Methylation profiling of twenty promoter-CpG islands of genes which may contribute to hepatocellular carcinogenesis

Yu, Jian; Ni, Min; Xu, Jian; Zhang, Hongyu; Gao, Baomei; Gu, Jianren; Chen, Jianguo; Zhang, Lisheng; Wu, Mengchao; Zhen, Sushen; Zhu, Jingde

doi:10.1186/1471-2407-2-29

Cited by 152 publications

(175 citation statements)

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“…Allelic loss of RASSF1A locus could be detected in microdissected tissues from low-and high-grade dysplastic nasopharyngeal epithelial lesions (Lo and Huang, 2002;Chow et al, 2004). RASSF1A is also commonly inactivated in other human cancers including gastric cancer (Kang et al, 2002), hepatocellular carcinoma (Yu et al, 2002) and small-cell lung cancer (Dammann et al, 2001); suggesting its common involvement in human carcinogenesis. Reconstitution of RASSF1A expression in a NPC cell line, C666-1, induced loss of viability, growth suppression, diminished invasiveness and anchorage-independence growth properties (Chow et al, 2004).…”

Section: Introductionmentioning

confidence: 98%

Latent membrane protein 1 suppresses RASSF1A expression, disrupts microtubule structures and induces chromosomal aberrations in human epithelial cells

et al. 2006

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Epstein-Barr virus (EBV) infection is closely associatedwith nasopharyngeal carcinoma (NPC) and can be detected in early premalignant lesions of nasopharyngeal epithelium. The latent membrane protein 1 (LMP1) is an oncoprotein encoded by the EBV and is believed to play a role in transforming premalignant nasopharyngeal epithelial cells into cancer cells. RASSF1A is a tumorsuppressor gene commonly inactivated in many types of human cancer including NPC. In this study, we report a novel function of LMP1, in down-regulating RASSF1A expression in human epithelial cells. Downregulation of RASSF1A expression by LMP1 is dependent on the activation of intracellular signaling of NF-jB involving the C-terminal activating regions (CTARs) of LMP1. LMP1 expression also suppresses the transcriptional activity of the RASSF1A core promoter. RASSF1A stabilizes microtubules and regulates mitotic events. Aberrant mitotic spindles and chromosome aberrations are reported phenotypes in RASSF1A inactivated cells. In this study, we observed that LMP1 expression in human epithelial cells could induce aberrant mitotic spindles, disorganized interphase microtubules and aneuploidy. LMP1 expression could also suppress microtubule dynamics as exemplified by tracking movements of the growing tips of microtubules in live cells by transfecting EGFP-tagged EB1 into cells. The aberrant mitotic spindles and interphase microtubule organization induced by LMP1 could be rescued by transfecting RASSF1A expression plasmid into cells. Downregulation of RASS-F1A expression by LMP1 may facilitate its role in transformation of premalignant nasopharyngeal epithelial cells into cancer cells.

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Section: Introductionmentioning

confidence: 98%

Latent membrane protein 1 suppresses RASSF1A expression, disrupts microtubule structures and induces chromosomal aberrations in human epithelial cells

et al. 2006

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“…5,6 Several genes located on chromosome 3p have been studied in HCC as well as CC and include RASSF1A on 3p21.31, FHIT at 3p14.2, RIZ1, VHL at 3p25. [7][8][9][10] These results directed an intensive search for possible tumor suppressor genes located in the 3p21 region for one or more genes that could function as gatekeepers in molecular pathogenesis of human cancers. A group of candidate tumor suppressor genes (designated BLU, SEMAPHORIN 3B, or RASSF1A) has recently been mapped to this critical gene-rich region.…”

