Biomarkers for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) ranks high among the most common and fatal cancers in the world. HCC develops from chronic liver diseases, especially from hepatitis C virus-related and hepatitis B virus (HBV)-related liver diseases. In this sense, useful biomarkers for HCC detection for the patients at risk of HCC are quite important. Recently, new therapies for HCC have been developed, and the prognosis of the patients has improved. However, considering the recurrence rate of HCC after treatment is very high, biomarkers that detect recurrence at an early stage are also required. In addition, since new drugs such as multikinase inhibitors have been introduced to the clinical scene, surrogate biomarkers to predict the effectiveness of treatment will be required in the near future. So far, many biomarkers for HCC have been developed, and their clinical usefulness has been assessed. As a result, several biomarkers for HCC are widely used. However, investigations to discover more useful biomarkers that fit in clinical settings are under way. In this review article, biomarkers for HCC are overviewed to examine their clinical usefulness.     

蛋白芯片技术对肝细胞癌组织蛋白谱的建立及标志蛋白的筛选

目的:应用表面增强激光解吸附电离飞行时间质谱技术(SELDI-TOF-MS)对肝细胞癌组织的蛋白表达谱进行分析,从中筛选出标记蛋白.方法:采用CM10芯片及SELDI-TOF-MS技术对肝细胞癌组织26例和肝硬化组织18例进行蛋白指纹图谱检测分析;比较高、中、低分化肝细胞癌组织,不同TNM分期肿瘤以及AFP阴、阳性肝细胞癌组织的蛋白表达差异,所得结果均采用Biomarker Wizard软件进行分析;通过查询蛋白库,对特定分子质量所对应的标记蛋白进行初步确定.结果:肝细胞癌和肝硬化组织蛋白表达图谱之间存在16个稳定的标志蛋白,7个蛋白在肝细胞癌组织中表达上调.9个蛋白在肝细胞癌组织中表达下调,其中4.7 kDa,7.2 kDa和9.8 kDa蛋白峰差异性最明显;中分化和高分化肝细胞癌之间存在11个标志蛋白;通过查询蛋白库ExPasy并进行筛选,初步确定特定分子质量所对应的蛋白.结论:采用SELDI-TOF-MS技术,证实在肝细胞癌组织中存在多种高度特异性低分子蛋白.     

Glycogen storage disease type III-hepatocellular carcinoma a long-term complication?

BACKGROUND/AIMS: Glycogen storage disease III (GSD III) is caused by a deficiency of glycogen-debranching enzyme which causes an incomplete glycogenolysis resulting in glycogen accumulation with abnormal structure (short outer chains resembling limit dextrin) in liver and muscle. Hepatic involvement is considered mild, self-limiting and improves with age. With increased survival, a few cases of liver cirrhosis and hepatocellular carcinoma (HCC) have been reported. METHODS: A systematic review of 45 cases of GSD III at our center (20 months to 67 years of age) was reviewed for HCC, 2 patients were identified. A literature review of HCC in GSD III was performed and findings compared to our patients. CONCLUSIONS: GSD III patients are at risk for developing HCC. Cirrhosis was present in all cases and appears to be responsible for HCC transformation There are no reliable biomarkers to monitor for HCC in GSD III. Systematic evaluation of liver disease needs be continued in all patients, despite lack of symptoms. Development of guidelines to allow for systematic review and microarray studies are needed to better delineate the etiology of the hepatocellular carcinoma in patients with GSD III.     

MicroRNA-29a and MicroRNA-124 as novel biomarkers for hepatocellular carcinoma

BackgroundNumerous microRNAs (miRNAs) have been observed to be abnormally expressed in cancer. Therefore, miRNA signatures could be potential noninvasive diagnostic and prognostic biomarkers for hepatocellular carcinoma (HCC).AimsTo correlate miRNA-29a and miRNA-124 expression levels with the clinical features and survival rates of HCC patients.MethodsSerum miRNA expression in 150 samples (50 patients with HCC, 50 patients with liver cirrhosis, and 50 healthy controls) were quantified using real-time qRT-PCR.ResultsThe expression levels of serum miRNA-29a were higher and the levels of miRNA-124 were lower in patients with HCC than in patients with liver cirrhosis and controls. ROC curve analysis showed promising accuracy for both miRNAs in distinguishing patients with HCC from those with liver cirrhosis. Levels of miRNA-29a were related to tumor number, size, stage, and outcome, whereas levels of miRNA-124 were related to vascular invasion. The overall survival rate of patients with low miRNA-29a expression was significantly higher than that of patients with high expression. Additionally, the multivariate analysis identified miRNA-29a as an independent prognostic variable.ConclusionsThe investigated miRNAs showed acceptable accuracy in the diagnosis of HCC; therefore, both could be utilized as diagnostic biomarkers. Additionally, miRNA-29a could be used as a prognostic biomarker.     

