NFKB and NFKBI polymorphisms in relation to susceptibility of tumour and other diseases

Nuclear factor-kappaB (NF-kappaB) is responsible for the expression by regulating many genes for immune response, cell adhesion, differentiation, proliferation, angiogenesis and apoptosis. The function of NF-kappaB is inhibited by binding to NF-kappaB inhibitor (IkappaB), and imbalance of NF-kappaB and IkappaB has been associated with development of many diseases, including tumours. In this review, we focus on polymorphisms of the NFKB and NFKBI genes in relation to development of common inflammatory diseases including ulcerative colitis (UC), Crohn's disease (CD), rheumatoid arthritis, systemic lupus erythematosus, psoriatic arthritis, giant cell arthritis, type 1 diabetes, multiple sclerosis, celiac disease, and Parkinson's disease, as well as susceptibility of several cancers, such as oral squamous cell carcinoma, colorectal cancer (CRC), hepatocellular carcinoma, breast cancer and myeloma.     

白藜芦醇苷通过抑制microRNA-21表达抑制肝癌细胞增殖和迁移

原发性肝癌是临床上最常见的恶性肿瘤之一,目前仍在寻找有效的治疗手段. 白藜芦醇苷可抑制肺癌细胞以及大肠癌细胞的增殖,但其在肝癌中的作用及具体作用机制并不清楚. 本文探讨白藜芦醇苷对大鼠肝癌是否具有预防作用,及其对肝癌细胞系增殖和侵袭的影响. 构建大鼠原发性肝癌模型,将其分为正常组、模型组及白藜芦醇苷预防组. 病理检测结果显示,与模型组相比,白藜芦醇苷预防组的肝癌发生率明显降低.检测肝组织中microRNA-21表达情况,结果显示,白藜芦醇苷预防组肝中microRNA-21表达明显降低,并且microRNA-21的靶基因PTEN表达上调.在肝癌细胞系SMMC7721和HepG2中加入白藜芦醇苷,细胞增殖及侵袭能力明显下降,同时伴随microRNA-21表达降低,PTEN表达升高. 这提示,白藜芦醇苷可能通过抑制microRNA-21的表达,抑制肝癌的发生,本文结果为预防原发性肝癌提供了新的理论依据,但其临床疗效还需要进一步验证.     

氧调节蛋白150在人肝细胞癌中的过度表达及其对凋亡的作用

在前期研究中发现,氧调节蛋白150(ORP150)是与肝细胞癌相关的糖蛋白．进一步研究了ORP150的表达水平与肝细胞癌的相关性．免疫印迹、细胞免疫化学和定量PCR分别在蛋白质水平和mRNA水平检测了ORP150的表达．运用RNA干扰技术检测了其对凋亡和肝细胞癌侵袭性的影响．发现：无论是蛋白质水平还是mRNA水平,与正常肝细胞相比,ORP150在肝细胞癌中表达明显上调;经RNA干扰后,肝细胞癌的凋亡明显增加,但肿瘤细胞的侵袭性无改变．肝细胞癌中,ORP150表达上调,它可能抑制肿瘤细胞的凋亡而促进其生长．ORP150有可能成为肝细胞癌的治疗靶点．     

Usefulness of diagnostic criteria for aspiration cytology of hepatocellular carcinoma.

OBJECTIVE: To establish new criteria for cytodiagnosis of hepatocellular carcinoma by comparing cytologic findings of hepatocellular carcinoma with those of liver cirrhosis. STUDY DESIGN: Review of cytologic findings of hepatocellular carcinoma on preoperative aspiration biopsy of 31 lesions from 27 patients who underwent surgical resection and comparison of these findings with those of liver cirrhosis in 17 patients. RESULTS: In the 11 lesions of moderately and poorly differentiated hepatocellular carcinoma, significant cytologic findings included monotonous and abundant cytoplasm, thick cytoplasm, increased nuclear/cytoplasmic ratio, irregular nuclear contours, increased chromatin density, intranuclear vacuoles and naked nuclei. In the 20 lesions demonstrating well-differentiated hepatocellular carcinoma, significant cytologic findings included monotonous and scant cytoplasm, well-defined cytoplasmic borders, thick cytoplasm, eccentric nuclei, increased nuclear/cytoplasmic ratio, thick nuclear membranes and increased chromatin density. We established the criteria for moderately and poorly differentiated hepatocellular carcinoma as including three cytologic parameters: increased nuclear/cytoplasmic ratio, irregular nuclear contours and increased chromatin density. We also established the criteria for well-differentiated hepatocellular carcinoma as including six cytologic parameters: monotonous cytoplasm, scant cytoplasm, well-defined cytoplasmic borders, thick cytoplasm, eccentric nuclei and increased nuclear/cytoplasmic ratio. For all 31 hepatocellular carcinoma lesions, including 27 lesions that were < or = 2 cm in diameter, both sensitivity and specificity were 100% by concurrently employing both criteria. CONCLUSION: The new criteria for cytodiagnosis we established were useful for differentiating hepatocellular carcinoma from liver cirrhosis. In particular, our criteria ensured appropriate diagnostic accuracy for well-differentiated hepatocellular carcinoma.     

