Identification of c-Yes expression in the nuclei of hepatocellular carcinoma cells: involvement in the early stages of hepatocarcinogenesis

It is thought that the subcellular distribution of Src-family tyrosine kinases, including c-Yes binding to the cellular membrane, is membranous and/or cytoplasmic. c-Yes protein tyrosine kinase is known to be related to malignant transformation. However, the expression patterns of c-Yes in hepatocellular carcinoma (HCC) remains unknown. In the present study, we report that c-Yes is expressed not only in the membrane and cytoplasm, but also in the nuclei of cancer cells in some human HCC tissues and in a human HCC cell line. We examined the expression and localization of c-Yes in human HCC cell lines (HLE, HLF, PLC/PRF/5 and Hep 3B) by Western blotting and immunohistochemical analyses; we also examined the expression of c-Yes by immunohistochemistry and Western blotting in the tissues of various liver diseases, including 39 samples from HCC patients. We used an antibody array to detect proteins that bind to nuclear c-Yes in PLC/PRF/5 cell line. c-Yes was found to be expressed in the membranes and cytoplasm of HLE, HLF and Hep 3B HCC cells; it was also detected in the nuclei in addition to the membranes and cytoplasm of PLC/PRF/5 HCC cells. HCC with nuclear c-Yes was detected in 5 of 39 cases (13.0%), and nuclear c-Yes expression was not detected in normal, chronic hepatitis or cirrhotic livers. All HCCs with nuclear c-Yes expression were well-differentiated, small tumors at the early stages. In the PLC/PRF/5 cell line, the nuclear localization of c-Yes with cyclin-dependent kinase 1 was confirmed by a protein antibody array. In conclusion, nuclear c-Yes expression was found in cancer cells at the early stages of hepatocarcinogenesis, suggesting that nucleus-located c-Yes may be a useful marker to detect early-stage HCC.     

Relation of type II transforming growth factor-beta receptor to hepatic fibrosis and hepatocellular carcinoma

Hepatocarcinogenesis is closely related to hepatic fibrosis. In this study, we investigated the relationship of type II transforming growth factor-beta receptor (T beta RII) to hepatic fibrosis and hepatocellular carcinoma (HCC). In vivo: liver tissues were obtained from 30 patients (10 chronic hepatitis, 7 cirrhosis, 13 HCC). Protein expression and immunolocalization of T beta RII were examined by Western blot analysis and immunohistochemistry. In vitro: T beta RII protein expression in hepatoma cell lines (HepG2, Hep3B, HLE, HLF and Huh7) was examined by Western blot analysis. Next, we transfected T beta RII cDNA to Huh7, and compared the change of cell number and observed the induction of apoptosis after TGF-beta1 treatment using a FACScan flow cytometer. In vivo: T beta RII immunolocalization in liver tissues was significantly decreased in patients with HCC compared with that of patients with chronic hepatitis or liver cirrhosis. In Western blot analysis, T beta RII expression in tissues attenuated in comparison with that in non-tumor tissues in some patients with HCC. In vitro: T beta RII protein expression in HLE, HLF and Huh7 cells was weaker than that in HepG2 and Hep3B cells. In Huh7 cells transfected T beta RII cDNA, cell arrest and apoptosis were obviously induced. These results indicated that human HCC has a reduced expression of T beta RII for TGF-beta1. This may provide a selective growth advantage to HCC to escape the inhibitory growth signals of TGF-beta1, and may be linked with critical steps in the growth of hepatoma cells.     

Increased protein expression of DNA methyltransferase (DNMT) 1 is significantly correlated with the malignant potential and poor prognosis of human hepatocellular carcinomas

