derive a Radscore model. Subsequently, a Combined Model was constructed using the Radscore and clinical parameters. Model performance was assessed using calibration, discrimination, and clinical utility. RESULTS Multivariate logistic regression analysis identified Radscore (OR = 10.054, 95% CI: 5.931-19.120, p < 0.001) and AFP levels > 200 ng/mL (OR = 5.027, 95% CI: 2.089-12.784, p < 0.001) as significant predictors in the combined model. The AUC (Area Under the Curve) for the Combined Model was 0.954 in the training cohort and 0.927 in the validation cohort, compared to 0.939 and 0.917 for the Radscore Model alone. Calibration curves demonstrated strong concordance between predicted and actual outcomes. Decision curve analysis (DCA) showed that both the Radscore Model and the Combined Model exhibited good net benefits across a wide range of threshold values in both the training and validation cohorts. CONCLUSION The Radscore based on CEUS, combined with the serum markers AFP > 200 ng/L to construct a Combined Model, shows good predictive performance for CK19 + hepatocellular carcinoma (HCC).
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Affiliation(s)
- Li Liang
- Department of Medical Ultrasound, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning, Guangxi Zhuang Autonomous Region, China
| | - Jin-Shu Pang
- Department of Medical Ultrasound, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning, Guangxi Zhuang Autonomous Region, China
| | - Rui-Zhi Gao
- Department of Medical Ultrasound, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning, Guangxi Zhuang Autonomous Region, China
| | - Qiao Que
- Department of Medical Ultrasound, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning, Guangxi Zhuang Autonomous Region, China
| | - Yu-Quan Wu
- Department of Medical Ultrasound, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning, Guangxi Zhuang Autonomous Region, China
| | - Jin-Bo Peng
- Department of Medical Ultrasound, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning, Guangxi Zhuang Autonomous Region, China
| | - Xiu-Mei Bai
- Department of Medical Ultrasound, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning, Guangxi Zhuang Autonomous Region, China
| | - Qiong Qin
- Department of Medical Ultrasound, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning, Guangxi Zhuang Autonomous Region, China
| | - Quan-Quan Tang
- Department of Medical Ultrasound, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning, Guangxi Zhuang Autonomous Region, China
| | - Li-Peng Li
- Department of Medical Ultrasound, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning, Guangxi Zhuang Autonomous Region, China
| | - Yun He
- Department of Medical Ultrasound, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning, Guangxi Zhuang Autonomous Region, China.
| | - Hong Yang
- Department of Medical Ultrasound, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning, Guangxi Zhuang Autonomous Region, China.
- Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-constructed by the Province and Ministry, Guangxi Medical University, Nanning, China.
- Guangxi Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor/Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Guangxi Medical University, Nanning, China.
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Mazza S, Frigerio C, Alfieri D, Mauro A, Torello Viera F, Scalvini D, Barteselli C, Sgarlata C, Veronese L, Bardone M, Rovedatti L, Agazzi S, Strada E, Pozzi L, Maestri M, Ravetta V, Anderloni A. Prognostic Role of Basal Serum Alpha-Fetoprotein in Patients with Hepatocellular Carcinoma Suitable for Curative Treatment. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:692. [PMID: 38792876 PMCID: PMC11123130 DOI: 10.3390/medicina60050692] [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: 02/26/2024] [Revised: 04/07/2024] [Accepted: 04/20/2024] [Indexed: 05/26/2024]
Abstract
Background and Objectives: Serum alpha-fetoprotein (AFP) is a recognized affordable oncological marker in patients with hepatocellular carcinoma (HCC). However, AFP's prognostic role has been assessed mainly after specific treatments, and no unanimously recognized cut-offs have been identified. The aim of this study is to investigate the prognostic role of different basal AFP cut-offs on survival and HCC course. Materials and Methods: In this single-center, retrospective study, all patients newly diagnosed with HCC between January 2009 and December 2021 were prospectively enrolled. Only patients suitable for curative HCC treatments were included in the analyses. Patients were stratified according to AFP cut-offs of 20, 200, 400, and 1000 ng/mL, which were correlated with survival outcomes and clinical parameters. Results: A total of 266 patients were analyzed, with a median follow-up time of 41.5 months. Median overall survival (OS) of all cohort was 43 months. At the multivariate Cox-regression analysis, AFP value ≥ 1000 ng/mL correlated with impaired OS (1-year OS: 67% vs. 88%, 5-year OS: 1% vs. 43%; p = 0.005); other risk factors were tumor dimension ≥ 5 cm (HR 1.73; p = 0.002), Child-Pugh class B-C (HR 1.72; p = 0.002), BCLC stage A (vs. 0) (HR 2.4; p = 0.011), and malignant portal vein thrombosis (HR 2.57; p = 0.007). AFP ≥ 1000 ng/mL was also associated with a reduced recurrence-free survival (HR 2.0; p = 0.038), while starting from AFP ≥ 20 ng/mL, a correlation with development of HCC metastases over time (HR 3.5; p = 0.002) was seen. AFP values ≥ 20 ng/mL significantly correlated with tumor size and higher histological grading; starting from AFP values ≥ 400 ng/mL, a significant correlation with Child-Pugh class B-C and female gender was also observed. Conclusions: Basal AFP correlates with relevant outcomes in patients with HCC. It could help identify patients at a higher risk of worse prognosis who might benefit from personalized surveillance and treatment programs. Prospective studies are needed to confirm these results.
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Affiliation(s)
- Stefano Mazza
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - Chiara Frigerio
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
- Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy
| | - Daniele Alfieri
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
- Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy
| | - Aurelio Mauro
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - Francesca Torello Viera
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - Davide Scalvini
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
- Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy
| | - Chiara Barteselli
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - Carmelo Sgarlata
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - Letizia Veronese
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - Marco Bardone
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - Laura Rovedatti
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - Simona Agazzi
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - Elena Strada
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - Lodovica Pozzi
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - Marcello Maestri
- General Surgery I, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - Valentina Ravetta
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - Andrea Anderloni
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
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Koh JH, Wang M, Suzuki H, Muthiah M, Ng CH, Huang DQ. NAFLD and NAFLD-related HCC in Asia: Burden and Surveillance. J Clin Exp Hepatol 2024; 14:101213. [PMID: 38076360 PMCID: PMC10701133 DOI: 10.1016/j.jceh.2023.06.013] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Accepted: 06/30/2023] [Indexed: 06/21/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is rapidly emerging as a leading etiology of chronic liver disease (CLD) in Asia. The increasing incidence of NAFLD is projected to drive a surge in NAFLD-related hepatocellular carcinoma (HCC). A notable characteristic of NAFLD-HCC is its capacity for development in individuals without cirrhosis in more than a third of patients. Most practice guidelines recommend biannual ultrasound screening for patients with cirrhosis. In cases of severe limitations to ultrasound visualisation, cross-sectional abdominal imaging may be warranted. Improved strategies for HCC risk stratification are required for people with NAFLD but without cirrhosis. In this Review, we discuss the evolving trends of NAFLD and HCC in Asia, and implications for surveillance.
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Affiliation(s)
- Jia H. Koh
- Department of Medicine, National University Hospital, Singapore, Singapore
| | - Meng Wang
- Department of Medicine, National University Hospital, Singapore, Singapore
| | - Hiroyuki Suzuki
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Mark Muthiah
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore
| | - Cheng H. Ng
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore
| | - Daniel Q. Huang
- NAFLD Research Center, University of California at San Diego, USA
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Pourbagheri-Sigaroodi A, Fallah F, Bashash D, Karimi A. Unleashing the potential of gene signatures as prognostic and predictive tools: A step closer to personalized medicine in hepatocellular carcinoma (HCC). Cell Biochem Funct 2024; 42:e3913. [PMID: 38269520 DOI: 10.1002/cbf.3913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 12/14/2023] [Accepted: 12/17/2023] [Indexed: 01/26/2024]
Abstract
Hepatocellular carcinoma (HCC) is one of the growing malignancies globally, affecting a myriad of people and causing numerous cancer-related deaths. Despite therapeutic improvements in treatment strategies over the past decades, HCC still remains one of the leading causes of person-years of life lost. Numerous studies have been conducted to assess the characteristics of HCC with the aim of predicting its prognosis and responsiveness to treatment. However, the identified biomarkers have shown limited sensitivity, and the translation of these findings into clinical practice has faced challenges. The development of sequencing techniques has facilitated the exploration of a wide range of genes, leading to the emergence of gene signatures. Although several studies assessed differentially expressed genes in normal and HCC tissues to find the unique gene signature with prognostic value, to date, no study has reviewed the task, and to the best of our knowledge, this review represents the first comprehensive analysis of relevant studies in HCC. Most gene signatures focused on immune-related genes, while others investigated genes related to metabolism, autophagy, and apoptosis. Even though no identical gene signatures were found, NDRG1, SPP1, BIRC5, and NR0B1 were the most extensively studied genes with prognostic value. Finally, despite challenges such as the lack of consistent patterns in gene signatures, we believe that comprehensive analysis of pertinent gene signatures will bring us a step closer to personalized medicine in HCC, where treatment strategies can be tailored to individual patients based on their unique molecular profiles.
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Affiliation(s)
- Atieh Pourbagheri-Sigaroodi
- Pediatric Infections Research Center, Research Institute for Children's Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fatemeh Fallah
- Pediatric Infections Research Center, Research Institute for Children's Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abdollah Karimi
- Pediatric Infections Research Center, Research Institute for Children's Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Samarasinghe SM, Hewage AS, Siriwardana RC, Tennekoon KH, Niriella MA, De Silva S. Genetic and metabolic aspects of non-alcoholic fatty liver disease (NAFLD) pathogenicity. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2023; 24:53. [DOI: 10.1186/s43042-023-00433-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 08/21/2023] [Indexed: 01/03/2025] Open
Abstract
Abstract
Background
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease showing a rising prevalence globally. Genetic predisposition plays a key role in the development and progression of the disease pathogenicity.
Main body
This paper summarizes genetic associations based on their influence on several metabolic aspects such as lipid metabolism, glucose metabolism, hepatic iron accumulation and cholesterol metabolism toward the NAFLD pathogenicity. Furthermore, we present variations in some epigenetic characters and the microRNA profile with regard to NAFLD.
Conclusion
As reported in many studies, the PNPLA3 rs738409 variant seems to be significantly associated with NAFLD susceptibility. Other gene variants like TM6SF2 rs58542926, MBOAT7 rs641738 and GCKR variants also appear to be more prevalent among NAFLD patients. We believe these genetic variants may provide insights into new trends in developing noninvasive biomarkers and identify their suitability in clinical practice in the future.
Graphical abstract
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Li W, Li R, Yan Q, Feng Z, Ning J. Conditional concordance-assisted learning under matched case-control design for combining biomarkers for population screening. Stat Med 2023; 42:1398-1411. [PMID: 36733187 PMCID: PMC10121762 DOI: 10.1002/sim.9677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 09/15/2022] [Accepted: 01/23/2023] [Indexed: 02/04/2023]
Abstract
Incorporating promising biomarkers into cancer screening practices for early-detection is increasingly appealing because of the unsatisfactory performance of current cancer screening strategies. The matched case-control design is commonly adopted in biomarker development studies to evaluate the discriminative power of biomarker candidates, with an intention to eliminate confounding effects. Data from matched case-control studies have been routinely analyzed by the conditional logistic regression, although the assumed logit link between biomarker combinations and disease risk may not always hold. We propose a conditional concordance-assisted learning method, which is distribution-free, for identifying an optimal combination of biomarkers to discriminate cases and controls. We are particularly interested in combinations with a clinically and practically meaningful specificity to prevent disease-free subjects from unnecessary and possibly intrusive diagnostic procedures, which is a top priority for cancer population screening. We establish asymptotic properties for the derived combination and confirm its favorable finite sample performance in simulations. We apply the proposed method to the prostate cancer data from the carotene and retinol efficacy trial (CARET).
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Affiliation(s)
- Wen Li
- Division of Clinical and Translational Sciences, Department of Internal Medicine, The University of Texas McGovern Medical School at Houston, TX, USA
| | - Ruosha Li
- Department of Biostatistics and Data Science, The University of Texas School of Public Health, TX, USA
| | | | - Ziding Feng
- Department of Biostatistics, Fred Hutchinson Cancer Research Center, WA, USA
| | - Jing Ning
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, TX, USA
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Wu T, Li N, Luo F, Chen Z, Ma L, Hu T, Hong G, Li H. Screening prognostic markers for hepatocellular carcinoma based on pyroptosis-related lncRNA pairs. BMC Bioinformatics 2023; 24:176. [PMID: 37120506 PMCID: PMC10148420 DOI: 10.1186/s12859-023-05299-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Accepted: 04/20/2023] [Indexed: 05/01/2023] Open
Abstract
BACKGROUND Pyroptosis is closely related to cancer prognosis. In this study, we tried to construct an individualized prognostic risk model for hepatocellular carcinoma (HCC) based on within-sample relative expression orderings (REOs) of pyroptosis-related lncRNAs (PRlncRNAs). METHODS RNA-seq data of 343 HCC samples derived from The Cancer Genome Atlas (TCGA) database were analyzed. PRlncRNAs were detected based on differentially expressed lncRNAs between sample groups clustered by 40 reported pyroptosis-related genes (PRGs). Univariate Cox regression was used to screen out prognosis-related PRlncRNA pairs. Then, based on REOs of prognosis-related PRlncRNA pairs, a risk model for HCC was constructed by combining LASSO and stepwise multivariate Cox regression analysis. Finally, a prognosis-related competing endogenous RNA (ceRNA) network was built based on information about lncRNA-miRNA-mRNA interactions derived from the miRNet and TargetScan databases. RESULTS Hierarchical clustering of HCC patients according to the 40 PRGs identified two groups with a significant survival difference (Kaplan-Meier log-rank, p = 0.026). Between the two groups, 104 differentially expressed lncRNAs were identified (|log2(FC)|> 1 and FDR < 5%). Among them, 83 PRlncRNA pairs showed significant associations between their REOs within HCC samples and overall survival (Univariate Cox regression, p < 0.005). An optimal 11-PRlncRNA-pair prognostic risk model was constructed for HCC. The areas under the curves (AUCs) of time-dependent receiver operating characteristic (ROC) curves of the risk model for 1-, 3-, and 5-year survival were 0.737, 0.705, and 0.797 in the validation set, respectively. Gene Set Enrichment Analysis showed that inflammation-related interleukin signaling pathways were upregulated in the predicted high-risk group (p < 0.05). Tumor immune infiltration analysis revealed a higher abundance of regulatory T cells (Tregs) and M2 macrophages and a lower abundance of CD8 + T cells in the high-risk group, indicating that excessive pyroptosis might occur in high-risk patients. Finally, eleven lncRNA-miRNA-mRNA regulatory axes associated with pyroptosis were established. CONCLUSION Our risk model allowed us to determine the robustness of the REO-based PRlncRNA prognostic biomarkers in the stratification of HCC patients at high and low risk. The model is also helpful for understanding the molecular mechanisms between pyroptosis and HCC prognosis. High-risk patients may have excessive pyroptosis and thus be less sensitive to immune therapy.