Hepatocellular Carcinoma in Non-alcoholic Fatty Liver Disease: Epidemiology,Pathogenesis, and Prevention

Hepatocellular cancer (HCC) is the fifth most prevalent cancer worldwide and the third leading cause of cancer-related deaths. Non-alcoholic fatty liver disease (NAFLD), a spectrum of hepatic disorders associated with obesity and the metabolic syndrome, is a recognized risk factor for HCC. NAFLD that is advanced to cirrhosis carries the highest risk for HCC, but there is increasing concern that NAFLD-associated HCC may also occur in non-cirrhotic liver. As NAFLD is rapidly becoming the most common liver condition, it has been implicated in the worrisome trend of rising HCC incidence in a number of countries, which may offset successful measures in reducing the effect of virus-related liver cancer. Independently or in synergy with cirrhosis, NAFLD may provide a special oncogenic microenvironment through its pathogenic association with chronic nutrient excess and adipose tissue remodeling, characterized by pro-inflammatory adipokine profiles, lipotoxicity, altered hepatocellular bioenergetics, and insulin resistance. Better understanding of this complex process, and development of reliable biomarkers for HCC will be critical for early recognition and risk prediction. Moreover, correcting deranged lipid metabolism and restoring insulin sensitivity by lifestyle measures and targeted pharmacotherapy holds major promise for effective prevention of NAFLD-associated HCC.     

代谢组学在肝细胞癌标志物研究中的应用

代谢组学技术作为一种新的组学研究手段,能够揭示肝细胞癌(HCC)发生发展过程中的代谢谱差异,成为HCC生物标志物研究的热点。简述了代谢组学在HCC诊断中的意义,概括了HCC相关的生物标志物的代谢组学研究,这些研究主要以血清、尿液及肝组织代谢物为对象,通过动物实验和临床研究两个方面进行。指出分析和监视HCC发生发展过程中相应代谢物的变化,对于患者的个体化治疗具有重要价值。     

Validation of a serum microRNA panel as biomarkers for early diagnosis of hepatocellular carcinoma post-hepatitis C infection in Egyptian patients

AIM To investigate the prospective importance of serum micro(mi)RNAs(mi R-125 b, mi R-138 b, mi R-1269, mi R-214-5p, mi R-494, mi R375 and mi R-145) as early biomarkers for the diagnosis of hepatitis C virus(HCV)-related hepatocellular carcinoma(HCC).METHODS Two-hundred and fifty HCV4 a patients, 224 HCV4 aHCC patients, and 84 healthy controls were enrolled in the study. Expression levels of mi R214-5p, mi R-125 b, mi R-1269 and mi R-375 were quantified using quantitative real-time PCR.RESULTS Expression of the selected mi RNAs in serum wassignificantly lower in HCC patients than in the healthy controls, except for mi R-1269 and mi R-494. There was a significant difference between HCC and HCV patients, in particular for HCC and late stage fibrosis, rather than HCV patients and early fibrosis. It is obvious that mi R-1269 was significantly upregulated in HCC cases compared to hepatic fibrosis cases. Each mi RNA can show HCC progression. Multivariate logistic regression analysis indicated that the tested panel of mi RNAs(mi R214-5p, mi R-125 b, mi R-1269 and mi R-375) represent accurate and specific indictors of HCC development.CONCLUSION This study presents a panel of mi RNAs with strong power as putative diagnostic and prognostic biomarkers for HCV-induced HCC. Moreover, mi R-214-5p and mi R-1269 could be considered as early biomarkers for tracking the progress of liver fibrosis to HCC.     

