Proliferating cell nuclear antigen (PCNA) in medullary thyroid carcinoma

Summary We investigated the expression of proliferating cell nuclear antigen (PCNA) in paraffin sections from 20 cases of medullary thyroid carcinoma (MTC). Follow-up data were available in eleven cases. PCNA index positively correlated with the degree of cellular pleomorphism (grade) of the tumor (p<0.01), the pathologic state (p<0.01) and the poor clinical outcome (p<0.05). These findings suggest that PCNA may be of prognostic significance in MTC.     

Proliferating cell nuclear antigen (PCNA) expression in regenerating rat liver after partial hepatectomy

Proliferating cell nuclear antigen (PCNA) is a nuclear protein maximally elevated in the S phase of proliferating and transformed cells and is recognized by the monoclonal antibody PC-10 in paraffin tissue sections. The liver regenerative process after partial hepatectomy in rats was estimated with thein vivo incorporation of [³H]thymidine into liver DNA and the liver thymidine kinase activity. The expression of PCNA in rat liver after partial hepatectomy was performed by immunohistochemical staining with PC-10 in paraffin embedded tissues, at different time intervals up to 240 hr. Proliferating cell nuclear antigen expression, [³H]thymidine incorporation into DNA, and liver thymidine kinase activity exhibited marked oscillations during the liver regenerative process. A close relationship was demonstrated among DNA synthesis, thymidine kinase activity, and PC-10 score. Our results suggest that PC-10 monoclonal antibody may be used as a worthwhile proliferation index in the evaluation of the rate of liver regeneration in rats.     

Autoantibody to proliferating cell nuclear antigen (PCNA) in SLE: a clinical and serological study

In a clinical and serological follow-up study on a large series of subjects with different connective tissue disorders, anti-PCNA/cyclin autoantibodies were found in about 3% of patients with SLE. Positive subjects showed a higher incidence of diffuse proliferative glomerulonephritis and hematological disorders than the general SLE population. A highly significant serological association between PCNA and SL/Ki autoantibodies (p less than 0.001) has been observed. Persistence or disappearance of serum PCNA antibodies were independent of any clinical and serological feature or the therapeutic regimen employed.     

Proliferating cell nuclear antigen (PCNA) and MIB 1: Markers of locally advanced and biologically aggressive prostate cancer

Using archival radical prostatectomy specimens from patients with prostate cancer (n=19) we studied the relationship between staining with two different markers of cellular proliferation and the local extent or eventual progression of disease. In cases where the disease had spread outside the capsule of the prostate (n=9) the average staining patterns for proliferating cell nuclear antigen (PCNA) and MIB 1 were higher than in cases where the disease was organ-confined (n=10). The difference in the staining patterns for these two groups was greater for the MIB 1 antigen and this was shown to be statistically significant (p=0.01) whereas the smaller difference seen for proliferating cell nuclear antigen was not statistically significant. There was a higher staining pattern seen for these antigens in cases where disease progression was evident by a rising prostatic specific antigen level. The difference was greater and statistically significant (p相似文献   

Proliferating cell nuclear antigen (PCNA)-associated KIAA0101/PAF15 protein is a cell cycle-regulated anaphase-promoting complex/cyclosome substrate

The anaphase-promoting complex/cyclosome (APC/C) is a cell cycle-regulated E3 ubiquitin ligase that controls the degradation of substrate proteins at mitotic exit and throughout the G1 phase. We have identified an APC/C substrate and cell cycle-regulated protein, KIAA0101/PAF15. PAF15 protein levels peak in the G2/M phase of the cell cycle and drop rapidly at mitotic exit in an APC/C- and KEN-box-dependent fashion. PAF15 associates with proliferating cell nuclear antigen (PCNA), and depletion of PAF15 decreases the number of cells in S phase, suggesting a role for it in cell cycle regulation. Following irradiation, PAF15 colocalized with γH2AX foci at sites of DNA damage through its interaction with PCNA. Finally, PAF15 depletion led to an increase in homologous recombination-mediated DNA repair, and overexpression caused sensitivity to UV-induced DNA damage. We conclude that PAF15 is an APC/C-regulated protein involved in both cell cycle progression and the DNA damage response.     

Proliferating cell nuclear antigen immunolocalization in gastro-intestinal epithelia.