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Affiliation(s)
- Tong Wu
- School of Medical Information Engineering, Gannan Medical University, Ganzhou, 341000, China
| | - Na Li
- School of Medical Information Engineering, Gannan Medical University, Ganzhou, 341000, China
| | - Fengyuan Luo
- School of Medical Information Engineering, Gannan Medical University, Ganzhou, 341000, China
| | - Zhihong Chen
- School of Medical Information Engineering, Gannan Medical University, Ganzhou, 341000, China
| | - Liyuan Ma
- School of Public Health and Health Management, Gannan Medical University, Ganzhou, 341000, China
| | - Tao Hu
- School of Medical Information Engineering, Gannan Medical University, Ganzhou, 341000, China
| | - Guini Hong
- School of Medical Information Engineering, Gannan Medical University, Ganzhou, 341000, China.
| | - Hongdong Li
- School of Medical Information Engineering, Gannan Medical University, Ganzhou, 341000, China.
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Zhao D, Cao J, Zhang L, Zhang S, Wu S. Targeted Molecular Imaging Probes Based on Magnetic Resonance Imaging for Hepatocellular Carcinoma Diagnosis and Treatment. BIOSENSORS 2022; 12:bios12050342. [PMID: 35624643 PMCID: PMC9138815 DOI: 10.3390/bios12050342] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 05/09/2022] [Accepted: 05/11/2022] [Indexed: 11/30/2022]
Abstract
Hepatocellular carcinoma (HCC) is the sixth most commonly malignant tumor and the third leading cause of cancer-related death in the world, and the early diagnosis and treatment of patients with HCC is core in improving its prognosis. The early diagnosis of HCC depends largely on magnetic resonance imaging (MRI). MRI has good soft-tissue resolution, which is the international standard method for the diagnosis of HCC. However, MRI is still insufficient in the diagnosis of some early small HCCs and malignant nodules, resulting in false negative results. With the deepening of research on HCC, researchers have found many specific molecular biomarkers on the surface of HCC cells, which may assist in diagnosis and treatment. On the other hand, molecular imaging has progressed rapidly in recent years, especially in the field of cancer theranostics. Hence, the preparation of molecular imaging probes that can specifically target the biomarkers of HCC, combined with MRI testing in vivo, may achieve the theranostic purpose of HCC in the early stage. Therefore, in this review, taking MR imaging as the basic point, we summarized the recent progress regarding the molecular imaging targeting various types of biomarkers on the surface of HCC cells to improve the theranostic rate of HCC. Lastly, we discussed the existing obstacles and future prospects of developing molecular imaging probes as HCC theranostic nanoplatforms.
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Affiliation(s)
- Dongxu Zhao
- Department of Urology, The Third Affiliated Hospital of Shenzhen University (Luohu Hospital Group), Shenzhen 518000, China;
- Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Jian Cao
- Department of Gastroenterology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou 215006, China;
| | - Lei Zhang
- Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
- Center of Interventional Radiology & Vascular Surgery, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing 210009, China
- Correspondence: (L.Z.); (S.Z.); (S.W.)
| | - Shaohua Zhang
- Department of Urology, The Third Affiliated Hospital of Shenzhen University (Luohu Hospital Group), Shenzhen 518000, China;
- Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
- Correspondence: (L.Z.); (S.Z.); (S.W.)
| | - Song Wu
- Department of Urology, The Third Affiliated Hospital of Shenzhen University (Luohu Hospital Group), Shenzhen 518000, China;
- Department of Urology, The Affiliated South China Hospital of Shenzhen University, Shenzhen University, Shenzhen 518000, China
- Correspondence: (L.Z.); (S.Z.); (S.W.)
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Jearth V, Patil PS, Mehta S, Sundaram S, Seth V, Goel M, Patkar S, Bal M, Rao V. Correlation of Clinicopathological Profile, Prognostic Factors, and Survival Outcomes with Baseline Alfa-Fetoprotein Levels in Patients With Hepatocellular Carcinoma: A Biomarker that is Bruised but Not Broken. J Clin Exp Hepatol 2022; 12:841-852. [PMID: 35677513 PMCID: PMC9168719 DOI: 10.1016/j.jceh.2021.11.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 11/10/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND AND AIMS The role of Alfa-fetoprotein (AFP) in the management of hepatocellular carcinoma (HCC) is still debated, with differences in recommendations between international guidelines. We analyzed the relationship of the clinicopathological profile, prognostic features, and survival outcomes with baseline serum AFP levels in patients with HCC. METHODS Retrospective analysis of a prospectively accrued dataset of consecutive HCC patients was done. RESULTS 508 treatment naive patients were included in the analysis. AFP at presentation was normal (<10 ng/ml) in 18% patients. Patients with very high AFP (>400 ng/ml) had poor hepatic reserves (higher mean serum bilirubin, AST, ALT, INR, and lower mean albumin) and advanced disease at presentation (higher incidence of extrahepatic metastasis, and less proportion of patients with well-differentiated tumors). AFP >400 ng/ml was an independent predictor for presence of portal vein tumor thrombosis (PVTT) (OR, 4.08; 95% CI, 2.34-7.12; P < 0.001), higher tumor size (OR, 2.19; 95% CI, 1.36-3.54, P = 0.001) and advanced BCLC stage (OR, 4.19; 95% CI, 2.51-7.03; P < 0.001). Two-third of patients with small HCC (MTD <3 cm) and more than half with early-stage HCC (BCLC stage 0/A) had elevated AFP levels. No significant relationship was seen between overall survival (OS) and baseline AFP in patients who underwent surgery, but median OS in patients subjected to nonsurgical therapies was 19.4,10.5 and 5.7 months in patients having AFP <10 ng/ml, 10-400 ng/ml and >400 ng/ml respectively (P = 0.003). AFP >400 ng/ml was an independent predictor of survival in patients receiving any form of therapy (HR = 2.23; 95% CI = 1.19-4.18, P = 0.012). CONCLUSION AFP as a biomarker still has a significant role to play in the management of HCC patients and is here to stay till the search for an ideal biomarker in HCC is over.
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Key Words
- AFP, Alfa-fetoprotein
- BCLC, Barcelona clinic liver cancer
- BSC, Best supportive care
- Barcelona clinic liver cancer staging
- EHM, Extrahepatic metastasis
- HBHC, HBV or HCV related
- HBV, Hepatitis B virus
- HCC, Hepatocellular carcinoma
- HCV, Hepatitis C virus
- MDT, Multidisciplinary team
- MTD, Maximum tumor diameter
- NAFLD, Nonalcoholic fatty liver disease
- NBNC, Non B Non C related
- OS, Overall survival
- PVTT, Portal vein tumor thrombosis
- RFA, Radiofrequency ablation
- SBRT, Stereotactic body radiation therapy
- TACE, Transarterial chemo-embolization
- TARE, Transarterial radio-embolization
- alfa-fetoprotein
- biomarker
- hepatocellular carcinoma
- portal vein tumor thrombosis
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Affiliation(s)
- Vaneet Jearth
- Department of Digestive Diseases and Clinical Nutrition, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Prachi S. Patil
- Department of Digestive Diseases and Clinical Nutrition, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, India,Address for correspondence: Prachi S. Patil, Professor, Department of Digestive Diseases and Clinical Nutrition, Tata Memorial Hospital, Mumbai, Maharashtra, 400012, India. Tel.: +91-22-24177000. Ext-7205.
| | - Shaesta Mehta
- Department of Digestive Diseases and Clinical Nutrition, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Sridhar Sundaram
- Department of Digestive Diseases and Clinical Nutrition, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Vishal Seth
- Department of Digestive Diseases and Clinical Nutrition, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Mahesh Goel
- Division of Hepatobiliary Surgery, Department of Surgical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, India
| | - Shraddha Patkar
- Division of Hepatobiliary Surgery, Department of Surgical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, India
| | - Munita Bal
- Department of Pathology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Vidya Rao
- Department of Pathology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, India
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11
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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.
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12
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Al-Harazi O, Kaya IH, Al-Eid M, Alfantoukh L, Al Zahrani AS, Al Sebayel M, Kaya N, Colak D. Identification of Gene Signature as Diagnostic and Prognostic Blood Biomarker for Early Hepatocellular Carcinoma Using Integrated Cross-Species Transcriptomic and Network Analyses. Front Genet 2021; 12:710049. [PMID: 34659334 PMCID: PMC8511318 DOI: 10.3389/fgene.2021.710049] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 09/09/2021] [Indexed: 01/08/2023] Open
Abstract
Background: Hepatocellular carcinoma (HCC) is considered the most common type of liver cancer and the fourth leading cause of cancer-related deaths in the world. Since the disease is usually diagnosed at advanced stages, it has poor prognosis. Therefore, reliable biomarkers are urgently needed for early diagnosis and prognostic assessment. Methods: We used genome-wide gene expression profiling datasets from human and rat early HCC (eHCC) samples to perform integrated genomic and network-based analyses, and discovered gene markers that are expressed in blood and conserved in both species. We then used independent gene expression profiling datasets for peripheral blood mononuclear cells (PBMCs) for eHCC patients and from The Cancer Genome Atlas (TCGA) database to estimate the diagnostic and prognostic performance of the identified gene signature. Furthermore, we performed functional enrichment, interaction networks and pathway analyses. Results: We identified 41 significant genes that are expressed in blood and conserved across species in eHCC. We used comprehensive clinical data from over 600 patients with HCC to verify the diagnostic and prognostic value of 41-gene-signature. We developed a prognostic model and a risk score using the 41-geneset that showed that a high prognostic index is linked to a worse disease outcome. Furthermore, our 41-gene signature predicted disease outcome independently of other clinical factors in multivariate regression analysis. Our data reveals a number of cancer-related pathways and hub genes, including EIF4E, H2AFX, CREB1, GSK3B, TGFBR1, and CCNA2, that may be essential for eHCC progression and confirm our gene signature's ability to detect the disease in its early stages in patients' biological fluids instead of invasive procedures and its prognostic potential. Conclusion: Our findings indicate that integrated cross-species genomic and network analysis may provide reliable markers that are associated with eHCC that may lead to better diagnosis, prognosis, and treatment options.
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Affiliation(s)
- Olfat Al-Harazi
- Department of Biostatistics, Epidemiology, and Scientific Computing, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Ibrahim H Kaya
- AlFaisal University, College of Medicine, Riyadh, Saudi Arabia
| | - Maha Al-Eid
- Department of Biostatistics, Epidemiology, and Scientific Computing, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Lina Alfantoukh
- Department of Biostatistics, Epidemiology, and Scientific Computing, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Ali Saeed Al Zahrani
- Gulf Centre for Cancer Control and Prevention, King Faisal Special Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Mohammed Al Sebayel
- Liver and Small Bowel Transplantation and Hepatobiliary-Pancreatic Surgery Department, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.,Department of Surgery, University of Almaarefa, Riyadh, Saudi Arabia
| | - Namik Kaya
- Translational Genomics Department, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Dilek Colak
- Department of Biostatistics, Epidemiology, and Scientific Computing, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
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13
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Actin-Binding Proteins as Potential Biomarkers for Chronic Inflammation-Induced Cancer Diagnosis and Therapy. ACTA ACUST UNITED AC 2021; 2021:6692811. [PMID: 34194957 PMCID: PMC8203385 DOI: 10.1155/2021/6692811] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 04/13/2021] [Accepted: 05/18/2021] [Indexed: 12/15/2022]
Abstract
Actin-binding proteins (ABPs), by interacting with actin, regulate the polymerization, depolymerization, bundling, and cross-linking of actin filaments, directly or indirectly, thereby mediating the maintenance of cell morphology, cell movement, and many other biological functions. Consequently, these functions of ABPs help regulate cancer cell invasion and metastasis when cancer occurs. In recent years, a variety of ABPs have been found to be abnormally expressed in various cancers, indicating that the detection and interventions of unusual ABP expression to alter this are available for the treatment of cancer. The early stages of most cancer development involve long-term chronic inflammation or repeated stimulation. This is the case for breast cancer, gastric cancer, lung cancer, prostate cancer, liver cancer, esophageal cancer, pancreatic cancer, melanoma, and colorectal cancer. This article discusses the relationship between chronic inflammation and the above-mentioned cancers, emphatically introduces relevant research on the abnormal expression of ABPs in chronic inflammatory diseases, and reviews research on the expression of different ABPs in the above-mentioned cancers. Furthermore, there is a close relationship between ABP-induced inflammation and cancer. In simple terms, abnormal expression of ABPs contributes to the chronic inflammation developing into cancer. Finally, we provide our viewpoint regarding these unusual ABPs serving as potential biomarkers for chronic inflammation-induced cancer diagnosis and therapy, and interventions to reverse the abnormal expression of ABPs represent a potential approach to preventing or treating the corresponding cancers.
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14
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Butt SS, Khan K, Badshah Y, Rafiq M, Shabbir M. Evaluation of pro-apoptotic potential of taxifolin against liver cancer. PeerJ 2021; 9:e11276. [PMID: 34113483 PMCID: PMC8162243 DOI: 10.7717/peerj.11276] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Accepted: 03/24/2021] [Indexed: 12/13/2022] Open
Abstract
Liver cancer is the second most common cause of cancer-induced deaths worldwide. Liver cirrhosis and cancer are a consequence of the abnormal angio-architecture formation of liver and formation of new blood vessels. This angiogenesis is driven by overexpression of hypoxia-inducible factor 1-alpha (Hif1-α) and vascular endothelial growth factor (VEGF). Apart from this, protein kinase B (Akt) is also impaired in liver cancer. Despite the advancement in conventional treatments, liver cancer remains largely incurable. Nowadays, the use of naturally occurring anticancer agents particularly flavonoids is subject to more attention due to their enhanced physicochemical properties. Therefore, this study underlines the use of a natural anticancer agent taxifolin in the treatment of liver cancer using hepatocellular carcinoma cell line HepG2 and Huh7. The aim of our study is to devise a natural and efficient solution for the disease prevalent in Pakistan. The study involved the assessment of binding of ligand taxifolin using molecular docking. The binding of taxifolin with the proteins (Hif1-α, VEGF and Akt) was calculated by docking using Vina and Chimera. Further evaluation was performed by cell viability assay (MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) Assay), colony formation assay, cell migration assay, DNA ladder assay and flow cytometry. To see whether taxifolin directly affected expression levels, analysis of gene expression of Hif1-α, VEGF and Akt was performed using real-time polymerase chain reaction (qPCR) and western blotting. In silico docking experiments revealed that these proteins showed favorable docking scores with taxifolin. Treatment with taxifolin resulted in the inhibition of the liver cancer growth and migration, and induced apoptosis in HepG2 and Huh7 cell lines at an inhibitory concentration (IC50) value of 0.15 µM and 0.22 µM, respectively. The expression of HIF1-α, VEGF and Akt was significantly reduced in a dose- dependent manner. The inhibitory effect of taxifolin on hepatic cells suggested its chemopreventive and therapeutic potential. The studied compound taxifolin exhibited pronounced pro-apoptotic and hepatoprotective potential. Our study has confirmed the pro-apoptotic potential of taxifolin in liver cancer cell lines and will pave a way to the use of taxifolin as a chemotherapeutic agent after its further validation on the animal models and humans based epidemiological studies.
