甲胎蛋白在肝癌的诊断和治疗中的研究进展

肝细胞癌(Hepatocellular carcinoma,HCC)是致死率第3的恶性肿瘤,也是全球第5大常见癌症。肝癌在临床上的治疗手段非常有限,患者的总生存率也很低。因此,肝癌的早期诊断和治疗对于患者总生存率有着重要的影响。甲胎蛋白(Alpha-fetoprotein,AFP)是最早发现也是目前应用最广泛的肝癌标志物之一。目前,多项研究表明,作为一个特异性的癌基因,AFP在肝癌的发生、发展、诊断和治疗中有巨大的研究价值。文中简述了AFP在肝癌发生发展中的分子调控机制以及在肝癌细胞逃避免疫监视中的作用,着重阐述AFP作为重要的肝癌靶标分子在肝癌的临床诊断和治疗研究中的应用。     

The underlying pathophysiology association between the Type 2-diabetic and hepatocellular carcinoma

Type 2-diabetic (T2D) disease has been reported to increase the incidence of liver cancer, however, the underlying pathophysiology is still not fully understood. Here, we aimed to reveal the underlying pathophysiology association between the T2D and hepatocellular carcinoma (HCC) and, therefore, to find the possible therapeutic targets in the occurrence and development of HCC. The methylation microarray data of T2D and HCC were extracted from the Gene Expression Omnibus and The Cancer Genome Atlas. A total of 504 differentially methylated genes (DMGs) between T2D samples and the controls were identified, whereas 6269 DMGs were identified between HCC samples and the control groups. There were 336 DMGs coexisting in diabetes and HCC, among which 86 genes were comethylated genes. These genes were mostly enriched in pathways as glycosaminoglycan biosynthesis, fatty acid, and metabolic pathway as glycosaminoglycan degradation and thiamine, fructose and mannose. There were 250 DMGs that had differential methylation direction between T2D DMGs and HCC DMGs, and these genes were enriched in the Sphingolipid metabolism pathway and immune pathways through natural killer cell-mediated cytotoxicity and ak-STAT signaling pathway. Eight genes were found related to the occurrence and development of diabetes and HCC. Moreover, the result of protein-protein interaction network showed that CDKN1A gene was related to the prognosis of HCC. In summary, eight genes were found to be associated with the development of HCC and CDKN1A may serve as the potential prognostic gene for HCC.     

Role of toll-like receptors gene polymorphism in hepatocellular carcinoma

Abstract

Toll-like receptors (TLRs), evolutionarily conserved innate, play important roles in the development of autoimmunity. TLRs proteins are localized on the cell surface or in endosomes and play critical roles in innate immune responses against different pathogens. Aberrant stimulation of the innate immune system through intracellular TLRs may lead to hyperactive immune responses and contribute to the pathogenesis of hepatocellular carcinoma (HCC). HCC is the seventh most common cancer and the third leading cause of cancer deaths worldwide, and innate immune takes a most important role in HCC. There was no review to sum up the role of TLRs gene polymorphism in HCC. This review was performed to sum up the role of TLRs gene polymorphism in HCC.     

Myasthenia gravis: pathophysiology,diagnosis, differential diagnosis and management

Myasthenia gravis is an autoimmune disorder caused by impaired synaptic transmission at the neuromuscular junction. The characteristic signs and symptoms of this disease manifest as increasing muscle fatigue. This article reviews myasthenia gravis with an emphasis on the pathophysiology, systemic and ocular manifestations, diagnostic testing, and management of this disease.     

血色病的临床与基础研究进展

遗传性血色病（Hereditary Hemochromatosis,HH）是一种西方常见的遗传性铁过载性疾病。目前已知的血色病基因主要包括剧硒、YfR2、HJV、FPN及HAMP。这些基因突变导致大量铁离子逐渐沉积在肝、心、胰腺等脏器的实质细胞,造成组织纤维化和结构改变,最终引起器官功能障碍和衰竭,常见症状有肝硬化、肝癌、糖尿病、心力衰竭、垂体及性腺功能减退、关节疾病和皮肤色素沉着等。当前,机体铁代谢分子机制研究的飞速发展,为深入了解血色病带来了契机。综合铁代谢研究领域最新进展,着重对血色病发展历程、发病机制、临床表现、诊断、治疗及中国血色病现状等方面展开综述。     

Fine needle aspiration biopsy of hepatocellular carcinoma and hepatocellular nodular lesions: role,controversies and approach to diagnosis

