Cyclin-D1 expression in human renal-cell carcinoma

Hedberg, Ylva; Davoodi, Estela; Roos, Göran; Ljungberg, Börje; Landberg, Göran

doi:10.1002/(sici)1097-0215(19990621)84:3<268::aid-ijc12>3.0.co;2-8

Cited by 43 publications

(7 citation statements)

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“…These G1/S defects also partly mirror the clinical aggressiveness of the disease by showing links to outcome and clinical stage. 6,10,16,[22][23][24][25][26] Our study confirmed earlier results showing that aberrations in the Rb gene and in the expression of pRb are rare in RCC. 12,13 In order to minimize problems associated with quantifying specific phosphorylation of pRb, 2 methods were used.…”

Section: Discussionsupporting

confidence: 89%

“…Protein extracts were prepared as described earlier and the Western blots were run according to standard procedures. 6 The pRb protein was detected by IF8 monoclonal antibodies (diluted 1:500; Santa Cruz Biotechnology), an antibody that produces 2 bands where the slower migrating form represents the phosphorylated form of the protein, defined as ppRb WB . The ppRb WB band was confirmed by the RD1-Ser780abR polyclonal antibody (diluted 1:500; Novakemi, Sweden).…”

Section: Western Blottingmentioning

confidence: 99%

“…High cyclin D1 levels could, theoretically, cause an increased CDK-activity and unbalanced phosphorylation of pRb. Cyclin D1 is highly expressed in several malignancies, [3][4][5][6] either due to amplification of the CCND1 gene or as a result of impaired degradation. [7][8][9] In RCC, the majority of the tumors expressed higher cyclin D1 levels compared to normal kidney cortex, suggesting that cyclin D1 was overexpressed in a fraction of the tumors.…”

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confidence: 99%

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Retinoblastoma protein in human renal cell carcinoma in relation to alterations in G1/S regulatory proteins

Hedberg

Ljungberg

Roos

et al. 2003

Intl Journal of Cancer

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The retinoblastoma gene product (pRb) is the main substrate for cyclin-dependent kinases (CDKs) during the G1/S transition. Aberrations in cell cycle regulatory proteins, which have been observed in many malignancies, can theoretically cause increased phosphorylation of pRb due to unbalanced CDK activities. The expression and phosphorylation of pRb and potential associations to cell cycle aberrations in renal cell carcinomas (RCC) has only partly been clarified. We therefore evaluated the presence of pRb and the level of pRb-phosphorylation in 216 RCCs arranged in tissue microarrays by using different pRb-antibodies, including pRb-phosphospecific antibodies. Most RCCs (95%) expressed pRb, while cases with the low pRb levels, potentially indicative for pRb-inactivation, were few. In order to detect secondary alterations to a potential pRb-inactivation, the p16 expression was also monitored. None of the tumors exhibited increased p16 levels, confirming that pRb-inactivation is rare in RCC. Phosphorylated pRb was detected in approximately 50% of the RCCs, using Western blotting or immunohistochemistry. The immunohistochemical ppRb ser807/811 levels were associated with high proliferation, cyclin D1, cyclin E and p27 protein content. Surprisingly, there was no association between pRb-phosphorylation and clinicopathological data. In summary, pRb seemed to be functional and aberrations in G1/S-regulatory proteins were associated with increased phosphorylation of pRb and proliferation. The data supports that pRb might be one of the main cell cycle regulators in RCC. © 2003 Wiley-Liss, Inc. Key words: retinoblastoma protein; phosphorylation; cell cycle; G1/ S-cyclins; renal cell carcinomaCell cycle progression and proliferation is controlled by sets of checkpoints with the G1/S-checkpoint as the main regulator. Essential cell cycle regulatory gene products are the cyclin-dependent kinases (CDKs) that are sequentially activated by various cyclins and inactivated by CDK inhibitors. Cyclin D1 is activated during early G1 and forms a complex with CDK4 or CDK6. 1 This complex initiates cell cycle progression by phosphorylation of the retinoblastoma gene product (pRb), which is followed by E2F release and activation of the cyclin E/CDK2 complex, which further phosphorylate pRb. 2 Many of the interplayers of this cascade, also called the "Rb-pathway," are deregulated in malignancies. High cyclin D1 levels could, theoretically, cause an increased CDK-activity and unbalanced phosphorylation of pRb. Cyclin D1 is highly expressed in several malignancies, 3-6 either due to amplification of the CCND1 gene or as a result of impaired degradation. [7][8][9] In RCC, the majority of the tumors expressed higher cyclin D1 levels compared to normal kidney cortex, suggesting that cyclin D1 was overexpressed in a fraction of the tumors. We showed in a previous study that high cyclin D1 in RCC was associated with good prognosis, small and diploid tumors, suggesting that activation of cyclin D1 is a characteristic for low malignant features in ...