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Affiliation(s)
- Sania Safdar Butt
- Atta-Ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Khushbukhat Khan
- Atta-Ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Yasmin Badshah
- Atta-Ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Mehak Rafiq
- Research Centre for Modelling and Simulation, National University of Sciences and Technology, Islamabad, Pakistan
| | - Maria Shabbir
- Atta-Ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
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15
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Khan IM, Gjuka D, Jiao J, Song X, Wang Y, Wang J, Wei P, El-Serag HB, Marrero JA, Beretta L. A Novel Biomarker Panel for the Early Detection and Risk Assessment of Hepatocellular Carcinoma in Patients with Cirrhosis. Cancer Prev Res (Phila) 2021; 14:667-674. [PMID: 33685927 DOI: 10.1158/1940-6207.capr-20-0600] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Revised: 02/01/2021] [Accepted: 03/02/2021] [Indexed: 12/14/2022]
Abstract
Novel biomarkers for hepatocellular carcinoma (HCC) surveillance in patients with cirrhosis are urgently needed. We previously identified osteopontin (OPN) as a promising biomarker for the early detection of HCC. This study is to further validate the performance of OPN and identify fatty acids (FA) that could improve OPN's performance in HCC risk assessment in patients with cirrhosis. To that end, we selected 103 patients with cirrhosis under surveillance. Among them, 40 patients developed HCC during follow-up. We investigated in these 103 patients, the association between HCC incidence and prediagnostic serum levels of AFP, OPN, and 46 FAs. OPN performance was higher than AFP in detecting prediagnosis HCCs and the combination with AFP further improved OPN's performance. For patients with a diagnosis of HCC within 18 months of follow-up (HCC < 18 months), AUC for OPN + AFP was 0.77. Abundance of 11 FAs [four long-chain saturated FAs (SFA), four n-3 poly-unsaturated FAs (PUFA), and three n-6 PUFAs] were statistically different between patients who developed HCC and those who did not. Abundance changes correlated with time to diagnosis for the PUFAs, but not for the SFAs. Adding arachidic acid (20:0) and n-3 docosapentaenoic acid (22:5n3) to OPN and AFP improved the discriminatory performance (AUC = 0.83). AUC for this panel reached 0.87 for HCC < 18 months (82% sensitivity at 81% specificity). In conclusion, we identified a panel of 4 markers with strong performances that could have significant utility in HCC early detection in patients with cirrhosis under surveillance. PREVENTION RELEVANCE: This study identified a panel of 4 biomarkers that identifies with high performance patients with cirrhosis at high risk for HCC. This panel could have utility in HCC early detection in patients with cirrhosis under surveillance.
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Affiliation(s)
- Ilvira M Khan
- Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Donjeta Gjuka
- Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jingjing Jiao
- Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Xiaoling Song
- Cancer Prevention Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Ying Wang
- Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jing Wang
- Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Peng Wei
- Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Hashem B El-Serag
- Department of Medicine, Baylor College of Medicine, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
| | - Jorge A Marrero
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Laura Beretta
- Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.
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16
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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.
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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
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17
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Ekmen N, Akalin Ç, Akyildiz M. Predictive value of protein induced by absence of vitamin K absence or antagonist II, alpha-fetoprotein and gamma-glutamyltransferase/aspartate aminotransferase ratio for the diagnosis of hepatocellular carcinoma in transplantation candidates. Eur J Gastroenterol Hepatol 2021; 32:294-299. [PMID: 32796360 DOI: 10.1097/meg.0000000000001884] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
OBJECTIVES Alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II) are used as tumour markers for the diagnosis of hepatocellular carcinoma (HCC). We investigate whether combined liver function marker such as gamma-glutamyl transferase (GGT) and aspartate aminotransferase (AST) with alpha-fetoprotein (AFP) and PIVKA-II increase their diagnostic predictive value in diagnosis of HCC. METHODS The serum levels of PIVKA-II, AFP and GGT/AST ratio were analysed in 112 transplant candidates. Of these patients, 66 (59%) had HCC and 46 (41%) patients did not. RESULTS Histological grade was positively correlated with serum levels of PIVKA-II and AFP (r = 0.255, P < 0.039 and r = 0.284, P < 0.021, respectively) and only tumour size positively correlated with the serum level of PIVKA-II (r = 0.270, P < 0.028), but no correlation between the number of tumour, Milan criteria and PIVKA-II (r = -0.002, P = 0.984 and r = 0.154, P = 0.216, respectively) with AFP (r = -0.024, P = 0.851 and r = 0.080, P = 0.522, respectively). Sensitivity and specificity of AFP, PIVKA-II and GGT/AST ratio at cutoff values of 6.08, 2.63 and 0.89, respectively, were as follows: 77, 77 vs 71, 83 vs 60 and 53%. The combination of AFP and PIVKA-II and GGT/AST ratio in HCC diagnosis increased AUROC values as follows; 0.860 vs 0.882 and 0.823 vs 0.840, respectively. CONCLUSIONS This study showed that combined tumour markers such as AFP, PIVKA-II and GGT/AST ratio increase their sensitivity in HCC diagnosis.
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Affiliation(s)
- Nergis Ekmen
- Department of Gastroenterology, Gazi University School of Medicine, Ankara
| | - Çağri Akalin
- Department of General Surgery, Ordu University School of Medicine, Ordu
| | - Murat Akyildiz
- Department of Gastroenterology, Koç University Hospital, İstanbul, Turkey
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18
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Trevisan França de Lima L, Broszczak D, Zhang X, Bridle K, Crawford D, Punyadeera C. The use of minimally invasive biomarkers for the diagnosis and prognosis of hepatocellular carcinoma. Biochim Biophys Acta Rev Cancer 2020; 1874:188451. [PMID: 33065194 DOI: 10.1016/j.bbcan.2020.188451] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 10/08/2020] [Accepted: 10/08/2020] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC) is a common cause of cancer-related deaths worldwide. Despite advances in systemic therapies, patient survival remains low due to late diagnosis and frequent underlying liver diseases. HCC diagnosis generally relies on imaging and liver tissue biopsy. Liver biopsy presents limitations because it is invasive, potentially risky for patients and it frequently misrepresents tumour heterogeneity. Recently, liquid biopsy has emerged as a way to monitor cancer progression in a non-invasive manner. Tumours shed content into the bloodstream, such as circulating tumour cells (CTCs), circulating nucleic acids, extracellular vesicles and proteins, that can be isolated from biological fluids of patients with HCC. These biomarkers provide knowledge regarding the genetic landscape of tumours and might be used for diagnostic or prognostic purposes. In this review, we summarize recent literature on circulating biomarkers for HCC, namely CTCs, circulating tumour DNA (ctDNA), RNA, extracellular vesicles and proteins, and their clinical relevance in HCC.
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Affiliation(s)
- Lucas Trevisan França de Lima
- Institute of Health & Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology, Kelvin Grove Campus, QLD, Australia; Gallipoli Medical Research Foundation, Greenslopes Private Hospital, Greenslopes, QLD, Australia
| | - Daniel Broszczak
- Institute of Health & Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology, Kelvin Grove Campus, QLD, Australia
| | - Xi Zhang
- Institute of Health & Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology, Kelvin Grove Campus, QLD, Australia
| | - Kim Bridle
- The University of Queensland, Faculty of Medicine, Herston, QLD, Australia; Gallipoli Medical Research Foundation, Greenslopes Private Hospital, Greenslopes, QLD, Australia
| | - Darrell Crawford
- The University of Queensland, Faculty of Medicine, Herston, QLD, Australia; Gallipoli Medical Research Foundation, Greenslopes Private Hospital, Greenslopes, QLD, Australia
| | - Chamindie Punyadeera
- Institute of Health & Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology, Kelvin Grove Campus, QLD, Australia.
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19
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Lu Y, Fang Z, Li M, Chen Q, Zeng T, Lu L, Chen Q, Zhang H, Zhou Q, Sun Y, Xue X, Hu Y, Chen L, Su S. Dynamic edge-based biomarker non-invasively predicts hepatocellular carcinoma with hepatitis B virus infection for individual patients based on blood testing. J Mol Cell Biol 2020; 11:665-677. [PMID: 30925583 PMCID: PMC6788726 DOI: 10.1093/jmcb/mjz025] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Revised: 01/27/2019] [Accepted: 03/20/2019] [Indexed: 02/07/2023] Open
Abstract
Hepatitis B virus (HBV)-induced hepatocellular carcinoma (HCC) is a major cause of cancer-related deaths in Asia and Africa. Developing effective and non-invasive biomarkers of HCC for individual patients remains an urgent task for early diagnosis and convenient monitoring. Analyzing the transcriptomic profiles of peripheral blood mononuclear cells from both healthy donors and patients with chronic HBV infection in different states (i.e. HBV carrier, chronic hepatitis B, cirrhosis, and HCC), we identified a set of 19 candidate genes according to our algorithm of dynamic network biomarkers. These genes can both characterize different stages during HCC progression and identify cirrhosis as the critical transition stage before carcinogenesis. The interaction effects (i.e. co-expressions) of candidate genes were used to build an accurate prediction model: the so-called edge-based biomarker. Considering the convenience and robustness of biomarkers in clinical applications, we performed functional analysis, validated candidate genes in other independent samples of our collected cohort, and finally selected COL5A1, HLA-DQB1, MMP2, and CDK4 to build edge panel as prediction models. We demonstrated that the edge panel had great performance in both diagnosis and prognosis in terms of precision and specificity for HCC, especially for patients with alpha-fetoprotein-negative HCC. Our study not only provides a novel edge-based biomarker for non-invasive and effective diagnosis of HBV-associated HCC to each individual patient but also introduces a new way to integrate the interaction terms of individual molecules for clinical diagnosis and prognosis from the network and dynamics perspectives.
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Affiliation(s)
- Yiyu Lu
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zhaoyuan Fang
- Key Laboratory of Systems Biology, Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institute of Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Meiyi Li
- Key Laboratory of Systems Biology, Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institute of Biological Sciences, Chinese Academy of Sciences, Shanghai, China.,Minhang Branch, Zhongshan Hospital/Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai, China
| | - Qian Chen
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Tao Zeng
- Key Laboratory of Systems Biology, Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institute of Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Lina Lu
- Key Laboratory of Systems Biology, Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institute of Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Qilong Chen
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hui Zhang
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Qianmei Zhou
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yan Sun
- Qidong Liver Cancer Institute, Qidong People's Hospital, Qidong, China
| | - Xuefeng Xue
- Qidong Liver Cancer Institute, Qidong People's Hospital, Qidong, China
| | - Yiyang Hu
- Institute of Liver Disease, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Luonan Chen
- Key Laboratory of Systems Biology, Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institute of Biological Sciences, Chinese Academy of Sciences, Shanghai, China.,Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, China.,School of Life Science and Technology, Shanghai Tech University, Shanghai, China.,Research Center for Brain Science and Brain-Inspired Intelligence, Shanghai, China
| | - Shibing Su
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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20
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Mohamed AA, Omran D, El-Feky S, Darwish H, Kassas A, Farouk A, Ezzat O, Abdo SM, Zahran FE, El-Demery A, Omran MM. Toll-like receptor 7 mRNA is reduced in hepatitis C-based liver cirrhosis and hepatocellular carcinoma, out-performs alpha-fetoprotein levels, and with age and serum aspartate aminotransferase is a new diagnostic index. Br J Biomed Sci 2020; 78:18-22. [PMID: 32573389 DOI: 10.1080/09674845.2020.1778842] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND Hepatitis B and C viruses are leading causes of liver cirrhosis and hepatocellular carcinoma (HCC). Toll-like receptor 7 (TLR-7) has been implicated in the pathogenesis of HCC linked to hepatitis B. We hypothesised a role of leukocyte TLR-7 mRNA in hepatitis C related liver cirrhosis and HCC, using alpha-fetoprotein (AFP) and liver function tests as comparators. METHODS We recruited 102 patients with HCV-related HCC, 97 with HCV-related liver cirrhosis and 60 healthy controls. Quantification of TLR-7 mRNA was performed using real-time PCR, AFP and routine LFTs by standard techniques. RESULTS TLR-7 mRNA levels were significantly lower in HCC patients compared to cirrhotic patients and lower again in healthy controls (p < 0.001 for trend). In multivariate analysis, age, aspartate transaminase (AST), AFP, and TLR-7 mRNA were significant predictors of HCC. The ROCC/AUC for age, AST and TLR-7 mRNA were all between 0.64 and 0.78 (all P < 0.01), but for AFP was 0.57 (95% CI 0.48-0.65, P = 0.09). We derived an index score using age, AST and TLR-7 mRNA for the diagnosis of HCC. The ROCC/AUC for the index was superior to all three root indices in the prediction of HCC. The index linked significantly with the Tokyo and Vienna liver cancer staging systems, but not with those of the CLIP and Okuda systems, in distinguishing HCC from liver cirrhosis. CONCLUSION The combination of TLR-7 mRNA levels with age and AST improves the performance of TLR-7 in HCC diagnosis, out-performs alpha-fetoprotein and predicts early HCC.
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Affiliation(s)
- A A Mohamed
- Biochemistry Department, National Hepatology and Tropical Medicine Research Institute, Cairo University , Giza, Egypt
| | - D Omran
- Department of Endemic Medicine and Hepatology, Faculty of Medicine, Cairo University , Giza, Egypt
| | - S El-Feky
- Biochemistry Department, Damanhur Medical National Institute , Egypt
| | - H Darwish
- Oncology Department, Ismailia Teaching Oncology Hospital , Ismailia, Egypt
| | - Ael Kassas
- Radiology Department, El Sahel Teaching Hospital , Cairo, Egypt
| | - A Farouk
- Radiology Department, National Institute of Diabetes and Endocrinology , Giza, Egypt
| | - O Ezzat
- Biochemistry Department, Faculty of Pharmacy, Egyptian Russian University , Cairo, Egypt
| | - S M Abdo
- Chemistry Department, Faculty of Science, Helwan University , Cairo, Egypt
| | - F E Zahran
- Internal Medicine Department, Faculty of Medicine (Girls), Al-azhar University , Cairo, Egypt
| | - A El-Demery
- Biochemistry Department, Faculty of Medicine, October 6 University , 6th of October City, Egypt
| | - M M Omran
- Chemistry Department, Faculty of Science, Helwan University , Cairo, Egypt
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21
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Low UGP2 Expression Is Associated with Tumour Progression and Predicts Poor Prognosis in Hepatocellular Carcinoma. DISEASE MARKERS 2020; 2020:3231273. [PMID: 32733617 PMCID: PMC7369654 DOI: 10.1155/2020/3231273] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 05/03/2020] [Accepted: 06/13/2020] [Indexed: 12/19/2022]
Abstract
Hepatocellular carcinoma (HCC) is a malignant tumour associated with a high mortality rate and poor prognosis worldwide. Uridine diphosphate-glucose pyrophosphorylase 2 (UGP2), a key enzyme in glycogen biosynthesis, has been reported to be associated with the occurrence and development of various cancer types. However, its diagnostic value and prognostic value in HCC remain unclear. The present study observed that UGP2 expression was significantly downregulated at both the mRNA and protein levels in HCC tissues. Receiver operating characteristic (ROC) curve analysis revealed that UGP2 may be an indicator for the diagnosis of HCC. In addition, Kaplan-Meier and Cox regression multivariate analyses indicated that UGP2 is an independent prognostic factor of overall survival (OS) in patients with HCC. Furthermore, gene set enrichment analysis (GSEA) suggested that gene sets negatively correlated with the survival of HCC patients were enriched in the group with low UGP2 expression levels. More importantly, a significant correlation was identified between low UGP2 expression and fatty acid metabolism. In summary, the present study demonstrates that UGP2 may contribute to the progression of HCC, indicating a potential therapeutic target for HCC patients.