Alteration of DNA methylation is one of the most consistent epigenetic changes in human cancers. DNA methyltransferase (DNMT) 1 is a major enzyme involved in establishing genomic methylation patterns. Most of the studies concerning DNMT1 expression in human cancers have been performed only at the mRNA level. To directly examine DNMT1 protein expression levels during human hepatocarcinogenesis, 16 histologically normal liver tissues, 51 noncancerous liver tissues exhibiting chronic hepatitis or cirrhosis, which are considered to be precancerous conditions, and 53 hepatocellular carcinomas (HCCs) were subjected to immunohistochemic examination. If more than 20% of the cells exhibited nuclear DNMT1 staining, the tissue sample was considered to be DNMT1-positive. DNMT1 immunoreactivity was observed in 23 (43%) of the HCCs, but in none (0%) of the histologically normal liver or noncancerous liver tissues exhibiting chronic hepatitis or cirrhosis. The incidence of increased DNMT1 protein expression in HCCs correlated significantly with poor tumor differentiation (p = 0.0006) and portal vein involvement (p = 0.0002). Moreover, the recurrence-free (p = 0.0001) and overall (p < 0.0001) survival rates of patients with HCCs exhibiting increased DNMT1 protein expression were significantly lower than those of patients with HCCs that did not exhibit increased expression. Increased DNMT1 protein expression may play a critical role in the malignant progression of HCCs and be a biologic predictor of both HCC recurrence and a poor prognosis in HCC patients.     

Increased Expression of Claudin-1 and Claudin-7 in Liver Cirrhosis and Hepatocellular Carcinoma

Claudins have been reported to be differentially regulated in malignancies and implicated in the process of carcinogenesis and tumor progression. Claudin-1 has been described as key factor in the entry of hepatitis C virus (HCV) into hepatocytes and as promoter of epithelial-mesenchymal transition in liver cells. The objective of the current study was to characterize claudin expression in hepatocellular carcinoma (HCC) as well as HCC-surrounding and normal liver samples with respect to cirrhosis and HCV infection. Expression of claudin-1, -2, -3, -4, and ?7 was measured by morphometric analysis of immunohistochemistry, and Western blotting in 30 HCCs with 30 corresponding non-tumorous tissues and 6 normal livers. Claudin-1 and ?7 protein expression was found significantly elevated in cirrhosis when compared with non-cirrhotic liver. HCCs developed in cirrhotic livers showed even higher expression of claudin-1 contrary to decreased claudin-7 expression when compared with cirrhosis. With reference to HCV status, HCCs or surrounding livers of HCV-infected samples did not show significant alterations in claudin expression when compared with HCV-negative specimens. Cirrhotic transformation associates with elevated claudin-1 and -7 expressions in both non-tumorous liver and HCC. The fact that no significant differences in claudin expression were found regarding HCV-positivity in our sample set suggests that HCV infection alone does not induce a major increase in the total amount of its entry co-factor claudin-1. Increased expression of claudin-1 seems to be a consequence of cirrhotic transformation and might contribute to a more effective HCV entry and malignant transformation.     

Immunohistochemical analysis of pro-apoptotic Bid level in chronic hepatitis, hepatocellular carcinoma and liver metastases

Bid, a member of the Bcl-2 family, mediates apoptosis by inducing the release of proapoptotic factors. The expression of Bid in liver diseases has not been investigated. This study evaluated Bid level in various liver diseases including hepatocellular carcinoma (HCC), liver metastases from colorectal cancer, chronic hepatitis and liver cirrhosis. The expression of Bid in tumorous tissues of HCC was lower than that in their corresponding non-tumorous tissues from the same patient. Heavy staining with Bid antibody was found in some localized tumorous liver tissues from patients with poorly differentiated tumors. In patients with chronic hepatitis and liver cirrhosis, there were gradient tumor-development centers, a gradient increase in reaction with Bid antibody from the middle of the center to its edge. The gradient tumor-development center was also found in non-tumorous tissues of HCC, suggesting that occurrence of this center in chronic hepatitis might be an early pathologic sign of HCC development. Bid was also expressed in the epithelial cells in tissues from liver metastases and their expression was often stronger than in the non-tumorous liver tissues. Heavy nuclear staining of Bid was not uncommon in these metastatic cells. The different patterns of staining between primary and secondary liver tumors may reflect a difference in tumor origin and in cell type. Nuclei of metastatic cells, though positive for Bid, still showed a considerable mitotic activity, indicating that they were in active proliferation rather than on a pathway deemed to be apoptotic. In conclusion, this study shows that the Bid level is decreased in HCC except in poorly differentiated HCC in which cells may undergo a process of apoptosis or necrosis. The existence of gradient tumor-development center in chronic hepatitis, liver cirrhosis and non-tumorous tissues from HCC may serve as a pathologic marker of a carcinogenic change of cell phenotypes.     