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Section: Discussionsupporting

confidence: 89%

Section: Western Blottingmentioning

confidence: 99%

mentioning

confidence: 99%

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Retinoblastoma protein in human renal cell carcinoma in relation to alterations in G1/S regulatory proteins

Hedberg

Ljungberg

Roos

et al. 2003

Intl Journal of Cancer

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“…The results of the current study are similar to those of previous studies reporting that high cyclin D1 expression significantly correlates with an improved prognosis, while low expression of cyclin D1 correlates with a poor prognosis of ccRCC (26–28). The expression of cyclin D1 is markedly correlated with that of p27 in ccRCC; low p27 expression independently predicts a poor prognosis of RCC, whilst low cyclin D1 expression appears to shorten the survival rate of RCC patients (29).…”

Section: Discussionsupporting

confidence: 90%

A GWAS-identified susceptibility locus on chromosome 11q13.3 and its putative molecular target for prediction of postoperative prognosis of human renal cell carcinoma

Han

et al. 2013

Oncology Letters

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Genome-wide association studies have been used to identify single nucleotide polymorphisms (SNPs) associated with renal cell carcinoma (RCC) in European individuals. The current study aimed to evaluate the correlation between significant SNPs identified in European individuals and the occurrence and postoperative prognosis of RCC in Chinese individuals. A total of 400 cases and 806 controls were involved in the current study. rs4765623, rs7105934, rs7579899 and rs1867785 were genotyped using qPCR, and the expression of cyclin D1 in renal tissue and RCCs was determined via western blotting and immunohistochemistry. The correlation between the SNPs/cyclin D1 expression and overall survival was evaluated using multivariate Cox regression analyses. Of the four SNPs, only rs7105934 was found to significantly correlate with RCC risk in Chinese individuals. The rs7105934 GA + AA genotype was correlated with a reduced risk of RCC with an odds ratio of 0.64 (95% confidence interval [CI], 0.43–0.96), following adjustment for age. This genotype was found to independently predict an improved postoperative prognosis in the multivariate analysis, with a hazard ratio (HR) of 0.12 (95% CI, 0.02–0.93). Expression of cyclin D1, a putative regulated protein of rs7105934, did not vary in adjacent renal tissue and tumors when compared with that of various rs7105934 genotypes. However, cyclin D1 expression in RCCs inversely correlated with advanced tumor stage, and moderate to high expression of cyclin D1 in RCCs independently predicted improved postoperative prognosis, with an HR of 0.13 (95% CI, 0.02–0.96). Observations of the present study indicate that the rs7105934 A allele is associated with reduced risk and improved postoperative prognosis of RCC; however, this effect is unlikely to be caused by cyclin D1 expression.

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“…Approximately 75% of the RCC tumors expressed higher level of cyclin D1 than the normal kidney context. Surprisingly, previous studies did not find cyclin D1 expression correlated with proliferation, as determined by Ki-67 or s-phase analysis [ 45 ].…”

Section: Discussionmentioning

confidence: 90%

DACH1 inhibits cyclin D1 expression, cellular proliferation and tumor growth of renal cancer cells

et al. 2014

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BackgroundRenal cell carcinoma (RCC) is a complex with diverse biological characteristics and distinct molecular signature. New target therapies to molecules that drive RCC initiation and progression have achieved promising responses in some patients, but the total effective rate is still far from satisfaction. Dachshund (DACH1) network is a key signaling pathway for kidney development and has recently been identified as a tumor suppressor in several cancer types. However, its role in renal cell carcinoma has not been fully investigated.MethodsImmunohistochemical staining for DACH1, PCNA and cyclin D1 was performed on human renal tissue microaraays and correlation with clinic-pathological characteristics was analyzed. In vitro proliferation, apoptosis and in vivo tumor growth were evaluated on human renal cancer cell lines with decitabine treatment or ectopic expression of DACH1. Downstream targets and potential molecular mechanism were investigated through western blot, immunoprecipitation and reporter gene assays.ResultsExpression of DACH1 was significantly decreased in human renal carcinoma tissue. DACH1 protein abundance was inversely correlated with the expression of PCNA and cyclin D1, tumor grade, and TNM stage. Restoration of DACH1 function in renal clear cell cancer cells inhibited in vitro cellular proliferation, S phase progression, clone formation, and in vivo tumor growth. In mechanism, DACH1 repressed cyclin D1 transcription through association with AP-1 protein.ConclusionOur results indicated that DACH1 was a novel molecular marker of RCC and it attributed to the malignant behavior of renal cancer cells. Re-activation of DACH1 may represent a potential therapeutic strategy.

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Cyclin-D1 expression in human renal-cell carcinoma

Cited by 43 publications

References 15 publications

Retinoblastoma protein in human renal cell carcinoma in relation to alterations in G1/S regulatory proteins

Retinoblastoma protein in human renal cell carcinoma in relation to alterations in G1/S regulatory proteins

A GWAS-identified susceptibility locus on chromosome 11q13.3 and its putative molecular target for prediction of postoperative prognosis of human renal cell carcinoma

DACH1 inhibits cyclin D1 expression, cellular proliferation and tumor growth of renal cancer cells

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