Aged ; Anthracosis ; complications ; metabolism ; pathology ; Cyclin-Dependent Kinase Inhibitor p16 ; metabolism ; Humans ; Lung ; metabolism ; pathology ; Lung Neoplasms ; complications ; metabolism ; pathology ; Male ; Middle Aged ; Retinoblastoma Protein ; metabolism

Hepatocellular carcinomas (HCCs) show genomic alterations, including DNA rearrangements associated with HBV DNA integration, loss of heterozygosity, and chromosomal amplification. The genes most frequently involved are those encoding tumor suppressors. The p16INK4A tumor suppressor gene frequently displays genetic alteration in HCC tissues. The present study was performed to examine the incidence of methylated p16INK4A in the sera of liver cirrhosis (LC) and HCC patients, and to evaluate its role as a tumor marker of HCC. The sera of 23 LC patients and 46 HCC patients were examined in this study. The methylation status of p16INK4A was evaluated by methylation-specific PCR of serum samples. Methylated p16INK4A was detected in 17.4% (4/23) of LC patients and in 47.8% (22/46) of HCC patients. No association was demonstrated between p16INK4A methylation and serum AFP level. As the status of p16INK4A methylation was not associated with serum AFP level, it may have a role as a tumor marker of HCC.
Aged ; Carcinoma, Hepatocellular/*genetics ; DNA/metabolism ; *DNA Methylation ; Female ; Fibrosis ; *Genes, p16 ; Human ; Liver/pathology ; Liver Cirrhosis/*genetics ; Liver Neoplasms/*genetics ; Male ; Middle Aged ; Polymerase Chain Reaction ; Predictive Value of Tests ; Protein p16/*blood ; Sensitivity and Specificity ; Time Factors ; Tumor Markers, Biological

BubR1 mitotic checkpoint kinase monitors attachment of microtubules to kinetochores and links regulation of the chromosome-spindle attachment to mitotic checkpoint signaling. Defects in BubR1-mediated signaling severely perturb checkpoint control and are linked to diseases such as cancer. Studies using BubR1 mouse models suggest that BubR1 activities prevent premature aging and infertility. In this study, we show that BubR1 depletion in human adipose-derived mesenchymal stem cells (ASCs) precedes loss of the differentiation potential and induction of replicative senescence. These effects occur independently of p16(INK4A) expression and may involve DNA methylation. Our results reveal a new and unsuspected feature of BubR1 expression in regulation of adult stem cell differentiation.
*Adipogenesis ; Adipose Tissue/*cytology ; Adult ; Cell Aging ; Cells, Cultured ; DNA Methylation ; Gene Expression Regulation ; Genes, p16 ; Humans ; Mesenchymal Stem Cells/*cytology/metabolism ; Protein-Serine-Threonine Kinases/genetics/*metabolism

Aging is an independent risk factor for chronic diseases in the elderly, and understanding aging mechanisms is one of the keys to achieve early prevention and effective intervention for the diseases. Aging process is dynamic and systemic, making it difficult for mechanistic study. With recent advances in aging biomarkers and development of live-imaging technologies, more and more reporter mouse models have been generated, which can live monitor the aging process, and help investigate aging mechanisms at systemic level and develop intervention strategies. This review summarizes recent advances in live-imaging aging reporter mouse models based on widely used aging biomarkers (p16^Ink4a, p21^Waf1/Cip1, p53 and Glb1), and discusses their applications in aging research.
Humans ; Animals ; Mice ; Aged ; Aging ; Cyclin-Dependent Kinase Inhibitor p16/metabolism* ; Cyclin-Dependent Kinase Inhibitor p21/metabolism* ; Biomarkers ; Tumor Suppressor Protein p53

OBJECTIVETo study the expression of retinoic acid receptor-beta (RAR-beta) mRNA and p16, p53, Ki67 proteins in squamous-cell carcinoma of the esophagus and its precursor lesions in a high risk population.

METHODSA total of 397 tissue specimens were collected from individuals with normal mucosa (NM, n = 25), mild dysplasia (MiD, n = 69), moderate dysplasia (MoD, n = 106), severe dysplasia (SD, n = 51), carcinoma in situ (CIS, n = 78), and squamous-cell carcinoma (SC, n = 68). Expression of RAR-beta mRNA was detected by in situ hybridization, and that of p16, p53 and Ki67 proteins by immunohistochemistry.