Activation of a system A amino acid transporter, ATA1/SLC38A1, in human hepatocellular carcinoma and preneoplastic liver tissues

The expression of amino acid transporter (AT) mRNAs including A system (ATA1/SNAT1/SLC38A1, ATA2/SNAT2/SLC38A2 and ATA3/SNAT3/SLC38A4), L system (LAT1/SLC7A5 and LAT2/SLC7A8), and y+ (CAT2/SLC7A2) genes, were compared among hepatocellular carcinoma (HCC) and non-cancerous liver cells. Among them the ATA1 mRNA expression was significantly elevated in all HCC cell lines (HepG2, HLF, HuH7 and JHH4) examined compared with normal liver tissue. We further discovered that the expression of ATA1 mRNA was significantly activated in HCC tissues and also elevated in pre-malignant cirrhotic livers from HCC patients, compared with normal livers from non-HCC patients. The ATA1 protein was extensively accumulated in the cytoplasm of pre-malignant liver and most HCCs, while being weak or undetectably low in normal liver tissues. SiRNA-mediated suppression of endogenous ATA1 lowered the viability of HepG2 cells. Thus, the activation of ATA1 confers growth and survival advantages in pre-malignant and malignant liver lesions.     

Extracellular signal-regulated kinase induces cyclin D1 and Cdk-2 expression and phosphorylation of retinoblastoma in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common malignancies in Southeast Asia. Hyperphosphorylation of retinoblastoma (pRB) by cyclin/CDKs in G1/S transition is required for its inactivation and cell cycle progression. In the present study, we report that phosphorylation of pRB at Ser780 and Ser795 was detected in 71% (33 of 46) and 63% (29 of 46) of HCCs examined respectively. pRB protein was undetectable in 13% (6 of 46) of HCCs examined. Phosphorylated pRB was localized in the nuclei of hepatocarcinoma cells. Benign hepatocytes exhibited very weakly or no nuclear staining for phosphorylated pRB. Over-expression of E2F-1, cyclin D1, Cdk-2, Cdk-4 and cyclin A was found in 64% (30 of 46), 43% (26 of 46), 28% (11 of 46), 71% (33 of 46) and 63% (29 of 46) of HCCs examined respectively and this was correlated with elevation of ERK. Treatment of HepG2 cells with MEK1/2 inhibitor U0126 resulted in cell cycle arrest, downregulation of cyclin D1 and Cdk-2 expression and inhibition of pRB phosphorylation at Ser780 and Ser795. Ectopic expression of activated MEK1 in HepG2 cells increased cyclin D1 and Cdk-2 expression, phosphorylation of pRB at Ser780 and Ser795, and percentage of cells in S phase. Our data indicate that activated ERK plays an important role in cyclin D1 and Cdk-2 expression and phosphorylation of pRB at Ser780 and Ser795 in liver cancer cells.     

肝癌及癌前病变中p27蛋白和mRNA的表达

[目的]研究肝细胞癌(HCC)及癌前病变中细胞周期负性调控因子p27的表达及其意义.[方法]应用免疫组织化学S-P染色法和原位分子杂交法检测正常肝组织、慢性肝炎、肝硬化、癌周肝硬化和肝癌组织中p27蛋白及其mRNA的表达,并对结果进行计算机图像定量分析.[结果]p27蛋白在正常肝组织和慢性肝炎中呈低表达,在肝硬化和癌周肝硬化中表达明显增强,而在肝癌中表达明显下降,与前4组比较差异有显著性(P＜0.05).p27mRNA在非肝癌组织中表达均较强,在肝癌中表达明显减弱,与前4组比较差异有显著性(P＜0.05).正常肝组织、慢性肝炎和肝硬化中p27蛋白阳性信号主要定位于胞核,而癌周肝硬化和HCC中主要定位于胞浆.随着HCC的分化程度降低,p27蛋白和p27mRNA的表达减弱,差异有显著性(P＜0.05).[结论]p27表达下降可能参与了HCC的发生,且与HCC的分化有关.p27的胞浆定位可能与HCC的早期发生有关.     