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22
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Aboelfotoh AO, Foda EM, Elghandour AM, Teama NM, Abouzein RA, Mohamed GA. Talin-1; other than a potential marker for hepatocellular carcinoma diagnosis. Arab J Gastroenterol 2020; 21:80-84. [PMID: 32439236 DOI: 10.1016/j.ajg.2020.04.017] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 02/11/2020] [Accepted: 04/19/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND STUDY AIMS Hepatocellular carcinoma (HCC) is a major cause of cancer mortality worldwide. Talin-1 was previously proposed as a potential novel biomarker for HCC diagnosis but with limited and inconsistent data. We aimed to study the possible role of talin-1 in diagnosis and prognostic stratification of patients with hepatocellular carcinoma. PATIENTS AND METHODS Ninety-six patients were recruited and classified into three groups; 1) cirrhosis group: 40 patients with liver cirrhosis, 2) HCC group: 40 patients with HCC, 3) control group: 16 healthy volunteers with matched age and sex. Serum talin-1 level was detected using enzyme-linked immunosorbent assay (ELISA). RESULTS The highest levels of talin-1 were observed among the HCC group followed by cirrhosis then control groups (p = 0.000). In the HCC group, a significant correlation was found between talin-1 and each of multifocal HCC (p = 0.013), portal vein invasion (p = 0.022) and presence of ascites (p = 0.001), while no significant correlation was detected with tumour foci size (p = 0.605). For HCC detection, talin-1 had AUC = 0.858, 100% sensitivity and 65% specificity, while AFP had AUC = 1.000, 100% sensitivity and specificity. CONCLUSION Talin-1 is a potential marker for diagnosis and prognostic assessment of HCC. Further studies are needed to investigate the ultimate diagnostic and prognostic utility of serum talin-1.
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Affiliation(s)
- Aly O Aboelfotoh
- Department of Internal Medicine, Faculty of Medicine, Ain Shams University, Ramses St, Abbassia, Cairo 11591, Egypt
| | - Enas M Foda
- Department of Internal Medicine, Faculty of Medicine, Ain Shams University, Ramses St, Abbassia, Cairo 11591, Egypt
| | - Ahmed M Elghandour
- Department of Internal Medicine, Faculty of Medicine, Ain Shams University, Ramses St, Abbassia, Cairo 11591, Egypt
| | - Nahla M Teama
- Department of Internal Medicine, Faculty of Medicine, Ain Shams University, Ramses St, Abbassia, Cairo 11591, Egypt
| | - Reham A Abouzein
- Department of Internal Medicine, Faculty of Medicine, Ain Shams University, Ramses St, Abbassia, Cairo 11591, Egypt
| | - Ghada A Mohamed
- Department of Internal Medicine, Faculty of Medicine, Ain Shams University, Ramses St, Abbassia, Cairo 11591, Egypt.
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23
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Ye C, Zhang X, Chen X, Cao Q, Zhang X, Zhou Y, Li W, Hong L, Xie H, Liu X, Cao H, Wang YJ, Kang B. Multiple novel hepatocellular carcinoma signature genes are commonly controlled by the master pluripotency factor OCT4. Cell Oncol (Dordr) 2020; 43:279-295. [PMID: 31848930 DOI: 10.1007/s13402-019-00487-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/22/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Worldwide, hepatocellular carcinoma (HCC) is a common solid tumor with a poor prognosis. HCC is often due to hepatitis B virus (HBV) infection. As yet, efficacious HCC treatment regimens for late-stage HCC patients are lacking. Therefore, the identification of more specific and sensitive biomarkers for its early diagnosis and treatment remains an urgent need. METHODS Total RNAs from paired HBV-derived HCC tumors and adjacent peritumor tissues (APTs) were subjected to RNA sequencing (RNA-seq), and differentially expressed genes (DEGs) between HCC tumors and APTs were selected and verified. RESULTS We identified 166 DEGs and found that eight top-ranked and verified DEGs (TK1, CTTN, CEP72, TRIP13, FTH1, FLAD1, CHRM2, AMBP) all contained putative OCT4 binding motifs in their promoter regions. TK1, TRIP13 and OCT4 were found to exhibit concurrent higher expression levels in HCC tumors than in APTs. The mRNA levels of TK1, TRIP13 and OCT4 in a cohort of 384 HCC samples from the TCGA database were all found to be negatively correlated with patient overall survival, relapse-free survival and progression-free survival, underscoring the HCC biomarker status of TK1 and TRIP13 on one hand, and implicating their association with OCT4 on the other hand. Furthermore, OCT4 proteins were found to bind to the promoters of both genes in vitro and in vivo. Knocking out OCT4 in HCC-derived cell lines reduced the expression of TK1 and TRIP13 and significantly decreased their tumorigenicity. CONCLUSIONS Using RNA-seq, we identified several novel HCC signature genes that may serve as biomarkers for its diagnosis and prognosis. Their common transcriptional regulation by OCT4 suggests key roles in the development of HCC, and indicates that OCT4 may serve as a potential therapeutic target.
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Affiliation(s)
- Chao Ye
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, 310003, Hangzhou, China
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, Anhui, China
| | - Xiaoqian Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, 310003, Hangzhou, China
| | - Xinyu Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, 310003, Hangzhou, China
| | - Qingyi Cao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, 310003, Hangzhou, China
| | - Xiaobing Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, 310003, Hangzhou, China
| | - Yanwen Zhou
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, 310003, Hangzhou, China
- Department of Infectious Diseases, the Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
| | - Wenxin Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, 310003, Hangzhou, China
- Department of Respiratory Medicine, Institute of Respiratory Disease, The First College of Clinical Medical Sciences, Yichang Central People's Hospital, China Three Gorges University, Yichang, 443003, Hubei, China
| | - Liangjie Hong
- NHFPC Key Laboratory of Combined Multi-organ Transplantation, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China
| | - Haiyang Xie
- NHFPC Key Laboratory of Combined Multi-organ Transplantation, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China
| | - Xiaoli Liu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, 310003, Hangzhou, China
| | - Hongcui Cao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, 310003, Hangzhou, China
| | - Ying-Jie Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, 310003, Hangzhou, China.
| | - Bo Kang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, 310003, Hangzhou, China.
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Wang W, Wei C. Advances in the early diagnosis of hepatocellular carcinoma. Genes Dis 2020; 7:308-319. [PMID: 32884985 PMCID: PMC7452544 DOI: 10.1016/j.gendis.2020.01.014] [Citation(s) in RCA: 263] [Impact Index Per Article: 52.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Revised: 01/10/2020] [Accepted: 01/20/2020] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent cancers globally. In contrast to the declining death rates observed for all other common cancers such as breast, lung, and prostate cancers, the death rates for HCC continue to increase by ~2–3% per year because HCC is frequently diagnosed late and there is no curative therapy for an advanced HCC. The early diagnosis of HCC is truly a big challenge. Over the past years, the early diagnosis of HCC has relied on surveillance with ultrasonography (US) and serological assessments of alpha-fetoprotein (AFP). However, the specificity and sensitivity of US/AFP is not satisfactory enough to detect early onset HCC. Recent technological advancements offer hope for early HCC diagnosis. Herein, we review the progress made in HCC diagnostics, with a focus on emerging imaging techniques and biomarkers for early disease diagnosis.
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Affiliation(s)
- Weiyi Wang
- Xiamen Amplly Bio-engineering Co., Ltd, Xiamen, PR China
| | - Chao Wei
- Xiamen Amplly Bio-engineering Co., Ltd, Xiamen, PR China
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25
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Franck M, Schütte K, Malfertheiner P, Link A. Prognostic value of serum microRNA-122 in hepatocellular carcinoma is dependent on coexisting clinical and laboratory factors. World J Gastroenterol 2020; 26:86-96. [PMID: 31933516 PMCID: PMC6952302 DOI: 10.3748/wjg.v26.i1.86] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Revised: 12/04/2019] [Accepted: 12/13/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND There is ongoing search for new noninvasive biomarkers to improve management of patients with hepatocellular carcinoma (HCC). Studies, mostly from the Asian-Pacific region, demonstrated differential expression of liver-specific microRNA-122 (miR-122) in tissue as well as in sera of patients with hepatitis B virus- and hepatitis C virus-induced HCC. AIM To evaluate prognostic value of miR-122 in patients with HCC in a European population and determine potential factors related to alteration of miR-122 in sera. METHODS Patients with confirmed HCC (n = 91) were included in the study over a two-year period. Patients were characterized according to Child-Pugh score, Barcelona clinic liver cancer (BCLC) staging system, etiology of liver disease, laboratory parameters and overall survival. MiR-122 was measured in sera using TaqMan assay normalized to spiked-in cel-miR-39. RESULTS Serum miR-122 quantity was independent of the Child-Pugh score, the BCLC stage or the underlying etiology. Significant positive correlation was found between miR-122 and alanine aminotransferase (P < 0.0001), aspartate aminotransferase (P = 0.0001), alpha-fetoprotein (AFP) (P = 0.0034) and hemoglobin concentration (P = 0.076). Negative correlation was observed between miR-122 level and creatinine concentration (P = 0.0028). AFP, Child-Pugh score and BCLC staging system were associated with survival differences. In overall cohort low miR-122 in sera was only associated with a trend for a better overall survival without reaching statistical significance. Subgroup analysis revealed that low miR-122 was significantly associated with better prognosis in patients with advanced cirrhosis (Child-Pugh class B/C), advanced tumor stage (BCLC B/C/D) and normal AFP (< 7 ng/mL). CONCLUSION Our results strongly support the value of miR-122 as potential biomarker of liver injury and probably prognosis. Nevertheless, the value of miR-122 in prediction of prognosis of HCC patients was limited to certain patients' subgroups. Since circulating miR-122 may be influenced by impaired renal function, AFP and hemoglobin concentration, those factors need to be considered while interpreting miR-122 level.
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Affiliation(s)
- Martin Franck
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, Magdeburg 39120, Germany
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover 30625, Germany
| | - Kerstin Schütte
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, Magdeburg 39120, Germany
- Department of Internal Medicine and Gastroenterology, Niels-Stensen-Kliniken Marienhospital, Osnabrück 49074, Germany
| | - Peter Malfertheiner
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, Magdeburg 39120, Germany
| | - Alexander Link
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, Magdeburg 39120, Germany
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26
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Ziogas IA, Sioutas G, Mylonas KS, Tsoulfas G. Role of MicroRNA in the Diagnosis and Management of Hepatocellular Carcinoma. Microrna 2020; 9:25-40. [PMID: 31218966 DOI: 10.2174/2211536608666190619155406] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 03/11/2019] [Accepted: 05/06/2019] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Hepatocellular Carcinoma (HCC) is one of the most common malignant tumors in the world and comes third in cancer-induced mortality. The need for improved and more specific diagnostic methods that can detect early-stage disease is immense, as it is amenable to curative modalities, while advanced HCC is associated with low survival rates. microRNA (miRNA) expression is deregulated in HCC and this can be implemented both diagnostically and therapeutically. OBJECTIVE To provide a concise review on the role of miRNA in diagnosis, prognosis, and treatment of HCC. METHODS We conducted a comprehensive review of the PubMed bibliographic database. RESULTS Multiple miRNAs are involved in the pathogenesis of HCC. Measurement of the levels of these miRNAs either in tumor tissue or in the blood constitutes a promising diagnostic, as well as prognostic tool. OncomiRs are miRNAs that promote tumorigenesis, thus inhibiting them by administering antagomiRs is a promising treatment option. Moreover, replacement of the depleted miRNAs is another potential therapeutic approach for HCC. Modification of miRNA levels may also regulate sensitivity to chemotherapeutic agents. CONCLUSION miRNA play a pivotal role in HCC pathogenesis and once the underlying mechanisms are elucidated, they will become part of everyday clinical practice against HCC.
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Affiliation(s)
- Ioannis A Ziogas
- Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
- Surgery Working Group, Society of Junior Doctors, Athens, Greece
| | - Georgios Sioutas
- Surgery Working Group, Society of Junior Doctors, Athens, Greece
- Medical School, Democritus University of Thrace, Alexandroupolis, Greece
| | - Konstantinos S Mylonas
- Surgery Working Group, Society of Junior Doctors, Athens, Greece
- Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Georgios Tsoulfas
- 1st Department of Surgery, Aristotle University of Thessaloniki, Thessaloniki, Greece
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27
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Kim DJ, Cho EJ, Yu KS, Jang IJ, Yoon JH, Park T, Cho JY. Comprehensive Metabolomic Search for Biomarkers to Differentiate Early Stage Hepatocellular Carcinoma from Cirrhosis. Cancers (Basel) 2019; 11:E1497. [PMID: 31590436 PMCID: PMC6826937 DOI: 10.3390/cancers11101497] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Revised: 10/02/2019] [Accepted: 10/02/2019] [Indexed: 02/06/2023] Open
Abstract
The established biomarker for hepatocellular carcinoma (HCC), serum α-fetoprotein (AFP), has suboptimal performance in early disease stages. This study aimed to develop a metabolite panel to differentiate early-stage HCC from cirrhosis. Cross-sectional metabolomic analyses of serum samples were performed for 53 and 47 patients with early HCC and cirrhosis, respectively, and 50 matched healthy controls. Results were validated in 82 and 80 patients with early HCC and cirrhosis, respectively. To retain a broad spectrum of metabolites, technically distinct analyses (global metabolomic profiling using gas chromatography time-of-flight mass spectrometry and targeted analyses using liquid chromatography with tandem mass spectrometry) were employed. Multivariate analyses classified distinct metabolites; logistic regression was employed to construct a prediction model for HCC diagnosis. Five metabolites (methionine, proline, ornithine, pimelylcarnitine, and octanoylcarnitine) were selected in a panel. The panel distinguished HCC from cirrhosis and normal controls, with an area under the receiver operating curve (AUC) of 0.82; this was significantly better than that of AFP (AUC: 0.75). During validation, the panel demonstrated significantly better predictability (AUC: 0.94) than did AFP (AUC: 0.78). Defects in ammonia recycling, the urea cycle, and amino acid metabolism, demonstrated on enrichment pathway analysis, may reliably distinguish HCC from cirrhosis. Compared with AFP alone, the metabolite panel substantially improved early-stage HCC detection.
