Genetic and epigenetic alterations as hallmarks of the intricate road to cancer

Macaluso, Marcella; Paggi, Marco G.; Giordano, Antonio

doi:10.1038/sj.onc.1206955

Cited by 94 publications

(61 citation statements)

References 88 publications

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“…25,26 Moreover, it has been suggested that this family of proteins exhibit growth suppressive properties in a cell type-dependent manner and could modulate the transcription of certain genes by chromatin remodeling. 27 Our hypothesis is that in the corneal and conjunctival epithelia, the distribution cytoplasm/nucleus of PAI-2 can be controlled by the interaction with pRb2/p130 and Rb1/p105 through multiple pathways. For instance, under specific 'stimuli', and/or at specific times of cell cycle, pRb2/p130 and Rb1/p105 could shuttle PAI-2 between cytoplasm and nucleus, thus controlling the concentration of PAI-2 in these cellular compartments.…”

Section: Resultsmentioning

confidence: 98%

Cytoplasmic and nuclear interaction between Rb family proteins and PAI-2: a physiological crosstalk in human corneal and conjunctival epithelial cells

et al. 2006

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Extracellular plasminogen activator inhibitor type-2 (PAI-2) is a potent inhibitor of urokinase-type plasminogen activator (u-PA) and also acts as a multifunctional protein. However, the biological activity of intracellular PAI-2, as well as its intracellular targets, until now remain an enigma. Here, we show that pRb2/p130 and Rb1/p105, but not p107, interact with PAI-2 in both the cytoplasm and nucleus of normal primary human corneal and conjunctival epithelial cells. We provided the first in vivo evidence that a specific fragment of the PAI-2 promoter is bound simultaneously by pRb2/ p130, PAI-2, E2F5, histone deacetylase 1 (HDAC1), DNA methyltransferase 1 (DNMT1), and histone methyltransferase (SUV39H1), in normal primary human corneal epithelial cells, and by pRb2/p130, PAI-2, E2F5, HDAC1, and DNMT1, in normal primary human conjunctiva epithelial cells. Our results strongly indicate a physiological interaction between pRb family members and PAI-2, suggesting the hypothesis that pRb2/p130 and PAI-2 may cooperate in modulating PAI-2 gene expression by chromatin remodeling, in normal corneal and conjunctival cells.

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Section: Resultsmentioning

confidence: 98%

Cytoplasmic and nuclear interaction between Rb family proteins and PAI-2: a physiological crosstalk in human corneal and conjunctival epithelial cells

et al. 2006

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“…Whether this loss of DDX3 expression is causally related to HCC development, or merely reflects a wide spectrum of gene expression alteration in HCC, is not clear yet. Gene expression alteration in tumors generally involves several mechanisms, including (i) genetic changes, such as amplification, mutation, deletion, loss of heterozygosity (LOH); (ii) epigenetic changes, such as aberrant methylation and acetylation; (iii) post-transcriptional regulation by microRNA (miRNA); and (iv) posttranslational modification, such as phosphorylation, acetylation, ubiquitination, and sumoylation (AlarconVargas and Ronai, 2002;Albertson et al, 2003;Brooks and Gu, 2003;Macaluso et al, 2003;Shackelford and Pagano, 2004;Gregory and Shiekhattar, 2005). Although numerous genetic changes have been observed in HCC, these changes have been identified only in a limited number of chromosome arms not including where DDX3 resides on the X chromosome (Buendia, 2000;Tannapfel and Wittekind, 2002;Thorgeirsson and Grisham, 2002).…”

Section: Discussionmentioning

confidence: 99%

DDX3, a DEAD box RNA helicase, is deregulated in hepatitis virus-associated hepatocellular carcinoma and is involved in cell growth control