Altered expression of cell cycle and apoptotic proteins in human liver pathologies

Τhe expression of cell cycle (P53, Ki-67, P21, and P27) and apoptotic proteins (BCL-2 and BAX) was investigated by immunohistochemistry in paraffin-embedded formalin-fixed tissues of normal and pathologic liver. An increased frequency of expression of P21 in cirrhosis and hepatocellular carcinoma (HCC) (p=0.003 and p=0.001 respectively) was found; P27 protein expression was more frequent in hepatitis (p=0.001) and HCC (p=0.003) when compared with normal tissue. BCL-2 protein was markedly more frequent in steatohepatitis (p<0.05) as compared to normal liver, in hepatitis cases (p=0.002) and in metastases (p<0.033). The expression of BAX was more frequent in hepatitis (p=0.001) and cirrhosis (p<0.001). We demonstrated in our study the expression of these proteins at different levels in liver pathologies. These findings have implications for understanding the evolution from liver inflammation to cirrhosis and associated carcinogenesis.     

Enhanced expression of adaptor molecule p46 Shc in nuclei of hepatocellular carcinoma cells: study of LEC rats

Shc protein is known to be related to cell proliferation and carcinogenesis. However, the involvement of Shc in hepatocellular carcinoma (HCC) remains unknown. In the present study, we report that p46 Shc is probably expressed in the nuclei of hepatocytes and/or cancer cells during the development of HCC in Long-Evans Cinnamon (LEC) rats. The expression and localization of Shc in various pathological liver tissues obtained from LEC rats were analyzed by immunohistochemical study and Western blotting. Furthermore, tyrosine phosphorylation of Shc in various pathological liver tissues of LEC rats was studied by immunoprecipitation using a monoclonal anti-phosphotyrosine antibody. Although p66 Shc was detected in none of the liver tissues, regardless of pathological status, the expression of p46 Shc and that of p52 Shc increased proportionately with the development of HCC in LEC rats. Furthermore, although p52 Shc was localized only in the cytoplasm of hepatocytes and/or cancer cells, p46 Shc was found to express in both the nuclei and the cytoplasm of hepatocytes and/or cancer cells in precancerous and cancerous tissues of LEC rat liver. Tyrosine phosphorylation of p46 Shc and p52 Shc was detected only in cancer cells, and p46 Shc in such cells was much more heavily phosphorylated than p52 Shc. These results suggest that enhanced expression of p46 Shc and p52 Shc, as well as p46 Shc tyrosine phosphorylation, was involved not only in the process from normal liver to chronic hepatitis, but also in the transition from chronic hepatitis into HCC in LEC rats. Furthermore, unlike p52 Shc, p46 Shc was detected not only in the cytoplasm but also in the nuclei of hepatocytes (especially in transformed hepatocytes), and p46 Shc expressed in the nuclei may be closely related to hepatocarcinogenesis in LEC rats.     

The E-cadherin gene is silenced by CpG methylation in human hepatocellular carcinomas

Our study was designed to clarify the significance of silencing the E-cadherin gene, which is located on 16q22.1, due to CpG methylation during hepatocarcinogenesis. The CpG methylation status of primary hepatocellular carcinomas (HCCs) and corresponding liver tissues showing chronic hepatitis or cirrhosis, which are widely considered to be precancerous conditions, were assessed by digesting DNA with methylation-sensitive and non-sensitive restriction enzymes. CpG methylation around the promoter region of the E-cadherin gene was detected in 46% of liver tissues showing chronic hepatitis or cirrhosis and 67% of HCCs examined. Immunohistochemical examination revealed reduced E-cadherin expression in 59% of HCCs examined. CpG methylation around the promoter region correlated significantly with reduced E-cadherin expression in HCCs (p < 0.05). CpG methylation around the promoter region, which increases during the progression from a precancerous condition to HCC, may participate in hepatocarcinogenesis through reduction of E-cadherin expression, resulting in loss of intercellular adhesiveness and destruction of tissue morphology. Int. J. Cancer 71:355-359, 1997. © 1997 Wiley-Liss Inc.     