The influence of plectin deficiency on stability of cytokeratin18 in hepatocellular carcinoma

Intermediate filaments are important in building the cellular architecture. Previously we found cytokeratin18 was modulated in human hepatocellular carcinoma. Plectin is a cross-linking protein that organizes the cytoskeleton into a stable meshwork, which can maintain the uniform size and shape of hepatocytes. Because the cells of hepatocellular carcinoma were morphologically different from the hepatocytes, we speculated that expression of plectin and organization of intermediate filament might play roles in the pleomorphism of hepatocellular carcinoma cells. In this paper, we studied the plectin expression of hepatocellular carcinoma and liver tissues by immunohistochemistry and immunoblot. The results revealed that plectin was deficient and cytokeratin18 was modulated in hepatocellular carcinoma. Furthermore, we knockdown the plectin mRNA in Chang cells, the result revealed the plectin was deficient and the organization of cytokeratin18 was altered. Conclusively, this study offers a hypothesis that plectin deficient might play an important role in the tumorigenesis of hepatocellular carcinoma. Dr. Yi-Hsiang Liu contributed equally as the first author.     

Smo 蛋白在肝癌和肝硬化中的表达及临床意义

目的:研究Smoothened(SMO)在肝癌和肝硬化中的表达及临床意义。方法:选取组织标本后,运用石蜡包埋,切片后,HE染色,构建组织芯片,免疫组织化学和原位杂交方法检测Smo蛋白在肝癌和肝硬化中的表达。结果:Smo蛋白在肝癌细胞浆、良性肝肿瘤组织细胞浆、肝硬化组织中强染色,在正常组织中无染色。并且在典型肝硬化中强染色,在中度肝硬化中弱阳性。结论:Smo蛋白表达与肝癌的发生有关,Smo基因的高表达可能激活某种机制而参与诱导肝癌的发生。可能是通过异常激活Sonic hedgchog信号通路,从而诱导肝癌的发生与发展。     

Imprint cytology of epithelioid angiomyolipoma in a patient with tuberous sclerosis. A case report

BACKGROUND: Angiomyolipoma composed predominantly of epithelioid cells has been referred to as epithelioid angiomyolipoma. As this subtype shows considerable cellular atypia, it may be erroneously diagnosed as malignant epithelioid tumor, such as renal cell carcinoma and hepatocellular carcinoma. So far, only one report describing the cytologic findings of epithelioid angiomyolipoma has been documented, and epithelioid angiomyolipoma occurring in the peritoneal cavity has not been reported. CASE: Eleven years after resection of a renal epithelioid angiomyolipoma in a 34-year-old male with tuberous sclerosis, a tumor appeared in the peritoneal cavity and three masses in the liver. The intraoperative smears imprinted from part of the peritoneal mass revealed many large, atypical cells. The well-preserved atypical cells showed abundant, round to polyhedral, granular cytoplasm. Bizarre, giant nuclei with hyperchromasia and huge nucleoli were occasionally seen. Intranuclear cytoplasmic inclusions and mitotic figures were occasionally observed. As the epithelioid cells were markedly pleomorphic, we could not rule out hepatocellular carcinoma, cytologically and histologically, in the intraoperative consultation. In permanent sections the tumor was composed predominantly of epithelioid cells showing an alveolar pattern or sheetlike arrangement. Mitotic counts were zero to one per 10 high-power fields. Immunohistochemically, the epithelioid tumor cells were positive for vimentin, alpha-smooth muscle actin and HMB-45, consistent with epithelioid angiomyolipoma. MIB-1-labeling index was 1.6%. CONCLUSION: When one sees atypical epithelioid tumor cells in a tuberous sclerosis patient during an intraoperative consultation, one must consider epithelioid angiomyolipoma.     