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Affiliation(s)
- Da Jung Kim
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul 03080, Korea.
| | - Eun Ju Cho
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea.
| | - Kyung-Sang Yu
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul 03080, Korea.
| | - In-Jin Jang
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul 03080, Korea.
| | - Jung-Hwan Yoon
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea.
| | - Taesung Park
- Department of Statistics, Seoul National University, Seoul 08826, Korea.
| | - Joo-Youn Cho
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul 03080, Korea.
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Zahid KR, Yao S, Khan ARR, Raza U, Gou D. mTOR/HDAC1 Crosstalk Mediated Suppression of ADH1A and ALDH2 Links Alcohol Metabolism to Hepatocellular Carcinoma Onset and Progression in silico. Front Oncol 2019; 9:1000. [PMID: 31637215 PMCID: PMC6787164 DOI: 10.3389/fonc.2019.01000] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Accepted: 09/17/2019] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is ranked the third deadliest cancer worldwide whose molecular pathogenesis is not fully understood. Although deregulated metabolic pathways have been implicated in HCC onset and progression, the mechanisms triggering this metabolic imbalance are yet to be explored. Here, we identified a gene signature coding catabolic enzymes (Cat-GS) involved in key metabolic pathways like amino acid, lipid, carbohydrate, drug, and retinol metabolism as suppressed in HCC. A higher expression of deregulated Cat-GS is associated with good survival and less aggressive disease state in HCC patients. On the other hand, we identified mTOR signaling as a key determinant in HCC onset and progression, whose hyperactivation is found associated with poor survival and aggressive disease state in HCC patients. Next, out of Cat-GS, we established two key regulators of alcohol metabolism, alcohol dehydrogenase 1A (ADH1A) and aldehyde dehydrogenase 2 (ALDH2), as being transcriptionally suppressed by histone deacetylase 1 (HDAC1) at the downstream of mTORC1 signaling. Suppressed ADH1A and ALDH2 expression aligns well with HCC-specific molecular profile and can efficiently predict disease onset and progression, whereas higher ADH1A and ALDH2 expression is associated with good survival and less aggressive disease state in HCC patients. Overall, our in silico findings suggest that transcriptional suppression of alcohol metabolism regulators, ADH1A and ALDH2, at the downstream of mTOR signaling is, in part, responsible for triggering oncogenic transformation of hepatocytes resulting in disease onset and progression in HCC.
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Affiliation(s)
- Kashif Rafiq Zahid
- Shenzhen Key Laboratory of Microbial Genetic Engineering, Vascular Disease Research Center, College of Life Sciences and Oceanography, Provincial Key Laboratory of Regional Immunity and Diseases, Carson International Cancer Center, Shenzhen University, Shenzhen, China.,Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong Province, College of Optoelectronic Engineering Shenzhen University, Shenzhen, China
| | - Shun Yao
- Department of Neurosurgery and Pituitary Tumor Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Abdur Rehman Raza Khan
- Military College of Signals, National University of Science and Technology, Rawalpindi, Pakistan
| | - Umar Raza
- Department of Biological Sciences, National University of Medical Sciences, Rawalpindi, Pakistan
| | - Deming Gou
- Shenzhen Key Laboratory of Microbial Genetic Engineering, Vascular Disease Research Center, College of Life Sciences and Oceanography, Provincial Key Laboratory of Regional Immunity and Diseases, Carson International Cancer Center, Shenzhen University, Shenzhen, China
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29
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Liao X, Yu T, Yang C, Huang K, Wang X, Han C, Huang R, Liu X, Yu L, Zhu G, Su H, Qin W, Deng J, Zeng X, Han B, Han Q, Liu Z, Zhou X, Liu J, Gong Y, Liu Z, Huang J, Lu L, Ye X, Peng T. Comprehensive investigation of key biomarkers and pathways in hepatitis B virus-related hepatocellular carcinoma. J Cancer 2019; 10:5689-5704. [PMID: 31737106 PMCID: PMC6843875 DOI: 10.7150/jca.31287] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Accepted: 06/30/2019] [Indexed: 02/06/2023] Open
Abstract
Objective: Our study is aim to explore potential key biomarkers and pathways in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) using genome-wide expression profile dataset and methods. Methods: Dataset from the GSE14520 is used as the training cohort and The Cancer Genome Atlas dataset as the validation cohort. Differentially expressed genes (DEGs) screening were performed by the limma package. Gene set enrichment analysis (GSEA), weighted gene co-expression network analysis (WGCNA), gene ontology, the Kyoto Encyclopedia of Genes and Genomes, and risk score model were used for pathway and genes identification. Results: GSEA revealed that several pathways and biological processes are associated with hepatocarcinogenesis, such as the cell cycle, DNA repair, and p53 pathway. A total of 160 DEGs were identified. The enriched functions and pathways of the DEGs included toxic substance decomposition and metabolism processes, and the P450 and p53 pathways. Eleven of the DEGs were identified as hub DEGs in the WGCNA. In survival analysis of hub DEGs, high expression of PRC1 and TOP2A were significantly associated with poor clinical outcome of HBV-related HCC, and shown a good performance in HBV-related HCC diagnosis. The prognostic signature consisting of PRC1 and TOP2A also doing well in the prediction of HBV-related HCC prognosis. The diagnostic and prognostic values of PRC1 and TOP2A was confirmed in TCGA HCC patients. Conclusions: Key biomarkers and pathways identified in the present study may enhance the comprehend of the molecular mechanisms underlying hepatocarcinogenesis. Additionally, mRNA expression of PRC1 and TOP2A may serve as potential diagnostic and prognostic biomarkers for HBV-related HCC.
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Affiliation(s)
- Xiwen Liao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Tingdong Yu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Chengkun Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Ketuan Huang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Xiangkun Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Chuangye Han
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Rui Huang
- Department of Hematology, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Xiaoguang Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China.,Department of Hepatobiliary Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, Guangdong Province, China
| | - Long Yu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China.,Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, Henan Province, China
| | - Guangzhi Zhu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Hao Su
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Wei Qin
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Jianlong Deng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China.,Department of Hepatobiliary Surgery, The Sixth Affiliated Hospital of Guangxi Medical University, Yulin, 537000, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Xianmin Zeng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Bowen Han
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Quanfa Han
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Zhengqian Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Xin Zhou
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Junqi Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Yizhen Gong
- Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China.,Department of Evidence-based Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Zhengtao Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China.,Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health and Key Laboratory of Organ Transplantation of Zhejiang Province, Hangzhou, 310003, Zhejiang Province, People's Republic of China.,Science for Life Laboratory, KTH-Royal Institute of Technology, Stockholm, SE-171 21, Sweden
| | - Jianlv Huang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China.,Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Guangxi Medical University, Nanning 530031, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Lei Lu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China.,Department of General Surgery, Beijing Haidian Hospital, Beijing Haidian Section of Peking University Third Hospital, Beijing, 100080, People's Republic of China
| | - Xinping Ye
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Tao Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
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El Mahdy HA, Abdelhamid IA, Amen AI, Abdelsameea E, Hassouna MM. MicroRNA-215 as a Diagnostic Marker in Egyptian Patients with Hepatocellular Carcinoma. Asian Pac J Cancer Prev 2019; 20:2723-2731. [PMID: 31554369 PMCID: PMC6976828 DOI: 10.31557/apjcp.2019.20.9.2723] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2019] [Indexed: 12/15/2022] Open
Abstract
Background: MicroRNAs are mentioned as a small non-coding RNAs groups and aberrant miRNA expression was
found in hepatocellular carcinoma (HCC) patients. Aim: To evaluate role of plasma MicroRNA-215 as a diagnostic
tool in HCC patients. Methods: A prospective study included 195 subjects: healthy controls (group I), cirrhotic patients
(group II), and patients with HCC (group III). Clinical examination, radiological and laboratory investigations which
included quantification of miR-215 by Real-time qPCR were done for all cases. Results: Spearman’s rank correlation
revealed that in HCC group, there was a negative correlation between MiRNA-215 and serum AFP levels and focal size
lesion (cm) (rs = -0.72, - 0.94 respectively, p<0.001). Receiver operating characteristics analysis for discrimination
between cirrhosis and HCC groups regarding microRNA-215 displayed 78.3% sensitivity, 88.0% specificity at cutoff
value of ≤ 1.90. Area under the curve (AUC) was 0.87 (p< 0.001). As regards AFP, it had a sensitivity of 81.7%, a
specificity of 66.7 at cutoff value of ≥ 11.50 (ng/mL). Conclusions: Plasma level of miR-215 may be a promising
biomarker in HCC diagnosis. Moreover, if miR-215 combined with AFP, it can be used as a diagnostic biomarker, for
early detection of HCC.
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Affiliation(s)
| | | | | | - Eman Abdelsameea
- Department of Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Egypt.
| | - Mona M Hassouna
- Department of Clinical pathology, National Liver Institute, Menoufia University, Egypt
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Ramkumar N, Jacobs JP, Berman RB, Parker DM, MacKenzie TA, Likosky DS, DiScipio A, Malenka DJ, Brown JR. Cardiac Biomarkers Predict Long-term Survival After Cardiac Surgery. Ann Thorac Surg 2019; 108:1776-1782. [PMID: 31255614 DOI: 10.1016/j.athoracsur.2019.04.123] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Revised: 04/10/2019] [Accepted: 04/30/2019] [Indexed: 12/20/2022]
Abstract
BACKGROUND Cardiac biomarkers soluble ST-2 (sST-2) and N-terminal prohormone B-type natriuretic peptide (NT-proBNP) may be associated with long-term survival after cardiac surgery. This study explored the relationship between long-term survival after cardiac surgery and serum biomarker levels. METHODS Patients undergoing cardiac surgery from 2004 to 2007 were enrolled in a prospective biomarker cohort in the Northern New England Cardiovascular Disease Study Group Registry. Preoperative serum biomarker levels, postoperative serum biomarker levels, and the change in serum biomarker levels were categorized by quartile. The study used Kaplan-Meier survival analysis and Cox regression models adjusted for variables in the American College of Cardiology Foundation-Society of Thoracic Surgeons Collaboration on the Comparative Effectiveness of Revascularization Strategy (ASCERT) long-term survival calculator to study the association of biomarker levels with long-term survival. After Kaplan-Meier analysis, quartiles 2 and 3 were found to have similar survival and were therefore combined into 1 category. RESULTS In the study cohort (n = 1648), median follow-up time was 8.5 years (interquartile range, 7.6-9.7 years), during which there were 227 deaths. The 10-year survival rate was 86%. Kaplan-Meier survival analysis demonstrated a significant (P < .001) difference across quartiles of each biomarker level measurement. After adjustment, preoperative levels, postoperative levels, and the change in biomarker levels in quartile 4 (highest serum levels or change) were significantly predictive of worse survival (hazard ratio range, 1.77-2.89; all P < .05) compared with quartile 1; however, levels of sST-2 and NT-proBNP in quartiles 2 and 3 demonstrated a nonstatistically significant trend with long-term survival. CONCLUSIONS Elevated preoperative and postoperative levels of sST-2 or NT-proBNP and large changes in these biomarkers' levels are associated with an increased risk of worse survival after cardiac surgery. These biomarkers can be used for risk stratification or assessing postsurgical prognosis.
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Affiliation(s)
- Niveditta Ramkumar
- The Dartmouth Institute for Health Policy and Clinical Practice, Lebanon, New Hampshire
| | - Jeffrey P Jacobs
- Division of Cardiovascular Surgery, Johns Hopkins All Children's Hospital, Tampa, Florida
| | - Richard B Berman
- The Dartmouth Institute for Health Policy and Clinical Practice, Lebanon, New Hampshire
| | - Devin M Parker
- The Dartmouth Institute for Health Policy and Clinical Practice, Lebanon, New Hampshire
| | - Todd A MacKenzie
- The Dartmouth Institute for Health Policy and Clinical Practice, Lebanon, New Hampshire
| | - Donald S Likosky
- Department of Cardiac Surgery, University of Michigan Medical School, Ann Arbor, Michigan
| | - Anthony DiScipio
- Section of Cardiology, Department of Surgery, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire
| | - David J Malenka
- Section of Cardiology, Department of Surgery, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire
| | - Jeremiah R Brown
- The Dartmouth Institute for Health Policy and Clinical Practice, Lebanon, New Hampshire; Department of Epidemiology, Geisel School of Medicine, Hanover, New Hampshire; Department of Biomedical Data Science, Geisel School of Medicine, Hanover, New Hampshire.
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Balaceanu LA. Biomarkers vs imaging in the early detection of hepatocellular carcinoma and prognosis. World J Clin Cases 2019; 7:1367-1382. [PMID: 31363465 PMCID: PMC6656675 DOI: 10.12998/wjcc.v7.i12.1367] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Revised: 04/07/2019] [Accepted: 05/03/2019] [Indexed: 02/05/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the 5th most frequently diagnosed cancer in the world, according to the World Health Organization. The incidence of HCC is between 3/100000 and 78.1/100000, with a high incidence reported in areas with viral hepatitis B and hepatitis C, thus affecting Asia and Africa predominantly. Several international clinical guidelines address HCC diagnosis and are structured according to the geographical area involved. All of these clinical guidelines, however, share a foundation of diagnosis by ultrasound surveillance and contrast imaging techniques, particularly computed tomography, magnetic resonance imaging, and sometimes contrast-enhanced ultrasound. The primary objective of this review was to systematically summarize the recent published studies on the clinical utility of serum biomarkers in the early diagnosis of HCC and for the prognosis of this disease.
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Affiliation(s)
- Lavinia Alice Balaceanu
- Department of Internal Medicine, Carol Davila University of Medicine and Pharmacy, Sf. Ioan Clinical Emergency Hospital, Bucharest 42122, Romania
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33
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Fan S, Tang J, Tian Q, Wu C. A robust fuzzy rule based integrative feature selection strategy for gene expression data in TCGA. BMC Med Genomics 2019; 12:14. [PMID: 30704464 PMCID: PMC6357346 DOI: 10.1186/s12920-018-0451-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Lots of researches have been conducted in the selection of gene signatures that could distinguish the cancer patients from the normal. However, it is still an open question on how to extract the robust gene features. METHODS In this work, a gene signature selection strategy for TCGA data was proposed by integrating the gene expression data, the methylation data and the prior knowledge about cancer biomarkers. Different from the traditional integration method, the expanded 450 K methylation data were applied instead of the original 450 K array data, and the reported biomarkers were weighted in the feature selection. Fuzzy rule based classification method and cross validation strategy were applied in the model construction for performance evaluation. RESULTS Our selected gene features showed prediction accuracy close to 100% in the cross validation with fuzzy rule based classification model on 6 cancers from TCGA. The cross validation performance of our proposed model is similar to other integrative models or RNA-seq only model, while the prediction performance on independent data is obviously better than other 5 models. The gene signatures extracted with our fuzzy rule based integrative feature selection strategy were more robust, and had the potential to get better prediction results. CONCLUSION The results indicated that the integration of expanded methylation data would cover more genes, and had greater capacity to retrieve the signature genes compared with the original 450 K methylation data. Also, the integration of the reported biomarkers was a promising way to improve the performance. PTCHD3 gene was selected as a discriminating gene in 3 out of the 6 cancers, which suggested that it might play important role in the cancer risk and would be worthy for the intensive investigation.
