Inactivation of p16INK4 in hepatocellular carcinoma

Hui, Ai Min; Sakamoto, Michiie; Kanai, Yae; Ino, Yoshinori; Gotoh, Masahiro; Yokota, Jun; Hirohashi, Setsuo

doi:10.1053/jhep.1996.v24.pm0008781327

Cited by 28 publications

(36 citation statements)

References 5 publications

(9 reference statements)

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“…However, as shown in Figure 2b, p16 protein expression was undetectable in cell lines STA-ET-3, the STA-ET-7 series, and STA-ET-8 expressing a p16 transcript (compare to Figure 2a and 3b). These results indicate that, in addition to homozygous gene loss, p16 is frequently inactivated by post-transcriptional mechanisms in Ewing tumors as has been previously observed in hepatocellular carcinoma (Hui et al, 1996).…”

Section: Status and Expression Of P15/p16 Genessupporting

confidence: 82%

Among genes involved in the RB dependent cell cycle regulatory cascade, the p16 tumor suppressor gene is frequently lost in the Ewing family of tumors

et al. 1997

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The pRB cell cycle regulatory cascade is frequently perturbed in neoplasia by overexpression of a component of the pRB-phosphorylating cyclin D1/CDK4 complex or by inactivation of pRB or the CDK4 inhibitors p16 and p15. We investigated the status and expression of p16, p15, CCND1, CDK4 and RB genes in the Ewing family of tumors. P16 loss was observed in 8 of 27 tumors (30%) and in 12 of 23 (52%) tumor cell lines from unrelated patients. There were no discrepancies in the p16 status between primary tumors and the corresponding cell lines and between cell lines established from consecutive tumor samples. p15 was codeleted in most cases but p15 mRNA was absent also in cell lines retaining the gene. In addition, posttranscriptional p16 inactivation was observed in two cases. Although no evidence for CDK4 or CCND1 ampli®cation was obtained, expression of these genes varied considerably in the cell lines in a case speci®c manner. In wild-type p16 cell lines, pRB expression was lost in one case. Our data indicate that, despite the absence of cytogenetically detectable 9p21 chromosomal aberrations, p16 deletions constitute the most frequent secondary molecular aberration in Ewing tumors so far. These results are discussed in the context of the stage of disease and the clinical outcome of the patients. The potential prognostic impact of these ®ndings remains to be further evaluated.

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Section: Status and Expression Of P15/p16 Genessupporting

confidence: 82%

Among genes involved in the RB dependent cell cycle regulatory cascade, the p16 tumor suppressor gene is frequently lost in the Ewing family of tumors

et al. 1997

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“…Recently, the locus of a tumor suppressor gene, p16 INK4 , coding for an inhibitor of cyclin D1/Cdk4, was found to be frequently lost in various malignancies. 35 Inactivation of the p16 INK4 gene has been reported in various human cancers, including human HCC, and in half of HCC cell lines and 34% of HCC tissues, p16 INK4 protein is not detected by immunoblot, 36 suggesting that the level of p16 INK4 is down-regulated. In addition, Ray et al 37 reported that the HCV core protein appears to act as a promoter of cell growth by repressing the transcription of another Cdk inhibitor (CKI), p21 WAF1 .…”

Section: Discussionmentioning

confidence: 99%

Cyclins and cyclin-dependent kinases: Comparative study of hepatocellular carcinoma versus cirrhosis