Metabolomics: From liver chiromancy to personalized precision medicine in advanced chronic liver disease

Currently there is a lack of accurate biomarkers for diagnosis and prognosis in advanced liver diseases. Either the occurrence of first decompensation, or diagnosis of acute on chronic liver failure, severe alcoholic hepatitis, or hepatocellular carcinoma(HCC), none of the available biomarkers are satisfactory. Metabolomics is the newest of omics, being much closer than the others to the actual phenotype and pathologic changes that characterizes a certain condition. It deals with a much wider spectrum of low molecular weight bio-compounds providing a powerful platform for discovering novel biomarkers and biochemical pathways to improve diagnostic, prognostication and therapy. Until now metabolomics was applied in a wide spectrum of liver conditions, but the findings were contradictory. This review proposes a synthesis of the existing evidences of metabolomics use in advanced chronic liver diseases, decompensated liver cirrhosis, severe alcoholic hepatitis and HCC.     

Hepatocellular carcinoma: Review of disease and tumor biomarkers

Hepatocellular carcinoma(HCC) is a common malignancy and now the second commonest global cause of cancer death. HCC tumorigenesis is relatively silent and patients experience late symptomatic presentation. As the option for curative treatments is limited to early stage cancers, diagnosis in non-symptomatic individuals is crucial. International guidelines advise regular surveillance of high-risk populations but the current tools lack sufficient sensitivity for early stage tumors on the background of a cirrhotic nodular liver. A number of novel biomarkers have now been suggested in the literature, which may reinforce the current surveillance methods. In addition, recent metabonomic and proteomic discoveries have established specific metabolite expressions in HCC, according to Warburg's phenomenon of altered energy metabolism. With clinical validation, a simple and non-invasive test from the serum or urine may be performed to diagnose HCC, particularly benefiting low resource regions where the burden of HCC is highest.     

Human microbiome is a diagnostic biomarker in hepatocellular carcinoma

Background:Hepatocellular carcinoma(HCC)is the third leading cause of cancer mortality worldwide.Increasing evidence indicates a close relationship between HCC and the human microbiota.Herein,we reviewed the important potential of the human microbiota as a diagnostic biomarker of HCC.Data sources:Several innovative studies have investigated the characteristics of the gut and oral micro-biomes in patients with HCC and proposed that the human microbiome has the potential to be a diag-nostic biomarker of HCC.Literature from February 1999 to February 2019 was searched in the PubMed database using the keywords"microbiota"or"microbiome"or"microbe"and"liver cancer"or"hepato-cellular carcinoma",and the results of clinical and experimental studies were analyzed.Results:Specific changes occur in the human microbiome of patients with HCC.Moreover,the gut mi-crobiome and oral microbiome can be used as non-invasive diagnostic biomarkers for HCC.Furthermore,they also have certain diagnostic potential for precancerous diseases of HCC.The diagnostic potential of the blood microbiota and ascites microbiota in HCC will be gradually discovered in the future.Conclusions:The human microbiome is valuable to the diagnosis of HCC and provides a novel strategy for targeted therapy of HCC.The human microbiome may be widely used in the diagnosis,treatment and prognosis for multiple system diseases or cancers in the future.     

Clinical applications of squamous cell carcinoma antigenimmunoglobulins M to monitor chronic hepatitis C

Hepatitis C virus(HCV) is the main cause of chronic liver disease and cirrhosis in Western countries. Over time, the majority of cirrhotic patients develop hepatocellular carcinoma(HCC), one of the most common fatal cancers worldwide- fourth for incidence rate. A high public health priority need is the development of biomarkers to screen for liver disease progression and for early diagnosis of HCC development, particularly in the high risk population represented by HCV-positive patients with cirrhosis. Several studies have shown that serological determination of a novel biomarker, squamous cell carcinoma antigen-immunoglobulins M(SCCA-Ig M), might be useful to identify patients with progressive liver disease. In the initial part of this review we summarize the main clinical studies that have investigated this new circulating biomarker on HCV-infected patients, providing evidence that in chronic hepatitis C SCCA-Ig M may be used to monitor progression of liver disease, and also to assess the virological response to antiviral treatment. In the last part of this review we address other, not less important, clinical applications of this biomarker in hepatology.     