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Affiliation(s)
- Shicai Fan
- School of Automation Engineering, University of Electronic Science and Technology of China, Chengdu, 611731 Sichuan China
- Center for Informational Biology, University of Electronic Science and Technology of China, Chengdu, 611731 Sichuan China
- Key Laboratory of Symbolic Computation and Knowledge Engineering of Ministry of Education, Jilin University, Changchun, 130012 China
| | - Jianxiong Tang
- School of Automation Engineering, University of Electronic Science and Technology of China, Chengdu, 611731 Sichuan China
| | - Qi Tian
- School of Automation Engineering, University of Electronic Science and Technology of China, Chengdu, 611731 Sichuan China
| | - Chunguo Wu
- Key Laboratory of Symbolic Computation and Knowledge Engineering of Ministry of Education, Jilin University, Changchun, 130012 China
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Wu L, Yang Z, Zhang J, Xie H, Zhou L, Zheng S. Long noncoding RNA HOTTIP expression predicts tumor recurrence in hepatocellular carcinoma patients following liver transplantation. Hepatobiliary Surg Nutr 2018; 7:429-439. [PMID: 30652087 DOI: 10.21037/hbsn.2018.10.07] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Background The long noncoding RNA HOTTIP has recently been described as a biomarker of poor prognosis in patients with hepatocellular carcinoma (HCC). Methods In the present study, we evaluated the clinical significance of HOTTIP expression in predicting the rate of tumor recurrence in HCC patients after liver transplantation (LT). We examined the expression pattern and single nucleotide polymorphism (SNP) genotype of HOTTIP in HCC samples from 155 patients underwent LT, and its correlation with clinical parameters and patient prognosis was analyzed. HOTTIP was suppressed using siRNA to explore the role HOTTIP plays in tumor progression. Results The expression level of HOTTIP in cancer tissues was higher than in adjacent noncancerous tissues. Multivariate analyses revealed that HOTTIP expression was an independent prognostic factor for tumor recurrence and lower overall survival times in HCC patients after LT. Patients who beyond the Milan criteria and exhibit decreased HOTTIP expression experienced longer recurrence-free survival and overall survival. HOTTIP rs2071265 is associated with an earlier recurrence in HCC patients. Moreover, the suppression of HOTTIP in liver cancer cell lines reduced cell invasion rates and increased chemosensitivity. Conclusions In summary, the high expression level of HOTTIP in HCC could serve as a candidate biomarker for predicting poor prognosis in HCC patients underwent liver transplant therapy. Furthermore, HOTTIP might be a potential therapeutic target.
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Affiliation(s)
- Liming Wu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.,Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, China.,Jingning National Hospital of the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Zhe Yang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.,Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, China
| | - Jie Zhang
- Department of Hepatobiliary Surgery, First Hospital of Jiaxing, Jiaxing University, Jiaxing 314000, China
| | - Haiyang Xie
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.,Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, China
| | - Lin Zhou
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.,Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, China
| | - Shusen Zheng
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.,Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, China
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Zhu Y, Zhu J, Lu C, Zhang Q, Xie W, Sun P, Dong X, Yue L, Sun Y, Yi X, Zhu T, Ruan G, Aebersold R, Huang S, Guo T. Identification of Protein Abundance Changes in Hepatocellular Carcinoma Tissues Using PCT-SWATH. Proteomics Clin Appl 2018; 13:e1700179. [PMID: 30365225 DOI: 10.1002/prca.201700179] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Revised: 10/16/2018] [Indexed: 12/16/2022]
Abstract
PURPOSE To rapidly identify protein abundance changes in biopsy-level fresh-frozen hepatocellular carcinoma (HCC). EXPERIMENTAL DESIGN The pressure-cycling technology (PCT) is applied and sequential window acquisition of all theoretical mass spectra (SWATH-MS) workflow is optimized to analyze 38 biopsy-level tissue samples from 19 HCC patients. Each proteome is analyzed with 45 min LC gradient. MCM7 is validated using immunohistochemistry (IHC). RESULTS A total of 11 787 proteotypic peptides from 2579 SwissProt proteins are quantified with high confidence. The coefficient of variation (CV) of peptide yield using PCT is 32.9%, and the R2 of peptide quantification is 0.9729. Five hundred forty-one proteins showed significant abundance change between the tumor area and its adjacent benign area. From 24 upregulated pathways and 13 suppressed ones, enhanced biomolecule synthesis and suppressed small molecular metabolism in liver tumor tissues are observed. Protein changes based on α-fetoprotein expression and hepatitis B virus infection are further analyzed. The data altogether highlight 16 promising tumor marker candidates. The upregulation of minichromosome maintenance complex component 7 (MCM7) is further observed in multiple HCC tumor tissues by IHC. CONCLUSIONS AND CLINICAL RELEVANCE The practicality of rapid proteomic analysis of biopsy-level fresh-frozen HCC tissue samples with PCT-SWATH has been demonstrated and promising tumor marker candidates including MCM7 are identified.
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Affiliation(s)
- Yi Zhu
- Westlake Institute for Advanced Study, Westlake University, Hangzhou, Zhejiang, P. R. China.,Department of Biology, Institute of Molecular Systems Biology, Eidgenössische Technische Hochschule (ETH) Zurich, Zurich, Switzerland
| | - Jiang Zhu
- Center for Stem Cell Research and Application, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P. R. China
| | - Cong Lu
- Center for Stem Cell Research and Application, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P. R. China
| | - Qiushi Zhang
- Westlake Institute for Advanced Study, Westlake University, Hangzhou, Zhejiang, P. R. China
| | - Wei Xie
- Center for Stem Cell Research and Application, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P. R. China
| | - Ping Sun
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P. R. China
| | - Xiaochuan Dong
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P. R. China
| | - Liang Yue
- Westlake Institute for Advanced Study, Westlake University, Hangzhou, Zhejiang, P. R. China
| | - Yaoting Sun
- Westlake Institute for Advanced Study, Westlake University, Hangzhou, Zhejiang, P. R. China
| | - Xiao Yi
- Westlake Institute for Advanced Study, Westlake University, Hangzhou, Zhejiang, P. R. China
| | - Tiansheng Zhu
- Westlake Institute for Advanced Study, Westlake University, Hangzhou, Zhejiang, P. R. China
| | - Guan Ruan
- Westlake Institute for Advanced Study, Westlake University, Hangzhou, Zhejiang, P. R. China
| | - Ruedi Aebersold
- Department of Biology, Institute of Molecular Systems Biology, Eidgenössische Technische Hochschule (ETH) Zurich, Zurich, Switzerland.,Faculty of Science, University of Zürich, Zürich, Switzerland
| | - Shi'ang Huang
- Center for Stem Cell Research and Application, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P. R. China
| | - Tiannan Guo
- Westlake Institute for Advanced Study, Westlake University, Hangzhou, Zhejiang, P. R. China.,Department of Biology, Institute of Molecular Systems Biology, Eidgenössische Technische Hochschule (ETH) Zurich, Zurich, Switzerland
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Novel tumor suppressor SPRYD4 inhibits tumor progression in hepatocellular carcinoma by inducing apoptotic cell death. Cell Oncol (Dordr) 2018; 42:55-66. [PMID: 30238408 DOI: 10.1007/s13402-018-0407-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/29/2018] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-associated deaths worldwide. Although recent studies have proposed different biomarkers for HCC progression and therapy resistance, a better understanding of the molecular mechanisms underlying HCC progression and recurrence, as well as the identification of molecular markers with a higher diagnostic accuracy, are necessary for the development of more effective clinical management strategies. Here, we aimed to identify novel players in HCC progression. METHODS SPRYD4 mRNA and protein expression analyses were carried out on a normal liver-derived cell line (HL-7702) and four HCC-derived cell lines (HepG2, SMMC7721, Huh-7, BEL-7402) using qRT-PCR and Western blotting, respectively. Cell proliferation Cell Counting Kit-8 (CCK-8) assays, protein expression analyses for apoptosis markers using Western blotting, and Caspase-Glo 3/7 apoptosis assays were carried out on the four HCC-derived cell lines. Expression comparison, functional annotation, gene set enrichment, correlation and survival analyses were carried out on patient data retrieved from the NCBI Gene module, the NCBI GEO database and the TCGA database. RESULTS Through a meta-analysis we found that the expression of SPRYD4 was downregulated in primary HCC tissues compared to non-tumor tissues. We also found that the expression of SPRYD4 was downregulated in HCC-derived cells compared to normal liver-derived cells. Subsequently, we found that the expression of SPRYD4 was inversely correlated with a gene signature associated with HCC cell proliferation. Exogenous SPRYD4 expression was found to inhibit HCC cell proliferation by inducing apoptotic cell death. We also found that SPRYD4 expression was associated with a good prognosis and that its expression became downregulated when HCCs progressed towards more aggressive stages and higher grades. Finally, we found that SPRYD4 expression may serve as a biomarker for a good overall and relapse-free survival in HCC patients. CONCLUSIONS Our data indicate that a decreased SPRYD4 expression may serve as an independent predictor for a poor prognosis in patients with HCC and that increased SPRYD4 expression may reduce HCC growth and progression through the induction of apoptotic cell death, thereby providing a potential therapeutic target.
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Lubecka K, Flower K, Beetch M, Qiu J, Kurzava L, Buvala H, Ruhayel A, Gawrieh S, Liangpunsakul S, Gonzalez T, McCabe G, Chalasani N, Flanagan JM, Stefanska B. Loci-specific differences in blood DNA methylation in HBV-negative populations at risk for hepatocellular carcinoma development. Epigenetics 2018; 13:605-626. [PMID: 29927686 PMCID: PMC6140905 DOI: 10.1080/15592294.2018.1481706] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Accepted: 05/15/2018] [Indexed: 12/31/2022] Open
Abstract
Late onset of clinical symptoms in hepatocellular carcinoma (HCC) results in late diagnosis and poor disease outcome. Approximately 85% of individuals with HCC have underlying liver cirrhosis. However, not all cirrhotic patients develop cancer. Reliable tools that would distinguish cirrhotic patients who will develop cancer from those who will not are urgently needed. We used the Illumina HumanMethylation450 BeadChip microarray to test whether white blood cell DNA, an easily accessible source of DNA, exhibits site-specific changes in DNA methylation in blood of diagnosed HCC patients (post-diagnostic, 24 cases, 24 controls) and in prospectively collected blood specimens of HCC patients who were cancer-free at blood collection (pre-diagnostic, 21 cases, 21 controls). Out of 22 differentially methylated loci selected for validation by pyrosequencing, 19 loci with neighbouring CpG sites (probes) were confirmed in the pre-diagnostic study group and subjected to verification in a prospective cirrhotic cohort (13 cases, 23 controls). We established for the first time 9 probes that could distinguish HBV-negative cirrhotic patients who subsequently developed HCC from those who stayed cancer-free. These probes were identified within regulatory regions of BARD1, MAGEB3, BRUNOL5, FXYD6, TET1, TSPAN5, DPPA5, KIAA1210, and LSP1. Methylation levels within DPPA5, KIAA1210, and LSP1 were higher in prospective samples from HCC cases vs. cirrhotic controls. The remaining probes were hypomethylated in cases compared with controls. Using blood as a minimally invasive material and pyrosequencing as a straightforward quantitative method, the established probes have potential to be developed into a routine clinical test after validation in larger cohorts.
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Affiliation(s)
- Katarzyna Lubecka
- Department of Nutrition Science, Purdue University, West Lafayette, IN, USA
| | - Kirsty Flower
- Division of Cancer, Department of Surgery and Cancer, Imperial College London, London, UK
| | - Megan Beetch
- Food, Nutrition and Health, Faculty of Land and Food Systems, The University of British Columbia, Vancouver, BC, Canada
| | - Jay Qiu
- Department of Nutrition Science, Purdue University, West Lafayette, IN, USA
| | - Lucinda Kurzava
- Department of Nutrition Science, Purdue University, West Lafayette, IN, USA
| | - Hannah Buvala
- Department of Nutrition Science, Purdue University, West Lafayette, IN, USA
| | - Adam Ruhayel
- Department of Nutrition Science, Purdue University, West Lafayette, IN, USA
| | - Samer Gawrieh
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Tracy Gonzalez
- Department of Statistics, Purdue University, West Lafayette, IN, USA
| | - George McCabe
- Department of Statistics, Purdue University, West Lafayette, IN, USA
| | - Naga Chalasani
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - James M Flanagan
- Division of Cancer, Department of Surgery and Cancer, Imperial College London, London, UK
| | - Barbara Stefanska
- Department of Nutrition Science, Purdue University, West Lafayette, IN, USA
- Food, Nutrition and Health, Faculty of Land and Food Systems, The University of British Columbia, Vancouver, BC, Canada
- Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN, USA
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38
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Caviglia GP, Ribaldone DG, Abate ML, Ciancio A, Pellicano R, Smedile A, Saracco GM. Performance of protein induced by vitamin K absence or antagonist-II assessed by chemiluminescence enzyme immunoassay for hepatocellular carcinoma detection: a meta-analysis. Scand J Gastroenterol 2018; 53:734-740. [PMID: 29667463 DOI: 10.1080/00365521.2018.1459824] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2017] [Revised: 03/22/2018] [Accepted: 03/26/2018] [Indexed: 02/04/2023]
Abstract
OBJECTIVES In the setting of surveillance for hepatocellular carcinoma (HCC) detection, the use of serum biomarkers in addition to ultrasonography (US) is still a matter of debate. Hence, we performed a meta-analysis to evaluate the diagnostic accuracy of protein induced by vitamin K absence or antagonist-II (PIVKA-II) and alpha-fetoprotein (AFP) alone or in combination for HCC detection in patients at risk of tumor development. MATERIALS AND METHODS We performed a systematic search in PubMed and Scopus database for original articles published in English from 2011 to 2017, investigating the accuracy of PIVKA-II alone or in combination with AFP (reported as area under the curve [AUC]) for HCC detection among patients at risk of tumor development. Furthermore, we focused on studies in which serum PIVKA-II was assessed by highly sensitive chemiluminescence immunoassay (CLEIA). RESULTS A total of 11 studies (873 patients with HCC and 1244 patients with advanced liver disease/cirrhosis) were included in the meta-analysis. The weighted summary AUC (sAUC) of PIVKA-II and AFP for the discrimination between patients with HCC and those without was 0.791 (0.746-0.837) and 0.767 (0.732-0.803), respectively. The combination of PIVKA-II + AFP results in a sAUC of 0.859 (0.837-0.882). The performance for HCC detection of PIVKA-II + AFP was significantly superior to each biomarker used alone (ΔsAUC = 0.068, p = .032 and ΔsAUC = 0.092, p < .001, respectively). CONCLUSION In clinical practice, the use of PIVKA-II + AFP in addition to US examination may improve the effectiveness of surveillance among patients at risk for HCC development.