原发性肝细胞癌组织中P21的亚细胞定位及其意义

目的探讨原发性肝细胞癌组织中P21的亚细胞定位及其意义。方法收集115例由肝硬化发展成肝癌的病理标本,包括同一病例的肝癌组织、癌旁组织、肝硬化组织。采用SP法分别行P21的免疫组织化学染色,观察P21的亚细胞分布,并对其与肝癌的临床病理特征、癌细胞分化程度进行相关性分析。结果HCC组和癌旁组均有P21的高表达（35．65％,38．26％）,两者之间的差异无统计学意义（P〉0．05）,但明显高于肝硬化组（10．43％,P〈0．01）。P21胞质表达的阳性率,肝硬化组与癌旁组相近（8．33％,6．82％,P〉0．05）,而肝癌组胞质表达的阳性率最高（75．61％,P〈0．01）。P21的亚细胞定位分布与肝癌患者的发病年龄、乙肝病毒的感染、肿瘤大小无明显相关性（P〉0．01或0．05）,但与肿瘤细胞的病理分级、肿瘤转移具有良好的相关性。Ⅲ-Ⅳ级、伴有肿瘤转移的肝癌患者,其P21的胞质表达率更高。结论在肝硬化向肝癌转化的过程中,伴有P21亚细胞定位的改变,即由胞核移位到胞质,且肿瘤细胞恶性程度愈高,肿瘤转移愈早,胞质移位比例愈高。但这种亚细胞定位分布的改变,与肿瘤患者的发病年龄、乙肝病毒的感染、肿瘤大小无关。     

Alterations of RB1, p53 and Wnt pathways in hepatocellular carcinomas associated with hepatitis C,hepatitis B and alcoholic liver cirrhosis

Major etiologic factors associated with human hepatocellular carcinomas (HCCs) include infection with hepatitis C (HCV) and hepatitis B virus (HBV), excess alcohol intake and aflatoxin B(1) exposure. While the G-->T p53 mutation at codon 249 has been identified as a genetic hallmark of HCC caused by aflatoxin B(1), the genetic profile associated with other etiologic factors appears to be less distinctive. In our study, we screened HCCs resulting from HCV infection (51 cases), HBV infection (26 cases) or excess alcohol intake (23 cases) for alterations in genes involved in the RB1 pathway (p16(INK4a), p15(INK4b), RB1, CDK4 and cyclin D1), the p53 pathway (p53, p14(ARF) and MDM2) and the Wnt pathway (beta-catenin, APC). Alterations of the RB1 pathway, mainly p16(INK4a) methylation, loss of RB1 expression and cyclin D1 amplification, were most common (69-100% of cases). There was a significant correlation between loss of RB1 expression and RB1 methylation. All 24 HCCs with RB1 promoter methylation lacked RB1 expression, while none of the 67 cases with RB1 expression exhibited RB1 methylation (p < 0.0001), suggesting that promoter methylation is a major mechanism of loss of RB1 expression in HCCs. Alterations of the p53 pathway consisted mostly of p53 mutations or p14(ARF) promoter methylation (20-48%). Mutations of the p53 gene were found at a similar frequency (13-15%) in all etiologic groups, without any consistent base change or hot spot. Mutations of beta-catenin were found in 13-31% of cases, while no APC mutations were detected in any of the HCCs analyzed. With the exception of only 3 of 39 cases (8%), cyclin D1 amplification and beta-catenin mutations were mutually exclusive, supporting the view that cyclin D1 is a target of the Wnt signaling pathway. Overall, the RB1, p53 and Wnt pathways were commonly affected in HCCs of different etiology, probably reflecting common pathogenetic mechanisms, i.e., chronic liver injury and cirrhosis, but tumors associated with alcoholism had more frequent alterations in the RB1 and p53 pathways than those caused by HCV infection.     

Expression of G1 phase-related cell cycle molecules in naturally developing hepatocellular carcinoma of Long-Evans Cinnamon rats

It has been shown that a variety of cell cycle-related proteins play important roles in the process of carcinogenesis including hepatocarcinogenesis. In the present study, we evaluated mRNA and protein expression of G1 phase-related cell cycle molecules in the process of hepatocarcinogenesis, using Long-Evans Cinnamon (LEC) rats, an animal model of hepatocellular carcinoma (HCC). The expression of cyclin D1, cyclin-dependent kinase 4 (Cdk4) and Cdk6 was measured quantitatively by real-time polymerase chain reaction. Cyclin D1 mRNA expression was increased significantly in chronic hepatitis liver compared with normal liver, and then decreased in HCC and the surrounding precancerous liver of LEC rats. Levels of Cdk4 mRNA were increased significantly in HCC compared to precancerous and chronic hepatitis livers. In contrast, mRNA levels of Cdk6 did not change significantly during hepatocarcinogenesis. We also evaluated the protein levels of these G1 phase-related cell cycle molecules by Western blot analyses and confirmed similar results. Total amounts of retinoblastoma protein (pRb) in the liver did not change significantly in the process of hepatocarcinogenesis in LEC rats. However, levels of phosphorylated pRb were increased markedly in the process of hepatocarcinogenesis, and the highest in HCC compared to precancerous, chronic hepatitis and normal livers. These results indicate that cyclin D1 may be involved in the regeneration of hepatocytes rather than hepatocarcinogenesis, while Cdk4 but not Cdk6 may play an important role in the development of HCC.     