Proliferating cell nuclear antigen (PCNA), also called DNA polymerase delta-associated protein, is found in the cells of the proliferative compartment of normal tissues and is essential for DNA replication. It can be recognized by many monoclonal antibodies to various epitopes on the molecule. In this investigation one of these, PC10, has been used on formalin-fixed, paraffin-embedded, human and rodent gastro-intestinal epithelial tissues to assess numerically the labelling index of PC10 and to compare it, in the rat liver and gastrointestinal tract, with the S-phase fraction as determined by bromodeoxyuridine (BrdUrd) labelling. The distribution of PC10-labelled cells was recorded with respect to cell position in the intestinal crypts of man. In tissues where both modes of assessment were used, PC10 staining in the well-established proliferative compartments was found to be more extensive than that of BrdUrd. The higher labelling index with PC10 can be explained by its identification of PCNA outside the S phase of the cell cycle and also by the long half-life of PCNA protein in post-proliferative intestinal epithelial cells as they migrate towards the villus. Nevertheless the data suggest PC10 immunostaining in gastro-intestinal epithelia is an operational marker of cell proliferation which is reproducible, quantifiable and can be performed on routinely processed tissues.     

Hepatocyte proliferation in rats after ventromedial hypothalamic lesions: Immunoreactivity patterns of proliferating cell nuclear antigen (PCNA)

Ventromedial hypothalamic (VMH) lesions result in increased DNA content in the rat liver. However, little information is available concerning the proliferative activity and lobular distribution of different cell populations in VMH-lesioned rat liver. The aim of the present study was to quantitatiely assess these parameters in VMH-lesioned rat liver by measuring proliferating cell nuclear antigen (PCNA) reactivity. We investigated to determine whether this mitotic response involves acinar zones 1, 2, or 3. Changes in immunohistochemical labeling indices in rat liver were measured with an antibody against PCNA until 7 days after VMH lesioning. The effects of hepatic vagotomy on proliferation were also examined. Proliferation of hepatocytes in acinar zones 1–3 began to increase on day 1, and reached a maximum at 3 days. The area of most intense proliferation progressively shifted from acinar zone 1 to zone 3 in several days. The proliferation was completely inhibited by hepatic vagotomy, indicating that VMH lesions induce cell proliferation in rat liver via hepatic vagus nerve activity. This study implicates the information available on neural factors which initiate hepatocyte proliferation. (Received Sept. 4, 1997; accepted Dec. 19, 1997)     

Proliferating cell nuclear antigen and Ki-67 labeling in hepatocellular nodules: a comparative study

Abstract: Aims/Background: The morphologic differential diagnosis of hepatocellular nodules (HCN) is frequently difficult and objective criteria would be useful in the categorization of such lesions. This study evaluated the proliferative activity of HCN, including regenerative, macroregenerative (MRN), cirrhotic, dysplastic, and hepatocellular carcinoma (HCC), as well as intranodular cytologic changes such as bile-stained hepatocytes, eosinophilia, clear, large cell (LCC) and small cell (SCC) change, by comparing the cellular density (CD), labeling indices (LI) and density (DP) of two proliferation markers. Methods: Routinely processed tissue sections from 45 HCN from 17 adult liver explants were studied by immunohistochemistry for PCNA and Ki-67 (MIB-1). Results: A progressive increase in LI from regenerative to dysplastic nodules to HCC was observed with both proliferation markers. The values of the two markers were significantly correlated (p < 0.001). CD, PCNA and MIB-1 LI and DP values were significantly lower in regenerative compared to dysplastic nodules or HCC. MRNs had lower PCNA and MIB-1 LI and DP than regenerative nodules, but similar CD. There were no statistically significant differences in CD, PCNA, and MIB-1 LI and DP between dysplastic nodules and HCC, comparing high versus low grade dysplasia, or HCC smaller than 2 cm with those larger than 2 cm. The CD and proliferation indices LI and DP were higher in HCC than in the surrounding non-neoplastic parenchyma. Lesions with clear cell, eosinophilic and large cell change had CD, PCNA and MIB-1 indices similar to those of regenerative nodules, while these were lower in bile-stained hepatocellular lesions (p < 0.01). SCC showed CD, PCNA and MIB-1LI and DP similar to HCC and higher than surrounding regenerative lesions (p < 0.003). Conclusions: Our results suggest that PCNA and MIB-1 values are closely correlated in HCN. Regenerative nodules are characterized by low cellular proliferation, while dysplastic nodules are usually highly proliferative lesions and may represent an early stage in hepatocarcinogenesis. Hepatocellular lesions characterized by bile stained hepatocytes, eosinophilic, clear and large cell change have low proliferation rates and may not be significant for the development of malignancy.     