Chang¹,

Chi²,

et al. 2005

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Hepatocellular carcinoma (HCC) is one of the leading causes of cancer deaths worldwide and is highly correlated with hepatitis virus infection. Our previous report shows that a DEAD box RNA helicase, DDX3, is targeted and regulated by hepatitis C virus (HCV) core protein, which implicates the involvement of DDX3 in HCV-related HCC development. In this study, the potential role of DDX3 in hepatocarcinogenesis is investigated by examining its expression in surgically excised human HCC specimens. Here we report the differential deregulation of DDX3 expression in hepatitis virus-associated HCC. A significant downregulation of DDX3 expression is found in HCCs from hepatitis B virus (HBV)-positive patients, but not from HCV-positive ones, compared to the corresponding nontumor tissues. The expression of DDX3 is differentially regulated by the gender and, moreover, there is a tendency that the downregulation of DDX3 expression in HCCs is more frequent in males than in females. Genetic knockdown of DDX3 with small interfering RNAs (siRNA) in a nontransformed mouse fibroblast cell line, NIH-3T3, results in a premature entry to S phase and an enhancement of cell growth. This enhanced cell cycle progression is linked to the upregulation of cyclin D1 and the downregulation of p21 WAF1 in the DDX3 knockdown cells. In addition, constitutive reduction of DDX3 expression increases the resistance of NIH-3T3 cells to serum depletion-induced apoptosis and enhances the ras-induced anchorage-independent growth, indicating the involvement of DDX3 in cell growth control. These findings together with the previous study suggest that the deregulation of DDX3, a DEAD box RNA helicase with cell growth-regulatory functions, is involved in HBV-and HCV-associated pathogenesis.

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“…Inactivation of these genes is believed to be involved in the progression of many human cancers. As one of the principal causes of gene inactivation, aberrant hypermethylation in the promoter of cancer-related genes is appealing more and more focuses (16,17). However, corresponding information on ESCC is still limited (16).…”

Section: Introductionmentioning

confidence: 99%

Aberrant DNA Methylation of P16, MGMT, and hMLH1 Genes in Combination with MTHFR C677T Genetic Polymorphism in Esophageal Squamous Cell Carcinoma

Wang

Sasco²,

et al. 2008

Cancer Epidemiology, Biomarkers &Amp; Prevention

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To explore the role of aberrant hypermethylation of cancer-related genes, such as P16, MGMT, and hMLH1, in the esophageal squamous cell carcinoma (ESCC) as well as its relation to dietary folate intake and MTHFR C677T polymorphism, we conducted a molecular epidemiologic study in China. One hundred and twentyfive histologically confirmed ESCC patients having undergone surgery in the Yangzhong People's Hospital between January 2005 and March 2006 were recruited. The aberrant CpG island hypermethylation of P16, MGMT, and hMLH1 genes could be found in cancer tissues with frequency of about 88.0%, 27.2%, and 3.2%, respectively, and in remote normal-appearing esophageal tissues with frequency of about 36.8%, 11.2%, and 0.0%, respectively. No hypermethylation was found in the normal esophageal tissues from healthy controls. Compared with those patients without lymph node metastasis, MGMT gene showed a higher proportion of hypermethylation in cancer tissues, whereas P16 gene showed a higher proportion of hypermethylation in remote normal-appearing esophageal tissues in patients with lymph node metastasis. A significant association was found between MTHFR C677T genetic polymorphism and CpG island methylation status of MGMT gene. After adjustment for potential confounders, individuals carrying CT or TT genotype have higher frequency of hypermethylation in MGMT gene in cancer tissues, with odds ratio of 3.34 (95% confidence interval, 1.07-10.39) and 3.83 (95% confidence interval, 1.13-12.94), respectively. This study indicated that the aberrant CpG island hypermethylation of cancerrelated genes was associated with ESCC and might be a promising biomarker in diagnosis and prognosis.

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Genetic and epigenetic alterations as hallmarks of the intricate road to cancer

Cited by 94 publications

References 88 publications

Cytoplasmic and nuclear interaction between Rb family proteins and PAI-2: a physiological crosstalk in human corneal and conjunctival epithelial cells

Cytoplasmic and nuclear interaction between Rb family proteins and PAI-2: a physiological crosstalk in human corneal and conjunctival epithelial cells

DDX3, a DEAD box RNA helicase, is deregulated in hepatitis virus-associated hepatocellular carcinoma and is involved in cell growth control

Aberrant DNA Methylation of P16, MGMT, and hMLH1 Genes in Combination with MTHFR C677T Genetic Polymorphism in Esophageal Squamous Cell Carcinoma

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