A. Wee
Fine needle aspiration biopsy of hepatocellular carcinoma and hepatocellular nodular lesions: role, controversies and appr oach to diagnosis The role of fine needle aspiration (FNA) biopsy of the liver has evolved. Advances in imaging modalities have obviated the need for tissue confirmation in clinically classic hepatocellular carcinoma (HCC). The risks of needle tract seeding and haematogenous dissemination have been actively debated. Nowadays, cytopathologists are confronted by smaller and smaller nodules, detected due to increased surveillance of high‐risk cirrhotic patients. Tissue characterization of small well‐differentiated hepatocellular nodular lesions (size less than and equal to 2 cm) is extremely challenging and has therapeutic implications. Major issues in the cytodiagnosis of HCC include: (i) distinguishing benign hepatocellular nodular lesions, namely, large regenerative nodules, dysplastic nodules, focal nodular hyperplasia and hepatocellular adenoma from reactive hepatocytes; (ii) distinguishing well‐differentiated HCC from benign hepatocellular nodular lesions; (iii) distinguishing poorly differentiated HCC from intrahepatic cholangiocarcinoma and metastatic carcinomas; (iv) determining the histogenesis of a malignant tumour; and (v) determining the site of origin of a malignant tumour. An overview of the biological evolution and histopathological aspects of dysplastic nodules, small HCCs and ‘nodule‐in‐nodule’ lesions is presented in tandem with clinically relevant nomenclature. An algorithmic approach to FNA diagnosis of HCC and hepatocellular nodular lesions is outlined. Optimal results depend on (i) a dedicated radiologist‐cytopathologist team; (ii) an on‐site cytology service, (iii) a combined cytohistological approach, (iv) immunohistochemistry, and (v) clinicopathological correlation. As we move towards personalized medicine, it is envisaged that hepatic FNA is likely to become a point of care in the management protocol as it takes on the additional role of procurement of tumour and peritumoural tissues for genomic and proteomic profiling to enable targeted molecular therapy.     

Role of fibrogenic markers in chronic hepatitis C and associated hepatocellular carcinoma

Detection and follow up of fibrogenesis in chronic hepatitis C (CHC) is mandatory for early treatment and risk stratification. The current study included 120 patients with CHC, of whom 30 had liver cirrhosis (LC) and 30 had hepatocellular carcinoma (HCC). 15 wedge liver biopsies, taken during laparoscopic cholecystectomy, were included as normal controls. Cases were subjected to laboratory investigations, serologic markers for viral hepatitis and assessment of circulating levels of hyaluronic acid (HA) and platelet-derived growth factor (PDGF). Immunohistochemical expression of connective tissue growth factor (CTGF), PDGF and transforming growth factor-β1 (TGF-β1) was also carried out. A significant increase (p < 0.01) in serum HA was noticed in CHC, LC and HCC compared to controls. Although, a significant decrease in serum PDGF was detected in CHC and LC compared to controls, HCC values were comparable. A significant up-regulation of CTGF was detected in CHC, LC and HCC (p < 0.01) in contrast to its limited mild expression in normal livers. Intense PDGF positive staining was noticed in CHC, LC and HCC compared to scattered faint expression in controls. The significant expression and marked intensity of PDGF staining matched the progress to tumorigenesis. A positive TGF-β1 immunostaining was also noticed in CHC, LC and HCC. An intense and extensive cytoplasmic expression of TGF-β1 was encountered in patients with LC revealing that CTGF, PDGF and TGF-β1 act synergistically in LC. Data revealed that HA and CTGF may be implicated as important diagnostic parameters for assessment of hepatic fibrosis and PDGF for monitoring malignant transformation in CHC.     

A systems biology-based classifier for hepatocellular carcinoma diagnosis

Aim

The diagnosis of hepatocellular carcinoma (HCC) in the early stage is crucial to the application of curative treatments which are the only hope for increasing the life expectancy of patients. Recently, several large-scale studies have shed light on this problem through analysis of gene expression profiles to identify markers correlated with HCC progression. However, those marker sets shared few genes in common and were poorly validated using independent data. Therefore, we developed a systems biology based classifier by combining the differential gene expression with topological features of human protein interaction networks to enhance the ability of HCC diagnosis.