Immunohistological study on the expression of proliferating cell nuclear antigen (PCNA/cyclin) in human colorectal lesions]

The purpose of this study was to clarify the significance of immunohistological staining for PCNA/cyclin in human colorectal lesions. Our results: The PCNA-positive cells existed at the bottom of colonic tubuli in the normal and hyperplastic conditions. In the neoplastic lesions, however, the positive cells were existed at the relatively surface of the mucosa (chi 2: P less than 0.01) and distributed irregularly from the bottom to the top of carcinoma tissue. These results suggested that immunohistological staining for PCNA would specifically detect the cell proliferation and be beneficial for practical use and clinical application of the diagnosis of the colorectal lesions.     

Clinicopathological study of proliferating cell nuclear antigen (PCNA) of hepatocytes in primary biliary cirrhosis

The DNA synthesis activities of hepatocytes in primary biliary cirrhosis (PBC) and other chronic liver diseases and control subjects were examined by staining proliferating cell nuclear antigen (PCNA) with anti-PCNA monoclonal antibody. The number of PCNA-positive cells (PCNA value) was significantly higher in PBC (375±281 parts per thousand; ppt) than in other chronic liver diseases, i.e., chronic hepatitis (95±83 ppt), liver cirrhosis (72±71 ppt), and alcoholic liver disease (73±56 ppt), and in control subjects (11±14 ppt). The PCNA value of PBC in stages I-III of Scheuer's classification was remarkably high, while in stage IV it was low. Even in identical, Scheuer's stages, the PCNA value of PBC was higher in patients who were not given ursodeoxycholic acid (UDCA) than in those who received UDCA. In identical patients, the PCNA value was lowered significantly after UDCA treatment. It was concluded that the DNA synthesis activity of PBC in stages I-III was accelerated and that UDCA can alleviate the abnormality in DNA synthesis activity.     

Proliferating cell nuclear antigen expression in normal, preneoplastic, and neoplastic colonic epithelium of the rat.

Expression of the proliferating cell nuclear antigen (PCNA) was examined in normal rat intestinal tissues and in carcinogen-treated nonneoplastic and neoplastic colonic mucosa. In the normal intestine, PCNA expression was confined to the expected region of the proliferative compartment. A strong correlation was observed between PCNA labeling index and both [3H]thymidine labeling index (R = 0.993, P = 0.007) and percent of cells in S phase as determined by flow cytometry (R = 0.982, P = 0.018) and between the location of the maximal staining for PCNA and [3H]thymidine (R = 0.997, P less than 0.05). In animals treated with dimethylhydrazine (DMH), crypt hyperplasia, an increased PCNA labeling index, and shifts in both the region of maximal and the upper extent of PCNA expression were observed during DMH exposure; significant crypt hyperplasia and expansion of the PCNA-positive compartment persisted after completion of DMH injections. The patterns of PCNA expression and bromodeoxyuridine incorporation were similar in DMH-induced tumors. It is concluded that PCNA immunohistochemistry can be used as a reliable marker of the proliferative compartment in both normal and neoplastic colonic mucosa.     

In human hepatocellular carcinoma in cirrhosis proliferating cell nuclear antigen (PCNA) is involved in cell proliferation and cooperates with P21 in DNA repair

BACKGROUND: Proliferating cell nuclear antigen (PCNA) is a nuclear protein involved in DNA-synthesis and repair. During DNA-synthesis and repair the only active PCNA fraction is tightly bound to DNA. Similarly, during DNA-repair, a fraction of p21 colocalizes with PCNA in a detergent-insoluble form. AIM: The aim of the study was to analyze to what extent the presence of DNA-bound PCNA and p21 correlates with cell proliferation and DNA-repair in hepatocellular carcinoma (HCC). METHODS: Twenty-six HCCs and surrounding cirrhosis were studied. The DNA-bound and detergent-soluble fractions of PCNA and p21 were analyzed by immunoblotting. P53 and Ki67-Labeling Index (Ki67-LI) were evaluated by immunocytochemistry. RESULTS: Soluble fractions of PCNA and p21 were found in all samples. One out of 26 cirrhotic samples displayed a DNA-bound fraction of PCNA while no case expressed DNA-bound p21. Fourteen HCCs showed a DNA-bound PCNA fraction. A highly significant correlation was found between Ki67-LI and DNA-bound PCNA but not with detergent-soluble PCNA. DNA-bound p21 and PCNA, indicating ongoing DNA repair activity, were present in 6 of these 14 HCCs and correlated with a high histological grade and high Ki67-LI. CONCLUSIONS: Our results suggest that in HCC PCNA participates both in DNA synthesis and repair and that highly proliferating HCCs may display a sustained DNA-repair.     