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Affiliation(s)
| | | | | | - Alessia Ciancio
- a Department of Medical Sciences , University of Turin , Turin , Italy
| | - Rinaldo Pellicano
- b Unit of Gastroenterology and Hepatology , Città della Salute e della Scienza, Molinette Hospital , Turin , Italy
| | - Antonina Smedile
- a Department of Medical Sciences , University of Turin , Turin , Italy
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Wu L, Yang F, Lin B, Chen X, Yin S, Zhang F, Xie H, Zhou L, Zheng S. MicroRNA-424 expression predicts tumor recurrence in patients with hepatocellular carcinoma following liver transplantation. Oncol Lett 2018; 15:9126-9132. [PMID: 29805644 PMCID: PMC5958633 DOI: 10.3892/ol.2018.8539] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2015] [Accepted: 10/20/2017] [Indexed: 12/15/2022] Open
Abstract
MicroRNA-424 (miR-424) has previously been described as a biomarker of poor prognosis in patients with hepatocellular carcinoma (HCC). In the present study, the clinical significance of miR-424 expression in predicting the rate of tumor recurrence in patients with HCC following liver transplantation (LT) was evaluated. miR-424 expression in HCC samples from 121 patients undergoing LT was examined, and the associations between clinical parameters and patient tumor recurrence were evaluated. The miR-424 expression level in cancer tissues was low compared with that in adjacent noncancerous tissues. Multivariate analyses revealed that low miR-424 expression was an independent prognostic factor for tumor recurrence in patients with HCC following liver transplantation. Patients who no longer met the Milan criteria and had decreased miR-424 expression levels exhibited earlier tumor recurrence following LT. In addition, the upregulation of miR-424 expression significantly reduced the migration, invasion and proliferation of HCC cells. Similarly, the downregulation of miR-424 in HCC cells significantly promoted the migration, invasion and proliferation of HCC cells.
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Affiliation(s)
- Liming Wu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, P.R. China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Ningbo, Zhejiang 315100, P.R. China.,Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Ningbo, Zhejiang 315100, P.R. China
| | - Feibiao Yang
- Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Ningbo, Zhejiang 315100, P.R. China.,Department of Hepatobiliary Surgery, Yinzhou People's Hospital of Ningbo City, Ningbo, Zhejiang 315100, P.R. China
| | - Bingyi Lin
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Ningbo, Zhejiang 315100, P.R. China.,Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Ningbo, Zhejiang 315100, P.R. China
| | - Xinhua Chen
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Ningbo, Zhejiang 315100, P.R. China.,Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Ningbo, Zhejiang 315100, P.R. China
| | - Shengyong Yin
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, P.R. China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Ningbo, Zhejiang 315100, P.R. China
| | - Feng Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, P.R. China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Ningbo, Zhejiang 315100, P.R. China
| | - Haiyang Xie
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, P.R. China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Ningbo, Zhejiang 315100, P.R. China
| | - Lin Zhou
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, P.R. China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Ningbo, Zhejiang 315100, P.R. China
| | - Shusen Zheng
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, P.R. China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Ningbo, Zhejiang 315100, P.R. China.,Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Ningbo, Zhejiang 315100, P.R. China
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Ma X, Cui Y, Zhou H, Li Q. Function of mitochondrial pyruvate carriers in hepatocellular carcinoma patients. Oncol Lett 2018; 15:9110-9116. [PMID: 29805642 PMCID: PMC5958719 DOI: 10.3892/ol.2018.8466] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2016] [Accepted: 07/09/2017] [Indexed: 12/13/2022] Open
Abstract
Mitochondrial pyruvate carriers (MPC) have been identified as a critical component of energy metabolism in the cancer cells of multiple malignant tumor types. The aim of the present study was to investigate the association between the expression of MPC1 and MPC2 and the prognosis of patients with hepatocellular carcinoma (HCC). A total of 85 formalin-fixed paraffin-embedded HCC tissues were assessed using immunohistochemistry. A further 20 fresh pathological specimens, including cancer and adjacent normal liver tissues from patients who had undergone a hepatectomy, were analyzed using western blotting and reverse transcription-quantitative polymerase chain reaction. The relative expression of MPC1 and MPC2 was quantified using Image-Pro Plus software, and the association between MPC expression and clinical outcomes was analyzed by Student's t-test. MPC1 and MPC2 protein expression was significantly downregulated in HCC, but no association was identified between the expression of MPC1 or MPC2 and the clinicopathological characteristics of the patients. MPC1 mRNA levels were decreased in each cancer sample, while a mixture of increased and decreased MPC2 mRNA levels observed in the HCC samples. Multivariate regression analysis indicated that the protein level and the microvascular invasion of MPC1 were positively associated with the recurrence of HCC (P=0.000 and P=0.017, respectively). MPC1 may therefore serve as an attractive biomarker for the identification of patients with HCC at a high risk of recurrence following curative resection.
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Affiliation(s)
- Xiangming Ma
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin 300060, P.R. China
| | - Yunlong Cui
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin 300060, P.R. China
| | - Hongyuan Zhou
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin 300060, P.R. China
| | - Qiang Li
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin 300060, P.R. China
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41
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Lv Z, Tao Y, Cai X, Zhou X, Li Y. Cluster of specified microRNAs in tissues and serum as biomarkers for early diagnosis of hepatocellular carcinoma. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2018; 11:990-997. [PMID: 31938193 PMCID: PMC6958011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 11/23/2017] [Accepted: 01/08/2018] [Indexed: 06/10/2023]
Abstract
OBJECTIVE Hepatocellular carcinoma (HCC) is a global public health concern that lacks efficient methods for early diagnosis. Accumulated evidence has revealed great potential using microRNAs (miRNAs) as noninvasive biomarkers in HCC detection. METHODS Serum miRNAs (miR21, miR122, miR-214, miR15b, and let-7f) were detected in 75 patients with HCC and 80 healthy controls (HC). In addition, 75 HCC tissues and paired normal adjacent tissues were also analyzed for comparison. Quantified by real-time quantitative RT-PCR was used to evaluate the expression of miRNAs. RESULTS We discovered significant up-regulation of miR-21 (P < 0.001) and miR-15b (P < 0.001) as well as a down-regulation of miR-122 (P = 0.01) in HCC tissues compared to adjacent non-tumor tissues. Additionally, miR-21 (P < 0.001) and miR-15b (P < 0.001) levels were upregulated in serum and miR-214 (P = 0.01) was decreased in HCC patients compared to that in healthy controls. Multivariate logistic regression analysis showed that serum miR-21 (OR = 1.68, P = 0.012) and miR-15b (OR = 1.736, P = 0.012) were independently associated with HCC whereas miR-214 (OR = 0.631, P = 0.006) was associated with a decreased risk of HCC. When we employed miR-(21 + 122 + 15b) classifier as biomarkers, we could discriminate HCC tissues from adjacent non-tumor tissues with an AUC of 0.885 (specificity: 89.7%; sensitivity: 73.1%). In serum, the cluster of miR-(21 + 214 + 15b) classifier (AUC = 0.887) had a sensitivity of 80.3% and a specificity of 87.0% for HCC diagnosis. CONCLUSION Our results suggest that these serum miRNAs may be useful markers for discriminating HCC patients from healthy controls. Combined determination of circulating miR-21, miR-122, miR-214, and miR-15b has great potential to serve as an accurate and noninvasive biomarker for the early HCC preliminary screening.
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Affiliation(s)
- Zhihua Lv
- Department of Clinical Laboratory, Rennin Hospital of Wuhan UniversityWuhan 430060, Hubei, China
| | - Yu Tao
- Department of Nephrology, Renmin Hospital of Wuhan UniversityWuhan 430060, Hubei, China
| | - Xuan Cai
- Department of Clinical Laboratory, Rennin Hospital of Wuhan UniversityWuhan 430060, Hubei, China
| | - Xin Zhou
- Department of Clinical Laboratory Medicine and Center for Gene Diagnosis, Zhongnan Hospital of Wuhan UniversityWuhan 430071, Hubei, China
| | - Yan Li
- Department of Clinical Laboratory, Rennin Hospital of Wuhan UniversityWuhan 430060, Hubei, China
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Kwok GT, Zhao JT, Weiss J, Mugridge N, Brahmbhatt H, MacDiarmid JA, Robinson BG, Sidhu SB. Translational applications of microRNAs in cancer, and therapeutic implications. Noncoding RNA Res 2017; 2:143-150. [PMID: 30159433 PMCID: PMC6084838 DOI: 10.1016/j.ncrna.2017.12.002] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Revised: 12/11/2017] [Accepted: 12/11/2017] [Indexed: 12/19/2022] Open
Abstract
The search for targeted novel therapies for cancer is ongoing. MicroRNAs (miRNAs) display a number of characteristics making them an attractive and realisable option. In this review, we explore these applications, ranging from diagnostics, prognostics, disease surveillance, to being a primary therapy or a tool to sensitise patients to treatment modalities such as chemotherapy and radiotherapy. We take a particular perspective towards miRNAs and their impact on rare cancers. Advancement in the delivery of miRNAs, from viral vectors and liposomal delivery to nanoparticle based, has led to a number of pre-clinical and clinical applications for microRNA cancer therapeutics. This is promising, especially in the setting of rare cancers.
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Affiliation(s)
- Grace T. Kwok
- Cancer Genetics Laboratory, Kolling Institute of Medical Research, St Leonards, 2065 NSW, Australia
- Northern Clinical School, Royal North Shore Hospital and University of Sydney, St Leonards, 2065 Sydney, NSW, Australia
- University of Sydney Endocrine Surgery Unit, Royal North Shore Hospital, St Leonards, 2065 Sydney, NSW, Australia
| | - Jing Ting Zhao
- Cancer Genetics Laboratory, Kolling Institute of Medical Research, St Leonards, 2065 NSW, Australia
- Northern Clinical School, Royal North Shore Hospital and University of Sydney, St Leonards, 2065 Sydney, NSW, Australia
| | - Jocelyn Weiss
- EnGeneIC Pty Ltd, Lane Cove West, 2066 NSW, Australia
| | | | | | | | - Bruce G. Robinson
- Cancer Genetics Laboratory, Kolling Institute of Medical Research, St Leonards, 2065 NSW, Australia
- Northern Clinical School, Royal North Shore Hospital and University of Sydney, St Leonards, 2065 Sydney, NSW, Australia
| | - Stan B. Sidhu
- Cancer Genetics Laboratory, Kolling Institute of Medical Research, St Leonards, 2065 NSW, Australia
- Northern Clinical School, Royal North Shore Hospital and University of Sydney, St Leonards, 2065 Sydney, NSW, Australia
- University of Sydney Endocrine Surgery Unit, Royal North Shore Hospital, St Leonards, 2065 Sydney, NSW, Australia
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43
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Hu T, Li J, Zhang C, lv X, Li S, He S, Yan H, Tan Y, Lei M, Wen M, Zuo J. The potential value of microRNA-4463 in the prognosis evaluation in hepatocellular carcinoma. Genes Dis 2017; 4:116-122. [PMID: 30258914 PMCID: PMC6136594 DOI: 10.1016/j.gendis.2017.03.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2016] [Accepted: 03/06/2017] [Indexed: 02/08/2023] Open
Abstract
The purpose of this study is to measure the expression of microRNA-4463 and microRNA-6087 between normal persons and patients with hepatocellular carcinoma (HCC), and to clarify the meaning of them in the prognosis evaluation in HCC. Forty-five samples from healthy people and patients, who had been diagnosed with hepatocellular carcinoma before any treatment, were collected to study respectively. Real-time PCR was used to detect the expression of miRNA-4463 and miRNA-6087 in the serum of control group and hepatocellular carcinoma patients. The expression of miR-4463 in the serum of HCC patients was significantly higher than that in control group (P < 0.05), and the expression level was independent of gender, tumor size, cell types, stages, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL) and HBsAg status (P > 0.05). But there was a significant difference of different level of AFP in HCC (P < 0.05), and the difference between the group of AFP lower than 400 ug/l and the control group is statistically significant (P < 0.05). Besides, the survival time had showed a significant difference at the high and low expression levels (P < 0.05). But the expression level of miRNA-6087 was no difference in HCC and control group. The disorder of miRNA-4463 occurred in HCC, even the AFP level doesn't rises. What's more, patients who get the high level of miRNA-4463 seem to have a shorter survival time. And it contributes great to the prognostic evaluation. This is the first study to illustrate the potential significance of miRNA-4463 in the prognosis in HCC.
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Affiliation(s)
- Tian Hu
- The Affiliated Nanhua Hospital, University of South China, Hengyang, Hunan, 421001, China
- School of Medicine, University of South China, Hengyang, Hunan, 421001, China
| | - Jincheng Li
- Medical School, Shaoyang University, Shaoyang, Hunan, 422000, China
| | - Chuhong Zhang
- The Affiliated Nanhua Hospital, University of South China, Hengyang, Hunan, 421001, China
| | - Xiu lv
- The Affiliated Nanhua Hospital, University of South China, Hengyang, Hunan, 421001, China
| | - Sai Li
- The Affiliated Nanhua Hospital, University of South China, Hengyang, Hunan, 421001, China
| | - Sha He
- The Affiliated Nanhua Hospital, University of South China, Hengyang, Hunan, 421001, China
| | - Hanxing Yan
- The Affiliated Nanhua Hospital, University of South China, Hengyang, Hunan, 421001, China
| | - Yixi Tan
- The Affiliated Nanhua Hospital, University of South China, Hengyang, Hunan, 421001, China
| | - Mingsheng Lei
- Department of Respiratory and Critical Care Medicine, Zhangjiajie City Hospital, Zhangjiajie, Hunan, 427000, China
| | - Meiling Wen
- The Affiliated Nanhua Hospital, University of South China, Hengyang, Hunan, 421001, China
| | - Jianhong Zuo
- The Affiliated Nanhua Hospital, University of South China, Hengyang, Hunan, 421001, China
- School of Medicine, University of South China, Hengyang, Hunan, 421001, China
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44
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Tunissiolli NM, Castanhole-Nunes MMU, Biselli-Chicote PM, Pavarino ÉC, da Silva RF, da Silva RDCMA, Goloni-Bertollo EM. Hepatocellular Carcinoma: a Comprehensive Review of
Biomarkers, Clinical Aspects, and Therapy. Asian Pac J Cancer Prev 2017; 18:863-872. [PMID: 28545181 PMCID: PMC5494234 DOI: 10.22034/apjcp.2017.18.4.863] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a cause of several deaths related to cancer worldwidely. In early stage, curative treatments such as surgical resection, liver transplant and local ablation can improve the patient ´s survival. However, the disease is detected in advanced stage; moreover some available therapies are restricted to palliative care and local treatment. Early detections of HCC and adequate therapy are crucial to increase survival as well as to improve the patient´s quality of life. Therefore, researchers have been investigating molecular biomarkers with high sensibility and reliability as Golgi 73 protein (GP73), Glypican-3 (GPC3), Osteopontin (OPN), microRNAs and others. MicroRNAs can regulate important pathways on carcinogenesis, as tumor angiogenesis and progression. So, they can be considered as possible markers of prognosis in HCC, and therapeutic target for this tumor type. In this review, we discuss the recent advances related to the cause (highlighting the main risk factors), treatment, biomarkers, clinic aspects, and outcome in hepatocellular carcinoma.
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Affiliation(s)
- Nathalia Martines Tunissiolli
- Research Unit of Genetics and Molecular Biology (UPGEM), São José do Rio Preto Medical School (FAMERP), São José do Rio Preto- SP, Brazil
- Liver Tumors Study Group (GETF),São Jose do Rio Preto Medical
School (FAMERP), Sao Jose do Rio Preto- SP, Brazil.