直接注射法制作ICR小鼠肝癌原位移植瘤模型

目的：培养鼠肝癌H22细胞,直接注射法制作ICR小鼠肝癌原位移植瘤,为后续实验奠定基础。方法：鼠肝癌H22细胞体外培养,将调整好的对数生长期的肝癌细胞直接注射小鼠肝脏,2周后解剖观察,并进行组织HE染色。结果：所有实验小鼠均可见肿瘤生长,HE染色示肝细胞肝癌。结论：直接注射法制作ICR小鼠肝癌原位移植瘤模型简便易行,值得推广应用。     

COTE1在肝细胞癌中的表达及其与临床病理参数及预后的相关性

目的:探究重组人序列相似性家族189成员B(FAM189B,别名COTE1)在肝细胞癌组织中的表达及与肝细胞癌患者预后的相关性。方法:收集59例行肝细胞癌根治术的患者,取其肝细胞癌组织及癌旁组织,采用免疫组织化学法检测COTE1表达,分析COTE1表达与临床病理参数的关系,采用Kaplan-Meier生存曲线分析COTE1表达与患者预后的关系,并采用COX比例风险回归模型分析预后的影响因素。结果:免疫组织化学法检测结果显示,肝细胞癌组织中37例COTE 1高表达,癌旁组织中24例COTE1高表达,肝细胞癌组织中COTE1的表达率明显高于癌旁组织(P<0.05);COTE1表达与甲胎蛋白(AFP)值及肿瘤复发情况存在相关性(P<0.05),而与年龄、性别、肿瘤大小无关(P>0.05)。Kaplan-Meier曲线分析发现,COTE1高表达的肝细胞癌患者术后生存期较短(P<0.05)。COX比例风险回归分析发现COTE1表达可以作为影响肝细胞癌患者预后的一个独立危险因素(P<0.05)。结论:COTE1在肝细胞癌组织中表达高于癌旁组织,COTE1表达可以作为一个独立因素来预测肝细胞癌患者的预后。     

直接注射法制作ICR 小鼠肝癌原位移植瘤模型

目的:培养鼠肝癌H22细胞,直接注射法制作ICR小鼠肝癌原位移植瘤,为后续实验奠定基础。方法:鼠肝癌H22细胞体外培养,将调整好的对数生长期的肝癌细胞直接注射小鼠肝脏,2周后解剖观察,并进行组织HE染色。结果:所有实验小鼠均可见肿瘤生长,HE染色示肝细胞肝癌。结论:直接注射法制作ICR小鼠肝癌原位移植瘤模型简便易行,值得推广应用。     

Fine needle aspiration cytology of metastatic hepatic adrenocortical carcinoma mimicking hepatocellular carcinoma: a case report

BACKGROUND: Adrenocortical carcinoma (AC) is a rare neoplasm, usually considered one of the most morbid and lethal human tumors. It occurs primarily in children and young adults and often presents with advanced and/or metastatic disease. CASE: A 9-year-old boy with a previous diagnosis of adrenocortical carcinoma underwent computed tomography (CT)-guided fine needle aspiration (FNA) for preoperative investigation of a hepatic mass. All smears revealed abundant groups of cells surrounding an interconnective, thin-walled, central vascular core. These cells showed finely vacuolated, large cytoplasm with eccentrically placed nuclei. Occasionally, cells underwent a sudden, marked increase in size, with prominent atypia. Multinucleated, atypical giant cells and high mitotic rate were also evident. The cytologic findings resembled the previous histologic adrenocortical carcinoma features. CONCLUSION: The cytologic features of metastatic hepatic adrenocortical carcinoma may mimic those of hepatocellular carcinoma. However, the presence of atypical multinucleated and pleomorphic cells with microvacuolated cytoplasm and eccentric nuclei as well as the absence of naked nuclei and endothelial linings yield the diagnosis of adrenocortical carcinoma. Nevertheless, other space-occupying liver lesions in children must also be considered. This case demonstrates the usefulness of CT-localized FNA biopsy in hepatic masses in children, and discusses the possible cytologic differential diagnosis.     

