Hypomethylation of Long Interspersed Nuclear Element-1 (LINE-1) is Associated with Poor Prognosis via Activation of c-MET in Hepatocellular Carcinoma

Zhu, Chunhui; Utsunomiya, Tohru; Ikemoto, Tetsuya; Yamada, Shinichiro; Morine, Yuji; Imura, Satoru; Arakawa, Yusuke; Takasu, Chie; Ishikawa, Daichi; Imoto, Issei; Shimada, Mitsuo

doi:10.1245/s10434-014-3874-4

Cited by 47 publications

(42 citation statements)

References 25 publications

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“…In CRC and HCC, L1 insertion into the intronic region of MET (L1-MET) leads to elevated expression of MET. 38,46 In CRC and associated liver metastasis tissue, the hypomethylation of L1 ASP within L1-MET is correlated with elevated MET expression. 38 In HCC, L1-MET was also identified and its hypomethylation was found to be correlated with elevated c-MET expression.…”

Section: Functions Of L1s In Cancer Retrotransposition-dependent Funcmentioning

confidence: 99%

“…38 In HCC, L1-MET was also identified and its hypomethylation was found to be correlated with elevated c-MET expression. 46 Chromosomal rearrangements and processed pseudogenes.…”

Section: Functions Of L1s In Cancer Retrotransposition-dependent Funcmentioning

confidence: 99%

“…In cervical carcinoma samples, L1 hypomethylation levels were found to be significantly higher than those of paracancerous tissues. 44 L1 hypomethylation has been reported to correlate with unfavorable prognosis of many cancers such as CRC, 45 hepatocellular carcinoma (HCC), 46 gastric cancer, 47 and esophageal cancer. 34 The result of a meta-analysis 48 also supports the correlation between L1 hypomethylation and poor prognosis of cancer patients.…”

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confidence: 99%

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LINE-1 in cancer: multifaceted functions and potential clinical implications

Han

et al. 2016

Genetics in Medicine

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ReviewThe human genome is abundant with interspersed repetitive sequences originated from retrotransposons. Until now, three categories of retrotransposons have remained unequivocally active: LINE-1(L1), Alu, and SVA elements. The first one is autonomous-capable of self-propagation through RNA intermediates-and the latter two are nonautonomous and thus rely on L1 for mobilization. There are approximately 500,000 L1 copies in the human genome, composing 17% of human DNA.

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Section: Functions Of L1s In Cancer Retrotransposition-dependent Funcmentioning

confidence: 99%

“…38 In HCC, L1-MET was also identified and its hypomethylation was found to be correlated with elevated c-MET expression. 46 Chromosomal rearrangements and processed pseudogenes.…”

Section: Functions Of L1s In Cancer Retrotransposition-dependent Funcmentioning

confidence: 99%

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confidence: 99%

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LINE-1 in cancer: multifaceted functions and potential clinical implications

Han

et al. 2016

Genetics in Medicine

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“…More recently, LINE-1 hypomethylation was recognised as an important feature of early-onset CRCs and a prognostic biomarker for CRCs with a distinct molecular subtype (Ogino et al , 2008; Antelo et al , 2012; Sahnane et al , 2015). Among the specific genes potentially altered by LINE-1 hypomethylation, the MET oncogene contains a LINE-1 sequence in its second intron whose antisense promoter can drive the transcription of a chimeric isoform of the MET gene, LINE-1 MET or L1- MET (Weber et al , 2010; Wolff et al , 2010; Hur et al , 2014; Zhu et al , 2014). …”

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confidence: 99%

Oxidative DNA damage induces hypomethylation in a compromised base excision repair colorectal tumourigenesis

et al. 2017

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Background:A compromised base excision repair (BER) promotes carcinogenesis by accumulating oxidative DNA-damaged products as observed in MUTYH-associated polyposis, a hereditary colorectal cancer syndrome marked by adenomas and cancers with an accumulation of 8-oxoguanine. Remarkably, DNA global demethylation has been shown to be mediated by BER, suggesting a relevant interplay with early colorectal tumourigenesis. To check this hypothesis, we investigated a cohort of 49 adenomas and 10 carcinomas, derived from 17 MUTYH-associated polyposis patients; as adenoma controls, we used a set of 36 familial adenomatous polyposis and 24 sporadic polyps.Methods:Samples were analysed for their mutational and epigenetic status, measured as global LINE-1 (long interspersed nuclear element) and gene-specific LINE-1 MET methylation by mass spectrometry and pyrosequencing.Results:MUTYH-associated polyposis adenomas were strikingly more hypomethylated than familial adenomatous and sporadic polyps for both DNA demethylation markers (P=0.032 and P=0.007 for LINE-1; P=0.004 and P<0.0001 for LINE-1 MET, respectively) with levels comparable to those of the carcinomas derived from the same patients. They also had mutations due mainly to KRAS/NRAS p.G12C, which was absent in the controls (P<0.0001 for both sets).Conclusions:Our results show that DNA demethylation, together with specific KRAS/NRAS mutations, drives the early steps of oxidative damage colorectal tumourigenesis.