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45
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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.
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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
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46
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Zou CD, Zhao WM, Wang XN, Li Q, Huang H, Cheng WP, Jin JF, Zhang H, Wu MJ, Tai S, Zou CX, Gao X. MicroRNA-107: a novel promoter of tumor progression that targets the CPEB3/EGFR axis in human hepatocellular carcinoma. Oncotarget 2016; 7:266-78. [PMID: 26497556 PMCID: PMC4807997 DOI: 10.18632/oncotarget.5689] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2015] [Accepted: 10/06/2015] [Indexed: 01/05/2023] Open
Abstract
MicroRNAs (miRNAs) are dysregulated in many types of malignancies, including human hepatocellular carcinoma (HCC). MiR-107 has been implicated in several types of cancer regulation; however, relatively little is known about miR-107 in human HCC. In the present study, we showed that the overexpression of miR-107 accelerates the tumor progression of HCC in vitro and in vivo through its new target gene, CPEB3. Furthermore, our results demonstrated that CPEB3 is a newly discovered tumor suppressor that acts via the EGFR pathway. Therefore, our study demonstrates that the newly discovered miR-107/CPEB3/EGFR axis plays an important role in HCC progression and might represent a new potential therapeutic target for HCC treatment.
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Affiliation(s)
- Chen-Dan Zou
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China
| | - Wei-Ming Zhao
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China
| | - Xiao-Na Wang
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China
| | - Qiang Li
- Department of General Surgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Hui Huang
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China
| | - Wan-Peng Cheng
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China
| | - Jian-Feng Jin
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China
| | - He Zhang
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China
| | - Ming-Juan Wu
- Academy of Traditional Chinese Medicines, Harbin, China
| | - Sheng Tai
- Department of General Surgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Chao-Xia Zou
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China
| | - Xu Gao
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China.,Heilongjiang Academy of Medical Science, Harbin, China
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Zhang X, Lu Y, Rong C, Yang D, Li S, Qin X. Role of superoxide dismutase in hepatitis B virus-related hepatocellular carcinoma. JOURNAL OF RESEARCH IN MEDICAL SCIENCES 2016; 21:94. [PMID: 28163740 PMCID: PMC5244649 DOI: 10.4103/1735-1995.192510] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/02/2015] [Revised: 01/03/2016] [Accepted: 06/22/2016] [Indexed: 12/25/2022]
Abstract
Background: Reactive oxygen species (ROS) play important roles in hepatocarcinogenesis. Superoxide dismutase (SOD) is involved in the repair of ROS. Serum alpha-fetoprotein (AFP) is the “golden marker” for diagnosing hepatocellular carcinoma (HCC), and one major shortcoming of its use is that it is insensitive for the early detection of HCC. Therefore, we evaluated serum SOD levels and their association with AFP in hepatitis B virus (HBV)-related HCC. Materials and Methods: A total of 279 subjects were divided into three groups: 99 HBV patients with HCC, 73 HBV patients without HCC, and 107 sex- and age-matched healthy controls. Serum levels of SOD were assayed using colorimetry, while AFP levels were measured by electrochemiluminescence immunoassay. Results: A highly significant elevation was found in AFP in HBV-with HCC patients compared to HBV-without HCC patients and control subjects (P < 0.001). Alternatively, serum SOD levels were significantly decreased in patients with HCC compared to HBV patients without HCC and healthy controls (P < 0.001). Furthermore, serum SOD was negatively correlated with AFP (r = −0.505, P < 0.001) in HBV-with HCC patients. Conclusion: SOD and AFP might be simultaneously evaluated to improve the HCC detection rate.
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Affiliation(s)
- Xiaolian Zhang
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Yu Lu
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Chengzhi Rong
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Dongmei Yang
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Shan Li
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Xue Qin
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
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Chávez-López MDG, Zúñiga-García V, Pérez-Carreón JI, Avalos-Fuentes A, Escobar Y, Camacho J. Eag1 channels as potential early-stage biomarkers of hepatocellular carcinoma. Biologics 2016; 10:139-148. [PMID: 27703327 PMCID: PMC5036561 DOI: 10.2147/btt.s87402] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Hepatocellular carcinoma (HCC) is a major cause of cancer death worldwide. HCC is usually asymptomatic at potential curative stages, and it has very poor prognosis if detected later. Thus, the identification of early biomarkers and novel therapies is essential to improve HCC patient survival. Ion channels have been proposed as potential tumor markers and therapeutic targets for several cancers including HCC. Especially, the ether à-go-go-1 (Eag1) voltage-gated potassium channel has been suggested as an early marker for HCC. Eag1 is overexpressed during HCC development from the cirrhotic and the preneoplastic lesions preceding HCC in a rat model. The channel is also overexpressed in human HCC. Astemizole has gained great interest as a potential anticancer drug because it targets several proteins involved in cancer including Eag1. Actually, in vivo studies have shown that astemizole may have clinical utility for HCC prevention and treatment. Here, we will review first some general aspects of HCC including the current biomarkers and therapies, and then we will focus on Eag1 channels as promising tools in the early diagnosis of HCC.
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Affiliation(s)
| | - Violeta Zúñiga-García
- Department of Pharmacology, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional
| | | | - Arturo Avalos-Fuentes
- Department of Physiology, Biophysics and Neuroscience, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional
| | - Yesenia Escobar
- Centro de Investigación Clínica Acelerada Sc, Mexico City, Mexico
| | - Javier Camacho
- Department of Pharmacology, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional
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49
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Ma XP, Yu G, Chen X, Xiao Q, Shi Z, Zhang LY, Chen H, Zhang P, Ding DL, Huang HX, Saiyin H, Chen TY, Lu PX, Wang NJ, Yu H, Conran C, Sun J, Zheng SL, Xu J, Yu L, Jiang DK. MiR-608 rs4919510 is associated with prognosis of hepatocellular carcinoma. Tumour Biol 2016; 37:9931-9942. [PMID: 26815502 DOI: 10.1007/s13277-016-4897-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2015] [Accepted: 01/20/2016] [Indexed: 12/18/2022] Open
Abstract
Single nucleotide polymorphisms (SNPs) within microRNAs (miRNAs) are considered potential markers for risk and prognosis of various cancers. In the current study, we aimed to determine whether miR-608 rs4919510 affected hepatocellular carcinoma (HCC) prognosis. We genotyped rs4919510 using DNA from blood samples of 362 HCC patients receiving surgical resection of HCC tumor. Associations between rs4919510 and overall survival (OS) and demographic characteristics and clinical features were estimated using the Cox proportional hazards model. Results showed that HCC patients who carried the rs4919510 CC genotype had a significantly longer OS compared to those who carried the GG genotype (P = 0.013, hazard ratio [HR] = 0.600, 95 % confidence interval [CI] 0.402-0.897) and the CG + GG genotype (P = 0.033, HR = 0.681, 95 % CI 0.479-0.970) in univariate analysis. Similar results were obtained in multivariate analysis. Further stratification analysis indicated that rs4919510 was significantly associated with OS in patients who were satisfied with one of the following criteria: male gender, HbsAg-positive, α-fetoprotein (AFP)-positive, tumor size >5 cm, cirrhosis, solitary tumor, I + II pTNM stage, or no tumor capsule. Finally, a significantly higher frequency of rs4919510 CC genotype was observed in patients with cirrhosis (22.9 %, 55/240) than those without cirrhosis (14.0 %, 17/121) (P = 0.047). In conclusion, our results illustrated the potential role of miR-608 rs4919510 as a prognostic marker for HCC patients undergoing surgical resection of the tumor.
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Affiliation(s)
- Xiao-Pin Ma
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, 2005 Songhu Rd., Shanghai, 200438, China
| | - Guopeng Yu
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, 2005 Songhu Rd., Shanghai, 200438, China
- Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China
- Center for genetic Epidemiology, School of Life Sciences, Fudan University, Shanghai, China
- Center for Genetic Translational Medicine and Prevention, School of Public Health, Fudan University, Shanghai, China
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
- Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Xubo Chen
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, 2005 Songhu Rd., Shanghai, 200438, China
| | - Qianyi Xiao
- Center for Genetic Translational Medicine and Prevention, School of Public Health, Fudan University, Shanghai, China
| | - Zhuqing Shi
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, 2005 Songhu Rd., Shanghai, 200438, China
- Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China
- Center for genetic Epidemiology, School of Life Sciences, Fudan University, Shanghai, China
- Center for Genetic Translational Medicine and Prevention, School of Public Health, Fudan University, Shanghai, China
| | - Lu-Yao Zhang
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, 2005 Songhu Rd., Shanghai, 200438, China
| | - Haitao Chen
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, 2005 Songhu Rd., Shanghai, 200438, China
- Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China
- Center for genetic Epidemiology, School of Life Sciences, Fudan University, Shanghai, China
- Center for Genetic Translational Medicine and Prevention, School of Public Health, Fudan University, Shanghai, China
| | - Pengyin Zhang
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, 2005 Songhu Rd., Shanghai, 200438, China
- Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China
- Center for genetic Epidemiology, School of Life Sciences, Fudan University, Shanghai, China
- Center for Genetic Translational Medicine and Prevention, School of Public Health, Fudan University, Shanghai, China
| | - Dong-Lin Ding
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, 2005 Songhu Rd., Shanghai, 200438, China
| | - Hui-Xing Huang
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, 2005 Songhu Rd., Shanghai, 200438, China
| | - Hexige Saiyin
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, 2005 Songhu Rd., Shanghai, 200438, China
| | - Tao-Yang Chen
- Qidong Liver Cancer Institute, Qidong People's Hospital, Qidong, Jiangsu, China
| | - Pei-Xin Lu
- Qidong Liver Cancer Institute, Qidong People's Hospital, Qidong, Jiangsu, China
| | - Neng-Jin Wang
- Qidong Liver Cancer Institute, Qidong People's Hospital, Qidong, Jiangsu, China
| | - Hongjie Yu
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, 2005 Songhu Rd., Shanghai, 200438, China
- Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China
- Center for genetic Epidemiology, School of Life Sciences, Fudan University, Shanghai, China
- Center for Genetic Translational Medicine and Prevention, School of Public Health, Fudan University, Shanghai, China
| | - Carly Conran
- Center for Genomic Cancer Research, NorthShore University HealthSystem, Evanston, IL, USA
| | - Jielin Sun
- Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - S Lilly Zheng
- Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, NC, USA
- Center for Genomic Cancer Research, NorthShore University HealthSystem, Evanston, IL, USA
| | - Jianfeng Xu
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, 2005 Songhu Rd., Shanghai, 200438, China
- Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China
- Center for genetic Epidemiology, School of Life Sciences, Fudan University, Shanghai, China
- Center for Genetic Translational Medicine and Prevention, School of Public Health, Fudan University, Shanghai, China
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Center for Genomic Cancer Research, NorthShore University HealthSystem, Evanston, IL, USA
| | - Long Yu
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, 2005 Songhu Rd., Shanghai, 200438, China
- Institute of Biomedical Science, Fudan University, Shanghai, China
| | - De-Ke Jiang
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, 2005 Songhu Rd., Shanghai, 200438, China.
- Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China.
- Center for genetic Epidemiology, School of Life Sciences, Fudan University, Shanghai, China.
- Center for Genetic Translational Medicine and Prevention, School of Public Health, Fudan University, Shanghai, China.
- Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
- Center for Genomic Cancer Research, NorthShore University HealthSystem, Evanston, IL, USA.
- Pritzker School of Medicine, University of Chicago, Chicago, IL, USA.
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50
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Angileri F, Morrow G, Scoazec JY, Gadot N, Roy V, Huang S, Wu T, Tanguay RM. Identification of circulating microRNAs during the liver neoplastic process in a murine model of hereditary tyrosinemia type 1. Sci Rep 2016; 6:27464. [PMID: 27282650 PMCID: PMC4901289 DOI: 10.1038/srep27464] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2015] [Accepted: 05/17/2016] [Indexed: 12/21/2022] Open
Abstract
Hereditary tyrosinemia type 1 (HT1) is a severe inborn error of metabolism, impacting the tyrosine catabolic pathway with a high incidence of hepatocellular carcinoma (HCC). Using a HT1 murine model, we investigated the changes in profiles of circulating and hepatic miRNAs. The aim was to determine if plasma miRNAs could be used as non-invasive markers of liver damage in HT1 progression. Plasma and liver miRNAome was determined by deep sequencing after HT1 phenotype was induced. Sequencing analysis revealed deregulation of several miRNAs including let-7/miR-98 family, miR-21 and miR-148a, during manifestation of liver pathology. Three miRNAs (miR-98, miR-200b, miR-409) presenting the highest plasmatic variations among miRNAs found in both plasma and liver and with >1000 reads in at least one plasma sample, were further validated by RT-qPCR. Two of these miRNAs have protein targets involved in HT1 and significant changes in their circulating levels are detectable prior an increase in protein expression of alpha-fetoprotein, the current biomarker for HCC diagnosis. Future assessment of these miRNAs in HT1 patients and their association with liver neoplastic lesions might designate these molecules as potential biomarkers for monitoring HT1 damage progression, improving diagnosis for early HCC detection and the design of novel therapeutic targets.
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Affiliation(s)
- Francesca Angileri
- Laboratoire de génétique cellulaire et développementale, IBIS and PROTEO, Département de biologie moléculaire, biochimie médicale et pathologie, Faculté de médecine, 1030 avenue de la Médecine, Université Laval, Québec, Canada, G1V 0A6.,Dept of Occupational and Environmental Health and Key Laboratory of Environment and Health, Ministry of Education and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Geneviève Morrow
- Laboratoire de génétique cellulaire et développementale, IBIS and PROTEO, Département de biologie moléculaire, biochimie médicale et pathologie, Faculté de médecine, 1030 avenue de la Médecine, Université Laval, Québec, Canada, G1V 0A6
| | - Jean-Yves Scoazec
- Anipath, Faculté Laennec, rue Guillaume Paradin, 69372 Lyon Cedex 08, France
| | - Nicolas Gadot
- Anipath, Faculté Laennec, rue Guillaume Paradin, 69372 Lyon Cedex 08, France
| | - Vincent Roy
- Laboratoire de génétique cellulaire et développementale, IBIS and PROTEO, Département de biologie moléculaire, biochimie médicale et pathologie, Faculté de médecine, 1030 avenue de la Médecine, Université Laval, Québec, Canada, G1V 0A6
| | - Suli Huang
- Dept of Occupational and Environmental Health and Key Laboratory of Environment and Health, Ministry of Education and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.,Key Laboratory of Molecular Biology of Shenzhen, Center for Disease Control and Prevention, Shenzhen, 518055, Guangdong, China
| | - Tangchun Wu
- Dept of Occupational and Environmental Health and Key Laboratory of Environment and Health, Ministry of Education and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Robert M Tanguay
- Laboratoire de génétique cellulaire et développementale, IBIS and PROTEO, Département de biologie moléculaire, biochimie médicale et pathologie, Faculté de médecine, 1030 avenue de la Médecine, Université Laval, Québec, Canada, G1V 0A6
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