Cytokinesis regulators as potential diagnostic and therapeutic biomarkers for human hepatocellular carcinoma

Cytokinesis, the final step of mitosis, is critical for maintaining the ploidy level of cells. Cytokinesis is a complex, highly regulated process and its failure can lead to genetic instability and apoptosis, contributing to the development of cancer. Human hepatocellular carcinoma is often accompanied by a high frequency of aneuploidy and the DNA ploidy pattern observed in human hepatocellular carcinoma results mostly from impairments in cytokinesis. Many key regulators of cytokinesis are abnormally expressed in human hepatocellular carcinoma, and their expression levels are often correlated with patient prognosis. Moreover, preclinical studies have demonstrated that the inhibition of key cytokinesis regulators can suppress the growth of human hepatocellular carcinoma. Here, we provide an overview of the current understanding of the signaling networks regulating cytokinesis, the key cytokinesis regulators involved in the initiation and development of human hepatocellular carcinoma, and their applications as potential diagnostic and therapeutic biomarkers.     

GS、E—cadherin和β-catenin在肝细胞癌中的表达及其临床意义

目的探讨谷氨酰胺合成酶（glutamine synthetaseGS）、E-钙粘蛋白（E—cadherin）和β-连环蛋白（β-catenin）在肝细胞癌中的表达及其与临床病理特征和预后的关系。方法采用免疫组织化学Envision法检测182例肝细胞癌和92例癌旁肝组织中GS、E-cadherin和β-catenin的表达情况,并分析其与临床病理特征和预后的关系。结果GS在肝细胞癌阳性表达率为77．5％,明显高于癌旁肝组织（4．3％）,差异显著（P〈0．05）;肝细胞癌E—cadherin和β-catenin异常表达率分别为59．3％和58．8％,亦高于癌旁肝组织（30．4％和26．1％）,差异显著（P〈0．05）。肝细胞癌中GS的表达与TNM分期、转移和术后复发显著相关（P〈0．05）;E—cadherin和β-catenin异常表达与脉管内瘤栓、TNM分期、转移和术后复发显著相关（P〈0．05）。肝细胞癌中GS表达与E-cadherin、β-catenin异常表达正相关。结论肝细胞癌中GS的高表达,与E-cadherin和β-catenin表达的下调,可能是肝细胞癌侵袭和转移的重要机制之一,联合检测GS、E-cadherin和β-catenin可能有助于判断肝细胞癌的恶性程度、转移潜能及预后分析。     

凋亡诱导因子AIF在肝癌组织中的表达及临床意义

目的：探讨凋亡诱导因子（AIF）在肝细胞癌组织中的表达及其临床意义。方法：采用免疫组织化学Envision法检测75例肝细胞癌组织及其相应癌旁肝组织、30例正常肝组织中AIF的表达,并分析其表达与肝细胞癌临床病理因素的相关性。结果：肝癌组织中AIF阳性表达率明显高于癌旁组织及正常肝组织,差异均具有统计学意义（P〈0.01）。AIF在肝癌组织中的表达仅与病理分级密切相关（P〈0.01）,而与年龄、性别、肿瘤大小、临床分期、肿瘤数目、有无肿瘤包膜和有无淋巴结转移、有无门静脉癌栓均无关。结论：AIF表达可能参与了肝癌的发生和发展过程。     

Altered glycosaminoglycan composition in reactive and neoplastic human liver

We have investigated the glycosaminoglycan composition of normal human liver, focal nodular hyperplasia, hepatic adenoma, and hepatocellular carcinoma. Uronic acid increased about 4 fold in the benign and reactive lesions, and greater than 7 fold in the carcinoma. Whereas in focal nodular hyperplasia and adenoma dermatan sulfate was the predominant glycosaminoglycan, in hepatocellular carcinoma chondroitin sulfate was the predominant species; it increased 24 fold over normal liver and 3-5 fold over all the other tissues. HPLC analysis of chondroitinase ABC or AC digests showed a 58 fold increase in Delta-Di-OS disaccharides in hepatocellular carcinoma, indicating significant undersulfation of chondroitin sulfate. Surprisingly, the normal-appearing liver surrounding the carcinoma showed glycosaminoglycan changes similar to adenoma and nodular hyperplasia. These results thus indicate that specific glycosaminoglycan changes occur in hepatocellular carcinoma, and suggest for the first time that proteoglycan metabolism is also altered in the non-cirrhotic, hepatic parenchyma adjacent to liver carcinoma.     