利用组织芯片研究COX-2和mPGES-1在肝细胞癌中的表达及意义

目的：检测COX-2和mPGES-1在肝细胞癌（hepatocellular carcinoma,HCC）组织中的表达,探讨其在HCC发生、发展中的意义.方法：构建含HCC、癌旁肝硬化、癌旁慢性肝炎及正常肝组织的组织芯片,应用免疫组化和图像分析技术检测COX-2和mPGES-1蛋白的相对表达量,进行半定量分析.结果：COX-2和mPGES-1在HCC中表达均高于正常肝组织（P＜0.01）,随着病理学分级的升高,COX-2相对表达量明显下降（P＜0.01）,但mPGES-1表达量逐渐增高,包膜侵犯组中mPGES-1表达量高于包膜无侵犯组（P＜0.01）,转移组高于无转移组（P＜0.01）.在HCC组织中,COX-2与mPGES-1的表达无明显相关（r=-0.13,P＞0.05）.结论：COX-2和mPGES-1与HCC的发生密切相关,mPGES-1可能在HCC进展期发挥重要作用,选择性抑制mPGES-1有可能成为治疗HCC新的靶点.     

Expression of retinoid X receptor alpha is decreased in 3'-methyl-4-dimethylaminoazobenzene-induced hepatocellular carcinoma in rats

The identification of the specific molecular targets, which underlie liver carcinogenesis is essential for the establishment of an effective strategy for the prevention and/or treatment of hepatocellular carcinomas (HCCs). We previously found that a malfunction of RXRalpha due to its aberrant phosphorylation was associated with the development of HCCs. However, it has remained unclear whether the abnormalities in the expression of RXRalpha or the other retinoid receptors play a role in the early stage of liver carcinogenesis. The present study was designed to determine whether alterations in the expression of RXRalpha and the other retinoid receptors RARalpha and RARbeta are involved in hepatocarcinogenesis using a 3'-methyl-4-dimethylaminoazobenzene (3'-MeDAB)-induced rat liver carcinogenesis model. We found that immunohistochemical expression of RXRalpha was decreased in liver cell tumors (HCCs and adenoma) and glutathione S-transferase placental form (GST-P)-positive foci, which is a precancerous lesion of HCC, when compared with the non-cancerous tissues. Western blot and RT-PCR analyses revealed a progressive decrease in the expression levels of RXRalpha, RARalpha, and RARbeta proteins and their mRNAs in 3'-MeDAB-induced HCCs and their surrounding tissues, when compared with the normal liver tissues from the control group. Moreover, the expression level of beta-catenin, the heterodimeric partner for both RXRalpha and RARalpha, was immunohistochemically observed in the cytoplasm and, in some cases, in the nucleus of HCC cells. The nuclear expression of cyclin D1, the downstream target molecule of beta-catenin, was also increased in HCC cells when compared with their adjacent normal appearing tissues. Our findings suggest that loss of retinoid receptors, especially RXRalpha, plays a critical role in the chemically-induced rat liver carcinogenesis and this might be associated with the activation of beta-catenin-related signaling pathway.     

甘油二酯激酶α、蛋白激酶C在肝癌组织中的表达及临床意义

 目的 研究肝癌组织中甘油二酯激酶α (Diacylglycerol Kinase α, DGKα)和蛋白激酶C（PKC）的表达及临床意义。方法 应用免疫组化检测DGKα在60例肝癌、癌周组织及10例正常肝组织中的表达,统计分析DGKα的表达与临床病理因素的关系。 结果 DGKα和PKC蛋白在正常肝组织、癌周组织和肝癌组织的阳性表达率逐渐降低,但在肝细胞的表达部位却逐渐从胞浆移至胞膜。DGKα阳性表达率的差异与原发性肝癌的分化类型、是否有门静脉癌栓和TNM分期有统计学意义(P <0.05)。结论 在越晚期、分化越差的肝癌中DGKα的活性越强,DGKα促进了原发性肝癌的病理进程。