Methods and Results

In the Oncomine platform, genes differentially expressed in HCC tissues relative to their corresponding normal tissues were filtered by a corrected Q value cut-off and Concept filters. The identified genes that are common to different microarray datasets were chosen as the candidate markers. Then, their networks were analyzed by GeneGO Meta-Core software and the hub genes were chosen. After that, an HCC diagnostic classifier was constructed by Partial Least Squares modeling based on the microarray gene expression data of the hub genes. Validations of diagnostic performance showed that this classifier had high predictive accuracy (85.88∼92.71%) and area under ROC curve (approximating 1.0), and that the network topological features integrated into this classifier contribute greatly to improving the predictive performance. Furthermore, it has been demonstrated that this modeling strategy is not only applicable to HCC, but also to other cancers.

Conclusion

Our analysis suggests that the systems biology-based classifier that combines the differential gene expression and topological features of human protein interaction network may enhance the diagnostic performance of HCC classifier.     

Role of cadherin-17 in oncogenesis and potential therapeutic implications in hepatocellular carcinoma

Cadherin is an important cell adhesion molecule that plays paramount roles in organ development and the maintenance of tissue integrity. Dysregulation of cadherin expression is often associated with disease pathology including tissue dysplasia, tumor formation, and metastasis. Cadherin-17 (CDH17), belonging to a subclass of 7D-cadherin superfamily, is present in fetal liver and gastrointestinal tract during embryogenesis, but the gene becomes silenced in healthy adult liver and stomach tissues. It functions as a peptide transporter and a cell adhesion molecule to maintain tissue integrity in epithelia. However, recent findings from our group and others have reported aberrant expression of CDH17 in major gastrointestinal malignancies including hepatocellular carcinoma (HCC), stomach and colorectal cancers, and its clinical association with tumor metastasis and advanced tumor stages. Furthermore, alternative splice isoforms and genetic polymorphisms of CDH17 gene have been identified in HCC and linked to an increased risk of HCC. CDH17 is an attractive target for HCC therapy. Targeting CDH17 in HCC can inhibit tumor growth and inactivate Wnt signaling pathway in concomitance with activation of tumor suppressor genes. Further investigation on CDH17-mediated oncogenic signaling and cognate molecular mechanisms would shed light on new targeting therapy on HCC and potentially other gastrointestinal malignancies.     

Role of growth factor receptor bound protein 7 in hepatocellular carcinoma

The human growth factor receptor-bound protein 7 (Grb7) is an adaptor molecule and is related to cell invasion. In this present study, we investigated the clinical and biological significance of Grb7 expression in human hepatocellular carcinoma (HCC). We reviewed 64 consecutive patients who had undergone liver resection for HCC, and we investigated the correlation between Grb7 expression and clinical outcome. To analyze the biological behavior of Grb7 in vitro and in vivo, we established Grb7 stable knockdown HCC cells using RNA interference technology. The positive staining of Grb7 protein was correlated with portal venous invasion (P < 0.01), hepatic venous invasion (P < 0.01), and intrahepatic metastasis (P < 0.05). Positive expression of Grb7 was significantly correlated with focal adhesion kinase (FAK) protein levels in HCC (P < 0.01). The Grb7- and FAK-positive group showed a significantly poorer prognosis as compared with the Grb7- and FAK-negative group (P < 0.05). Grb7 knockdown HCC cells exhibited significantly lower levels of invasion potential (P < 0.05) and motility (P < 0.05) than the control cells in vitro; moreover, Grb7 knockdown HCC cells showed delayed onset of the tumors compared with the control cells in vivo. Grb7 expression can modulate the invasive phenotype of HCC. Grb7 plays an important role in HCC progression and is strongly associated with expression of FAK. Grb7 could be a therapeutic target in HCC.     

Carbohydrate-based measurements on alpha-fetoprotein in the early diagnosis of hepatocellular carcinoma

Serum alpha-fetoprotein (AFP) is a useful marker for the diagnosis of hepatocellular carcinoma (HCC), although this protein also increases moderately in benign liver diseases. The serum concentration of AFP in HCC at the time of initial diagnosis is now lower than before because of advancements in techniques for imaging the liver. The AFP concentration alone cannot distinguish between HCC and benign liver diseases, especially when it is less than 1000 ng ml^–1. These circumstances lead to the need to discriminate between these diseases. This has been achieved by determining the carbohydrate structures of AFP by its reactivity withLens culinaris agglutinin (LCA). The percentage of LCA-reactive species of AFP is significantly higher in HCC than in benign liver diseases. The fucosylation of the sugar chain at the innermostN-acetylglucosamine is the molecular basis of this variation. Therefore, the term fucosylation index has been introduced to express the percentage of LCA-reactive species of AFP. This index is useful for the diagnosis of HCC even if the carcinoma is at an early stage. Furthermore, it can predict the development of HCC in the follow-up of chronic liver diseases. Thus, the qualitative and quantitative measurements of carbohydrate in AFP provide us with very valuable information for the differential diagnosis of various liver diseases.     