Identification and analysis of immune-related subtypes of hepatocellular carcinoma

Hepatocellular carcinoma is a malignance that remains difficult to cure. Immunotherapy has shown its potential application in a variety of refractory malignancies. Due to the complexity of immune microenvironment of hepatocellular carcinoma, the efficacy of immunotherapy for hepatocellular carcinoma is not as effective as expected. Expression data of hepatocellular carcinoma from the TCGA and ICGC databases were used for classification and verification of hepatocellular carcinoma subtypes. The immune-related functions and pathways were identified via gene set enrichment analysis, while the sections denoting the subsets of the immune cells were estimated using the CIBERSORT algorithm. Immunity low (Immunity_L), immunity medium (Immunity_M), and immunity high (Immunity_H) were specified as the three immune-related subtypes of hepatocellular carcinoma. The quantity of stromal and immune cells was the most substantial in Immunity_H, compared to the other subtypes. Interestingly, the proportion of M0 macrophages decreased from Immunity_L to Immunity_H, while the proportion of CD8 T cells increased. Furthermore, the HLA genes expression levels, as well as those of six immune checkpoint genes were substantially lower in Immunity_L than in Immunity_H. Functional analysis was performed for 1512 differentially expressed genes between Immunity_L and Immunity_H. Finally, the PPI network was constructed with 118 nodes. The highest connectivity degree nodes were B2M, HLA-DRA, and HLA-DRB1. The above results were verified in ICGC-JP and ICGC-FR databases with a consistent trend. In this study, we divided hepatocellular carcinoma into three subtypes and explored the immune-related characteristics of these subtypes. These results may provide new insights for immunotherapy of hepatocellular carcinoma.     

Utility of CD34 reactivity in evaluating focal nodular hepatocellular lesions sampled by fine needle aspiration biopsy

OBJECTIVE: To determine the patterns of CD34 reactivity in hepatocellular adenoma and focal nodular hyperplasia and to evaluate the utility of CD34 reactivity in the diagnosis of hepatocellular carcinoma. STUDY DESIGN: Seventeen cases of well-differentiated hepatocellular carcinoma, 14 cases of cirrhosis, 9 cases of focal nodular hyperplasia and 7 cases of hepatocellular adenoma were stained with immunoperoxidase antibodies to CD34. The slides were scored according to the degree of lesional reactivity. RESULTS: Fourteen of 17 cell blocks with hepatocellular carcinoma showed unequivocal sinusoidal or peripheral reactivity for CD34. Five of seven cases of hepatocellular adenoma and four of nine cases of focal nodular hyperplasia showed > 50% sinusoidal reactivity for CD34. All 14 cases of cirrhosis showed peripheral to no sinusoidal reactivity. CONCLUSION: CD34 reactivity in a diffuse sinusoidal pattern can be helpful in the diagnosis of hepatocellular carcinoma. However, consideration should be given to the possibility of hepatocellular adenoma and focal nodular hyperplasia, which can also exhibit significant diffuse CD34 reactivity. In these cases, a reticulin stain may be helpful with the differential diagnosis.     

Occlusion of infusion vessels on gamma-linolenic acid infusion

gamma-Linolenic acid (GLA) is known to have selective tumoricidal action. In this study, the effect of lithium salt of GLA conjugated to iodized lymphographic oil (LGIOC) was injected intra-arterially close to the origin of tumor-feeding vessel(s) was studied. Four patients with stage 4 cancer disease (2 with hepatocellular carcinoma, 1 with giant cell tumor of the bone, and one with renal cell carcinoma), were selected for the study. Angiography, radiography and computed axial tomography were performed prior to and immediately after the injection of LGIOC and at periodic intervals. All four patients tolerated the treatment well. The most significant observation was the complete occlusion of the tumor-feeding vessels after LGIOC injection. Follow-up angiograms performed in all the patients showed occlusion of the tumor-feeding vessels is more or less permanent. A significant reduction in the size of the tumor was also observed in these patients. LGIOC showed occlusion of tumor-feeding vessels after infusion, and further studies are needed to confirm these preliminary results.