RESULTSThe frequencies of RAR-beta mRNA expression in NM, MiD, MoD, SD, CIS and SC were 96.0%, 89.9%, 67.9%, 68.6%, 62.8%, and 63.2%, respectively. The frequencies of p16 expression were 88.0%, 71.0%, 64.2%, 51.0%, 53.8% and 52.9%; those of p53 expression were 4.0%, 39.1%, 57.5%, 52.9%, 67.9% and 69.1%; those of Ki67 expression were 0, 40.6%, 61.3%, 58.8%, 59.0% and 75.0%, respectively.

CONCLUSIONThere are no significant differences in four biomarkers expression between carcinoma of the esophagus and its precursor lesions.

Biomarkers, Tumor ; metabolism ; Carcinoma, Squamous Cell ; metabolism ; Cyclin-Dependent Kinase Inhibitor p16 ; metabolism ; Esophageal Neoplasms ; metabolism ; Esophagus ; metabolism ; Humans ; Ki-67 Antigen ; metabolism ; Precancerous Conditions ; metabolism ; RNA, Messenger ; biosynthesis ; genetics ; Receptors, Retinoic Acid ; biosynthesis ; genetics ; Tumor Suppressor Protein p53 ; metabolism

Cyclin-Dependent Kinase Inhibitor p16 ; metabolism ; Cystadenocarcinoma, Serous ; metabolism ; pathology ; Diagnosis, Differential ; Endometrial Neoplasms ; metabolism ; pathology ; Female ; Humans ; Precancerous Conditions ; metabolism ; pathology ; RNA-Binding Proteins ; metabolism ; Tumor Suppressor Protein p53 ; metabolism

Cyclin-Dependent Kinase Inhibitor p16 ; metabolism ; Female ; Genes, p16 ; Genes, p53 ; Humans ; Hysterectomy ; methods ; Ki-67 Antigen ; metabolism ; Leiomyoma ; genetics ; metabolism ; pathology ; surgery ; Leiomyosarcoma ; genetics ; metabolism ; pathology ; surgery ; Prognosis ; Smooth Muscle Tumor ; genetics ; metabolism ; pathology ; surgery ; Tumor Suppressor Protein p53 ; metabolism ; Uterine Neoplasms ; genetics ; metabolism ; pathology ; surgery

OBJECTIVE(1) To investigate the promoter methylation status of gene p16(INK4a) and gene RB in breast carcinoma and the adjacent non-neoplastic hyperplastic epithelial tissue. (2) To study the correlation of p16(INK4a) gene expression at protein level with the abnormal gene methylation, the clinical manifestation and the pathological parameters.

METHODSMethylation status of promoters of p16(INK4a) gene and RB gene was detected by using methylation specific PCR in 46 cases of breast cancer, 22 cases of the adjacent non-neoplastic hyperplastic epithelium tissue and 7 cases of normal breast tissue. In addition, the p16(INK4a) gene protein expression level was also detected using immunohistochemical technique(SP method) in 46 cases of breast cancer and 22 cases of the adjacent hyperplastic epithelial tissue.

RESULTSThe methylation rate of p16(INK4a) gene was 23.9% (11/46) in breast cancer, 18.2% (4/22) in the adjacent non-neoplastic hyperplastic epithelial tissue and 1/7 in normal breast tissue, respectively. The methylation rate of RB gene was relatively low, which was 10.8% (5/46), 9.1% (2/22) and 0(0/7) in the above 3 groups, respectively. Methylation rate of p16(INK4a) gene and RB gene was not significantly different among the breast cancer, the adjacent non-neoplastic hyperplastic tissue and the normal tissues (P > 0.05). However, the methylation status of p16(INK4a) gene was closely correlated with its protein expression level and the negative ER expression result of the breast cancer (P < 0.05), but not correlated with the size of the cancer, differentiation status, lymph node metastasis, and age. The methylation status of RB gene was correlated with lymph node metastasis, but not with the size, the differentiation status, ER expression of the breast cancer and the age of the patients.