Architecture of the DNA polymerase B-proliferating cell nuclear antigen (PCNA)-DNA ternary complex

DNA replication in archaea and eukaryotes is executed by family B DNA polymerases, which exhibit full activity when complexed with the DNA clamp, proliferating cell nuclear antigen (PCNA). This replication enzyme consists of the polymerase and exonuclease moieties responsible for DNA synthesis and editing (proofreading), respectively. Because of the editing activity, this enzyme ensures the high fidelity of DNA replication. However, it remains unclear how the PCNA-complexed enzyme temporally switches between the polymerizing and editing modes. Here, we present the three-dimensional structure of the Pyrococcus furiosus DNA polymerase B-PCNA-DNA ternary complex, which is the core component of the replisome, determined by single particle electron microscopy of negatively stained samples. This structural view, representing the complex in the editing mode, revealed the whole domain configuration of the trimeric PCNA ring and the DNA polymerase, including protein-protein and protein-DNA contacts. Notably, besides the authentic DNA polymerase-PCNA interaction through a PCNA-interacting protein (PIP) box, a novel contact was found between DNA polymerase and the PCNA subunit adjacent to that with the PIP contact. This contact appears to be responsible for the configuration of the complex specific for the editing mode. The DNA was located almost at the center of PCNA and exhibited a substantial and particular tilt angle against the PCNA ring plane. The obtained molecular architecture of the complex, including the new contact found in this work, provides clearer insights into the switching mechanism between the two distinct modes, thus highlighting the functional significance of PCNA in the replication process.     

Proliferation cell nuclear antigen (clone 19A2) correlates with 5-bromo-2-deoxyuridine labelling in human colonic epithelium.

Measurements of cell proliferation can be used as biomarkers of preneoplastic change. In this study, two immunocytochemical methods that measure different components of the cell cycle were compared to assess cell proliferation on biopsy samples from human colonic mucosa. These methods are based on a monoclonal antibody against 5-bromo-2-deoxyuridine (BrdU), which is confined to S phase cells, and a more broad assessment of proliferation based on an antibody against proliferating cell nuclear antigen (PCNA, clone 19A2). In the PCNA assay, only strongly immunostained nuclei were included. The proliferation index was assessed in colonic mucosa from patients with no colonic disorders. Correlation between individual total proliferation indices determined by either method was significant with rs = 0.6 (p < 0.05). The mean proliferation index in the study group was 7.79% using BrdU and 7.64% using PCNA immunocytochemistry. Distribution of labelled cells within crypts was similar with respect to the two methods with a peak at the 18th and the 24th percentile in the case of BrdU and at the 23rd percentile for PCNA. Variance component analysis showed that at least two biopsy specimens should be evaluated per subject to allow a precise individual characterisation. It is concluded that PCNA (19A2) immunocytochemistry may be used as an operational marker of cell proliferation in normal colonic mucosa. A significant correlation and an agreement in the mean proliferation index between PCNA (19A2) and BrdU can only be achieved by a strictly standardised enumeration of labelled cells limited to strongly stained nuclei in the PCNA evaluation.     

增殖细胞核抗原（PCNA）在原发性胆囊癌中的表达及其预后意义

目的探讨ＰＣＮＡ在原发性胆囊癌的表达及其预后意义。方法３８例原发性胆囊癌石蜡包埋标本，用免疫组织化学方法（ＳＰ）测定。结果ＰＣＮＡ在原发性胆橐癌中的表达阶性率为４５．６±３６．１％，表达呈异质性，且ＰＣＮＡ指数无论是高、中、低分化均显著高于胆囊良性病变组（Ｐ＜０．０５％）。生存期分析表明，ＰＣＮＡ高值组生存划短，预后不佳。ＰＣＮＡ指数与胆囊癌的分化程度、浸润深度，淋巴结转移均显著相关（Ｐ＜０．０５）．在各病理组织类型差异无显著性（Ｐ＞０．０５）。结论ＰＣＮＡ表达在原发性胆囊癌鉴别诊断及预后有一定参考价值。