Role of CD10 immunochemistry in differentiating hepatocellular carcinoma from metastatic carcinoma of the liver

Background:  Differentiation of hepatocellular carcinoma (HCC) from metastatic carcinoma in liver may be difficult on fine needle aspiration cytology (FNAC), especially when both appear as moderate to poorly differentiated tumours. A panel of immunocytochemical stains is frequently used in case of diagnostic difficulty. Recently, CD10 immunostain with a canalicular staining pattern has been shown to be a specific marker for hepatocytic differentiation.
Objective:  The present study was designed to assess the value of CD10 immunostain in distinguishing HCC from metastatic carcinoma in material obtained by FNAC of liver masses.
Materials and methods:  Formalin-fixed, paraffin-embedded cell blocks of 22 cases (7 cases of HCC and 15 cases of metastatic carcinoma), direct acetone-fixed smears and destained smears of 28 cases (18 cases of HCC and 10 cases of metastatic carcinoma) prepared from FNAC of the liver were immunostained using monoclonal antibody against CD10.
Results:  Seventeen (68%) of twenty-five cases of HCC were positive for CD10 with a canalicular staining pattern. Among them 7 (70%) of 10 cases were well-differentiated HCC and 10 (66%) of 15 cases were moderate to poorly differentiated HCC. Of 25 cases of metastatic carcinoma, four (16%) were positive for CD10 with a cytoplasmic (three cases) and membranous staining (one case) pattern.
Conclusion:  CD10 immunostaining is useful in discriminating HCC and metastatic carcinoma of the liver and is easily applied on cell blocks as well as FNAC smears.     

Role of autophagy in liver physiology and pathophysiology

Autophagy is a highly conserved intracellular degradation pathway by which bulk cytoplasm and superfluous or damaged organelles are enveloped by double membrane structures termed autophagosomes. The autophagosomes then fuse with lysosomes for degradation of their contents, and the resulting amino acids can then recycle back to the cytosol. Autophagy is normally activated in response to nutrient deprivation and other stressors and occurs in all eukaryotes. In addition to maintaining energy and nutrient balance in the liver, it is now clear that autophagy plays a role in liver protein aggregates related diseases, hepatocyte cell death, steatohepatitis, hepatitis virus infection and hepatocellular carcinoma. In this review, I discuss the recent findings of autophagy with a focus on its role in liver pathophysiology.     

An inflammation-associated ferroptosis signature optimizes the diagnosis,prognosis evaluation and immunotherapy options in hepatocellular carcinoma

Inflammation and ferroptosis crosstalk complexly with immune microenvironment of hepatocellular carcinoma (HCC), thus affecting the efficacy of immunotherapy. Herein, our aim was to identify the inflammation-associated ferroptosis (IAF) biomarkers for contributing HCC. A total of 224 intersecting DEGs identified from different inflammation- and ferroptosis-subtypes were set as IAF genes. Seven of them including ADH4, APOA5, CFHR3, CXCL8, FTCD, G6PD and PON1 were used for construction of a risk model which classified HCC patients into two groups (high and low risk). HCC patients in the high-risk group exhibited shorter survival rate and higher immune score, and were predicted to have higher respond rate in immune checkpoint inhibition (ICI) therapy. Levels of the seven genes were significantly changed in HCC tissues in comparison to adjacent tissues. After inserting the gene expression into the risk model, we found that the risk model exhibited the higher diagnostic value for distinguish HCC tissues compared each single gene. Furthermore, HCC tissues from our research group with high-risk score exhibited more cases of microsatellite instability (MSI), heavier tumour mutational burden (TMB), higher expression level of PDL1 and cells with CD8. Knockdown of APOA5 reduced HCC cell proliferation combining with elevating inflammation and ferroptosis levels. In conclusion, we considered APOA5 maybe a novel target for suppressing HCC via simultaneously elevating inflammation and ferroptosis levels, and signature constructed by seven IAF genes including ADH4, APOA5, CFHR3, CXCL8, FTCD, G6PD and PON1 can act as a biomarker for optimising the diagnosis, prognosis evaluation and immunotherapy options in HCC patients.