Emerging biomolecules for practical theranostics of liver hepatocellular carcinoma

Most cases of hepatocellular carcinoma (HCC) are able to be diagnosed through regular surveillance in an identifiable patient population with chronic hepatitis B or cirrhosis. Nevertheless, 50% of global cases might present incidentally owing to symptomatic advanced-stage HCC after worsening of liver dysfunction. A systematic search based on PUBMED was performed to identify relevant outcomes, covering newer surveillance modalities including secretory proteins, DNA methylation, miRNAs, and genome sequencing analysis which proposed molecular expression signatures as ideal tools in the early-stage HCC detection. In the face of low accuracy without harmonization on the analytical approaches and data interpretation for liquid biopsy, a more accurate incidence of HCC will be unveiled by using deep machine learning system and multiplex immunohistochemistry analysis. A combination of molecular-secretory biomarkers, high-definition imaging and bedside clinical indexes in a surveillance setting offers a comprehensive range of HCC potential indicators. In addition, the sequential use of numerous lines of systemic anti-HCC therapies will simultaneously benefit more patients in survival. This review provides an overview on the most recent developments in HCC theranostic platform.     

challenges of advanced hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is an aggressive malignancy,resulting as the third cause of death by cancer each year. The management of patients with HCC is complex,as both the tumour stage and any underlying liver disease must be considered conjointly. Although surveillance by imaging,clinical and biochemical parameters is routinely performed,a lot of patients suffering from cirrhosis have an advanced stage HCC at the first diagnosis. Advanced stage HCC includes heterogeneous groups of patients with different clinical condition and radiological features and sorafenib is the only approved treatment according to Barcelona Clinic Liver Cancer. Since the introduction of sorafenib in clinical practice,several phase Ⅲ clinical trials have failed to demonstrate any superiority over sorafenib in the frontline setting. Locoregional therapies have also been tested as first line treatment,but their role in advanced HCC is still matter of debate. No single agent or combination therapies have been shown to impact outcomes after sorafenib failure. Therefore this review will focus on the range of experimental therapeutics for patients with advanced HCC and highlights the successes and failures of these treatments as well as areas for future development. Specifics such as dose limiting toxicity and safety profile in patients with liver dysfunction related to the underlying chronic liver disease should be considered when developing therapies in HCC. Finally,robust validated and reproducible surrogate end-points as well as predictive biomarkers should be defined in future randomized trials.     

Hepatocellular carcinoma in a cirrhotic liver becoming detectable within a month

A case of hepatocellular carcinoma (HCC) in a cirrhotic liver which became detectable within a month is reported here. The patient was admitted for treatment of oesophageal varices due to Child's C grade liver cirrhosis. A hepatic angiogram was performed before the treatment and showed no neovasculature. After undergoing variceal treatment by injection sclerotherapy, the patient underwent another angiogram 28 days later in order to measure the efficacy of the treatment. The second angiogram revealed the emergence of small multiple neovasculatures throughout the entire liver. From the angiographic findings, those tumours were considered to be HCC. The present report suggests that small HCC latent in a cirrhotic liver can thus acquire neovasculature within a short period of time.     

Liver transplantation as a management of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and has a poor prognosis if untreated. It is ranked the third among the causes of cancer-related death. There are multiple etiologic factors that can lead to HCC. Screening for early HCC is challenging due to the lack of well specific biomarkers. However, early diagnosis through successful screening is very important to provide cure rate. Liver transplantation (LT) did not gain wide acceptance until the mid-1980s, after the effective immunosuppression with cyclosporine became available. Orthotopic LT is the best therapeutic option for early, unresectable HCC. It is limited by both, graft shortage and the need for appropriate patient selection. It provides both, the removal of tumor and the remaining cirrhotic liver. In Milan, a prospective cohort study defined restrictive selection criteria known as Milan criteria (MC) that led to superior survival for transplant patients in comparison with any other previous experience with transplantation or other options for HCC. When transplantation occurs within the established MC, the outcomes are similar to those for nonmalignant liver disease after transplantation. The shortage of organs from deceased donors has led to the problems of long waiting times and dropouts. This has led to the adoption of extended criteria by many centers. Several measures have been taken to solve these problems including prioritization of patients with HCC, use of pretransplant adjuvant treatment, and living donor LT.