et al. 2003

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Increasing evidence has indicated that perturbation of cyclins is one of the major factors leading to cancer. The aim of this study was not only to investigate various cell cycle-related kinase activities in hepatocellular carcinoma (HCC), but also to analyze the difference of cell cycle-related kinase activity levels between hepatitis C virus (HCV)-induced HCC and HCVinduced cirrhosis. The protein levels of cyclins D1, E, A, and H, and of cyclin dependent kinase 1 (Cdk1), Cdk2, Cdk4, Cdk6, and Cdk7 in HCC and in surrounding nontumorous cirrhosis were determined by Western blot. The enzymatic activities of cyclins D1, E, A, Cdk1, Cdk4, Cdk6, Cdk7, and Wee1 were measured using in vitro kinase assays. Protein levels and kinase activities of cyclin D1, Cdk4, cyclin E, cyclin A, and Wee1 were significantly elevated in HCC compared with surrounding cirrhotic tissues. The enhanced cyclin D1-related kinase activity in HCC was accompanied by the up-regulation of Cdk4 activity, but not Cdk6 activity. The kinase activities of Cdk6, Cdk7, and Cdk1 did not differ between HCC and surrounding cirrhotic tissues. In addition, the protein levels and kinase activities of cyclin D1, Cdk4, and cyclin E were higher in poorly differentiated HCC and advanced HCC. In conclusion, the increases of cyclin D1, Cdk4, cyclin E, cyclin A, and Wee1 play an important role in the development of HCC from cirrhosis. Cyclin D1, Cdk4, and cyclin E activation may be closely related to the histopathologic grade and progression of HCC. R ecent studies, including our research, have revealed that the deranged expression of cell cyclerelated proteins is one of the major factors contributing to hepatocellular carcinoma (HCC) development. 1-6 Here we investigated biochemical differences of various cell cycle-related kinase activities and protein levels in cirrhosis and HCC.Specific cyclin/cyclin-dependent kinase (Cdk) complexes are activated at different intervals during the cell cycle. 7-15 Cyclin D1/Cdk4 and cyclin D1/Cdk6 are activated in mid-G1 (Fig. 1, phase 1), whereas cyclin E/Cdk2 complexes are required for the G1/S transition (Fig. 1, phase 2), cyclin A/Cdk2 for the progression of DNA synthesis (Fig. 1, phase 3), and cyclin A-B/Cdk1 for the G2/M transition (Fig. 1, phase 4) of mitosis. The activation of cyclin D1/Cdk4 and cyclin D1/Cdk6 complexes at mid-G1 is responsible for the phosphorylation of retinoblastoma protein (pRb), and 2 Rb related proteins, p107, and p130. Members of the pRb family form complexes with transcription factors of the E2F family. 16 This interaction with pRb family members blocks the transcriptional activity of E2Fs; the complexes formed also function as active transcriptional repressor complexes at the promoters of some cell cycle genes. Phosphorylation of the pRb family inhibits the interaction with E2F family transcription factor and permits the expression of genes necessary for S-phase entry (cyclin A, proliferating cell nuclear antigen, and so on). 17 The expression of cyclins E and A at mid-to late-G1 permits the form...

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“…This suggested that there might be another mechanism inactivating p16 and p15 genes in human primary hepatocarcinoma [5][6][7][8][9] . It has been demonstrated that aberrant methylation of CpG islands, which are CpG dinucleotide rich region located mainly in the promoter regions of many gene, serves as an alternative mechanism for inactivation of the tumor suppressor gene in cancers [10] .…”

Section: Introductionmentioning

confidence: 99%

Association of low p16INK4a and p15INK4b mRNAs expression with their CpG islands methylation with human hepatocellular carcinogenesis

Qin¹,

Liu²,

Li³

et al. 2004

WJG

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AIM:To study the significance of p16 and p15 transcription suppression with hypermethylation of their genes' 5'CpG islands during human hepatocellular carcinogenesis. METHODS:The mRNA expression levels of p16 and p15 genes were evaluated in cancerous, para-cancerous and noncancerous tissues of 20 HCC, 3 normal liver tissues from 3 accidentally died healthy adults using semi-quantitatively Northern blot. The methylation status was also assessed with methylation specific PCR. RESULTS: p16 mRNA expression level was decreased in the cancerous tissues in 60% (12/20) of HCC patients, of which 2 cases had no p16 mRNA detected, 5 cases (25%) displayed variation in the order of cancerous

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Inactivation of p16INK4 in hepatocellular carcinoma

Cited by 28 publications

References 5 publications

Among genes involved in the RB dependent cell cycle regulatory cascade, the p16 tumor suppressor gene is frequently lost in the Ewing family of tumors

Among genes involved in the RB dependent cell cycle regulatory cascade, the p16 tumor suppressor gene is frequently lost in the Ewing family of tumors

Cyclins and cyclin-dependent kinases: Comparative study of hepatocellular carcinoma versus cirrhosis

Association of low p16INK4a and p15INK4b mRNAs expression with their CpG islands methylation with human hepatocellular carcinogenesis

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