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“…a conversão do DNA por bissulfito de sódio seguido da amplificação por PCR de sequências conservadoras, porém, a verificação da porcentagem de metilação é dada de maneira global, sem distinção de sua posição no genoma. Nesta técnica quantidades mínimas de DNA são necessárias para sua amplificação e análise (OGINO et al, 2008;HUR et al, 2014;ZHU et al, 2014) O pirosequenciamento é uma técnica que monitora quantitativamente a incorporação em tempo real de nucleotídeos através da conversão enzimática do pirofosfato. …”

Section: Line-1 (Long Interspersed Nucleotide Elements) Ms-hrm (Methunclassified

Avaliação da exposição ao chumbo sobre o padrão de metilação de regiões promotoras de genes relacionados ao metabolismo do metal, em trabalhadores de fábricas de baterias automotivas

Devóz¹

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O chumbo (Pb) é um metal tóxico que se acumula no organismo e provoca diversos efeitos, afetando vários sistemas, tais como renal, gastrointestinal, reprodutor, endócrino, hepático e hematopoiético. No que se refere a estudos epigenéticos, quando comparados a outros metais, o Pb é, até o momento, o menos estudado e, portanto, muito pouco se sabe a respeito dos efeitos epigenéticos sobre a absorção, distribuição, metabolismo e excreção (ADME) do Pb e, consequentemente, sobre a toxicidade induzida pela exposição ao Pb. Assim, o objetivo do presente estudo consiste em avaliar o padrão de metilação de regiões promotoras dos genes GCLC e MT2A, quantificar a porcentagem de metilação global além das dosagens de parâmetros hepáticos e renais e associá-los à exposição ao Pb. De acordo com os guidelines STROBE e STREGA, 100 trabalhadores do sexo masculino com idades entre 18 e 67 anos participaram do trabalho. Cerca de 6,0 mL de sangue e 5,0 mL de soro foram coletados após a assinatura do Termo de Consentimento Livre e Esclarecido (TCLE). As concentrações de Pb no sangue (Pb-s) e no plasma (Pb-p) foram determinadas por espectrometria de massas com plasma indutivamente acoplado (ICP-MS); o DNA genômico foi extraído do sangue total e quantificado por kits específicos. As amostras de DNA foram tratadas com bissulfito de sódio e a quantificação da porcentagem de metilação global do DNA dos indivíduos expostos ao metal foi determinada pelo método de Elisa indireto e o sequenciamento das amostras para avaliar o padrão de metilação de regiões promotoras dos genes GCLC (Subunidade Catalítica de GlutamatoCisteína Ligase) e MT2A (Metalotioneína 2A), pela técnica de pirosequenciamento. Também foram determinadas as atividades das enzimas transaminase glutâmica oxalacética (TGO) e pirúvica (TGP), bem como da gama-glutamil transferase (GGT) no plasma por espectrofotometria UV/Visível. Cerca de 32% dos voluntários consomem bebidas alcoólicas regularmente e 12% são fumantes. A concentração de Pb-s em média foi de 19 ± 10 μg/dL (variando de 1,8 a 48 μg/dL) e Pb-p 0,56 ± 0,64 μg/dL atingindo valores de até 4,0 μg/dL. A maioria dos indivíduos, apresentou concentrações de ureia, creatinina, TGO, TGP e GGT dentro dos valores de referência. Em relação aos marcadores epigenéticos, foi observada uma associação inversa entre concentrações de Pb-s e Pb-p, ou seja, indivíduos que apresentavam altas concentrações do metal, tinham menor % de metilação global do DNA. Em relação ao estudo das regiões promotoras dos genes MT2A e GCLC, os resultados sugerem que o Pb não altera a metilação nas ilhas CpGs localizadas nas regiões promotoras dos genes MT2A e GCLC, entretanto, foi capaz de induzir alterações no padrão de metilação global do DNA, fornecendo resultados acerca das possíveis interações entre o genoma e o metal.Palavras-chave: chumbo, epigenética, interações gene-metais, toxicidade.

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Hypomethylation of Long Interspersed Nuclear Element-1 (LINE-1) is Associated with Poor Prognosis via Activation of c-MET in Hepatocellular Carcinoma

Abstract: LINE-1 hypomethylation is significantly associated with poor prognosis in patients with HCC, possibly due to activation of c-MET expression.

Cited by 47 publications

References 25 publications

LINE-1 in cancer: multifaceted functions and potential clinical implications

LINE-1 in cancer: multifaceted functions and potential clinical implications

Oxidative DNA damage induces hypomethylation in a compromised base excision repair colorectal tumourigenesis

Avaliação da exposição ao chumbo sobre o padrão de metilação de regiões promotoras de genes relacionados ao metabolismo do metal, em trabalhadores de fábricas de baterias automotivas

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