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confidence: 99%

Allele loss and epigenetic inactivation of 3p21.3 in malignant liver tumors

Tischoff

Markwarth

Witzigmann

et al. 2005

Intl Journal of Cancer

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Previously, the RASSF1A, BLU and SEMAPHORIN 3B (SEMA3B) candidate tumor suppressor genes on chromosome 3p21.3 were found to be inactivated and downregulated by genetic and epigenetic changes in lung cancer. We analyzed the methylation status of RASSF1A, BLU and SEMA3B in 35 hepatocellular carcinomas (HCCs) and 15 cholangiocarcinomas (CCs) by methylationspecific PCR and loss of heterozygosity (LOH) at 3p21.3 after microdissection. The presence of mRNA transcripts was confirmed by semiquantitative PCR. SEMA3B hypermethylation was found in 29/35 HCCs (83%) and in all (15/15) patients with CC. BLU promoter hypermethylation was detected in 7/35 (20%) HCCs and 3/15 (20%) CCs. In 2 corresponding specimens of hepatitis B virus-related liver cirrhosis, BLU methylation was also observed, but not in uninvolved normal liver tissue. RASSF1A was methylated in 21/35 HCCs (60%) and in 10/15 CCs (67%). LOH at 3p21.3 occurred in 8/35 (23%) HCCs and 3/15 (20%) CCs. The presence of hypermethylation was statistically associated with LOH of SEMA3B and correlated with downregulation of mRNA transcripts. SEMA3B transcripts increased upon treatment of HCC cell lines with the demethylation compound 5-aza-2-deoxycytidine. In conclusion, our data indicate that 2-hit gene silencing of SEMA3B through epigenetic changes and allele loss is a common and important event in the carcinogenesis of malignant liver tumors. ' 2005 Wiley-Liss, Inc.Key words: hepatocellular carcinoma; cholangiocarcinoma; methylation; loss of heterozygosity; BLU; SEMA3B; RASSF1A Primary liver cancer is one of the most frequent carcinomas worldwide. Besides hepatocellular carcinoma (HCC), accounting for 80-90% of all primary liver cancers, cholangiocarcinoma (CC) is the second most common primary hepatic malignancy. The short arm of chromosome 3 has been shown to exhibit loss of heterozygosity (LOH) in several types of cancer, including ovarian, kidney, lung, nasopharyngeal and also liver cancer. 1,2 In particular, overlapping homozygous deletions in lung cancers have been identified in region 3p21.3. 3,4 In HCC, LOH of chromosome 3p occurred in about 30% of the patients. 5,6 Several genes located on chromosome 3p have been studied in HCC as well as CC and include RASSF1A on 3p21.31, FHIT at 3p14.2, RIZ1, VHL at 3p25. 7-10 These results directed an intensive search for possible tumor suppressor genes located in the 3p21 region for one or more genes that could function as gatekeepers in molecular pathogenesis of human cancers. A group of candidate tumor suppressor genes (designated BLU, SEMAPHORIN 3B, or RASSF1A) has recently been mapped to this critical gene-rich region. 2,[11][12][13] SEMAPHORIN 3B (SEMA3B) is a member of the semaphorin family, which is also located on 3p21.3. Semaphorins are a family of signaling molecules initially identified to play a role in axonal guidance and can be classified as either membrane-bound (classes 1, 4, 5 and 6) or secreted (classes 2 and 3). 14 The receptors for the class 3 semaphorins are also known as neuropilin receptors. The intr...

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“…In the past decade, researches on hepatocellular carcinoma (HCC) related genes have successfully demonstrated that the expression of sets of genes are significantly down-regulated or silenced by the abnormal methylation of CpG islands in gene promoters in early HCCs. Multiple data from these studies in liver tissue demonstrate that except for the process from hepatic cirrhosis (HC) to HCC, there is an obvious change in the methylation rate during the process from normal to HC (Yu et al 2002;Li et al 2004;Nishida et al 2012). For example, in a qualitative investigation using methylation-specific PCR (MSP) to detect various gene methylation status, the hypermethylation rate of promoter was found to be 15% in liver cirrhosis tissue and 0% in normal liver tissue (Zhang et al 2008).…”

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confidence: 99%

“…CpG islands are CpG dinucleotide-rich areas located mainly in the gene promoter regions. DNA methylation can add methyl groups to CpG island, decrease gene transcription activity and may account for gene inactivation in the pathogenesis process (Yu et al 2002). Among various kinds of epigenetic modifications, many studies have focused on DNA methylation.…”

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confidence: 99%