CONCLUSIONSThe abnormal methylation of p16(INK4a) gene may not play a significant role in the early stage of breast cancinogenesis, but may play a role of in the progression of the cancer. RB gene methylation may also be a indicator in choice to identify the progression and prognosis of breast cancer.

Adult ; Aged ; Breast Neoplasms ; genetics ; metabolism ; pathology ; Carcinoma, Ductal, Breast ; genetics ; metabolism ; pathology ; Carcinoma, Intraductal, Noninfiltrating ; genetics ; metabolism ; pathology ; Cyclin-Dependent Kinase Inhibitor p16 ; genetics ; metabolism ; DNA Methylation ; Female ; Gene Expression Regulation, Neoplastic ; Genes, p16 ; Humans ; Lymphatic Metastasis ; Middle Aged ; Receptors, Estrogen ; metabolism ; Retinoblastoma Protein ; genetics ; metabolism

PURPOSE: The molecular mechanisms that are responsible for the initiation and progression of breast cancers are largely unknown. This study was to analyze the cyclin B1, cdc2, p53 and p16 tumor suppressor genes in human breast cancer. MATERIALS AND METHODS: To investigate the role of cyclin B1, cdc2, p53 and p16 in the pathogenesis and progression of breast carcinomas, 98 cases of breast cancers were examined by immunohistochemical method. The correlations of cyclin B1, cdc2, p53 and p16 expression with various clinico-pathologic findings were analysed. RESULTS: In the normal breast tissues, cyclin B1, cdc2 and p16 were weakly expressed, while p53 was not expressed. On the other hand, cyclin B1, cdc2, p53 and p16 were overexpressed in breast cancer, showing correlation between the expression of cyclin B1 and cdc2 and breast cancers (p=0.00). The overexpressions of cdc2 and p16 were correlated with an infiltrative tumor border pattern and this was statistically significant (p<0.05). In addition, the overexpression of cdc2 was correlated with histologic high grade carcinomas (p=0.00). CONCLUSION: Cyclin B1 and cdc2 appeared to be involved in the genesis or progression of breast cancers. In addition, the overexpressions of p16 and p53 may play important roles in more aggressive tumor and the overexpression of cdc2 is associated with progression of tumor to a higher grade of breast carcinomas. The deranged overexpressions of cyclin B1, cdc2, p16 and p53 may play an important role in human breast carcinogenesis.
Adult ; Aged ; Breast Neoplasms/*genetics/metabolism/pathology ; Cyclin B/*genetics/metabolism ; Cyclin B1/*genetics/metabolism ; Cyclin-Dependent Kinase Inhibitor p16/*genetics/metabolism ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Immunohistochemistry ; Middle Aged ; Tumor Suppressor Protein p53/*genetics/metabolism

SV40 large T antigen, a viral oncoprotein, is known to immortalize human diploid fibroblast by soaking up cellular RB and p53, but its frequency is extremely low. Additional genetic alteration is necessary for single-step immortalization. We attempted to find out what this alteration is by overexpressing cellular signal mediator genes; c-myc and cyclin D frequently amplified in many cancer cells. Overexpression of cyclin D did not affect the immortalization, but, overexpression of c-myc along with T antigen could immortalize normal human diploid fibroblast. Several cellular markers tested during immortalization process showed that p21, a cyclin-dependent kinase inhibitor and a marker of cellular senescence, disappeared in the life span-extended cells by T antigen and in the immortalized cells by c-myc. p21 was, however, elevated in the senescent cells and in the cells of crisis. Interestingly, p16 was upregulated whenever T antigen is overexpressed. Telomerase activity was also activated only in the immortalized cells. These results suggest that overexpression of c-myc contributes to immortalization of human diploid fibroblast by activating telomerase activity and suppressing p21 activity.
Antigens, Polyomavirus Transforming/genetics/*metabolism ; Biological Markers ; Cell Aging/*genetics ; Cell Transformation, Viral ; Cells, Cultured ; Cyclins/metabolism ; Diploidy ; Fibroblasts/*metabolism ; Genes, myc/*genetics ; Human ; Protein p16/metabolism ; Simian virus 40/genetics ; Support, Non-U.S. Gov't ; Telomerase/metabolism