<i>RASSF1A</i> is a target tumor suppressor from 3p21.3 in nasopharyngeal carcinoma

Chow, Lillian; Lo, Kwok Wai; Kwong, Joseph; To, Ka‐Fai; Tsang, K. S.; Lam, Ching‐Wan; Dammann, Reinhard; Huang, Dolly P.

doi:10.1002/ijc.20079

Cited by 99 publications

(86 citation statements)

References 22 publications

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“…3p and 9p abnormalities have been identified in low-grade dysplastic lesions and normal nasopharyngeal mucosa of individuals at high risk indicating that these genetic changes are early events in the pathogenesis of NPC [10,17,20,33]. Other genes frequently inactivated by promoter methylation in NPC include TSCL1 at 11q23 and EDNRB at 13q22, E-cadherin, and death-associated protein kinase (DAPK) [34][35][36]. Gene expression profiling has shown dysregulation of the PI3K/Akt, WNT/b-catenin, TGF-b, and MAPK signaling pathways in NPC with upregulation of NF-jB2, survivin, Bcl-2 upregulation, nuclear accumulation of bcatenin, and dysregulation of integrins [37].…”

Section: Molecular Genetic Alterationsmentioning

confidence: 99%

An Update on Epstein-Barr Virus and Nasopharyngeal Carcinogenesis

Perez-Ordoñez

2007

Head and Neck Pathol

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Section: Molecular Genetic Alterationsmentioning

confidence: 99%

An Update on Epstein-Barr Virus and Nasopharyngeal Carcinogenesis

Perez-Ordoñez

2007

Head and Neck Pathol

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“…The highest frequencies of allelic losses were identified in chromosomes 3p (96.3%) and 9p (85.2%) (Lo et al, 2004b). RASSF1A is a potential tumor-suppressor gene residing on chromosome 3p21, which is commonly inactivated in NPC by allelic deletion and promoter methylation (Chow et al, 2004(Chow et al, , 2006. 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).…”

Section: Introductionmentioning

confidence: 99%

“…RASSF1A is a potential tumor-suppressor gene residing on chromosome 3p21, which is commonly inactivated in NPC by allelic deletion and promoter methylation (Chow et al, 2004(Chow et al, , 2006. 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.…”

Section: Introductionmentioning

confidence: 99%

“…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). A lower expression level of RASSF1A was detected in an immortalized nasopharyngeal epithelial cell line expressing LMP1 (Tsao et al, 2002b), which prompted us to investigate if LMP1 may regulate RASSF1A expression in cells.…”

Section: Introductionmentioning

confidence: 99%

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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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“…9 Candidate genes in the smallest overlapping regions 4q12-q23 10 and 4q31-q35, on the other hands, remains undescribed. 11,12 As regions of aberrant genomic loci can harbor more than one tumor-related genes, such as RASSF1A, MLH1, TGFBR2 and BLU on chromosome 3p21, [13][14][15][16] the existence of more than one tumor-suppressor gene within common deleted sites of hepatocellular carcinoma cannot be ruled out.…”

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confidence: 99%

Positional expression profiling indicates candidate genes in deletion hotspots of hepatocellular carcinoma

et al. 2006

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Molecular characterizations of hepatocellular carcinoma have indicated frequent allelic losses on chromosomes 4q, 8p, 16q and 17p, where the minimal deleted regions have been further defined on 4q12-q23, 4q31-q35, 8p21-p22, 16q12.1-q23.1 and 17p13. Despite these regions are now well-recognized in early liver carcinogenesis, few underlying candidate genes have been identified. In an effort to define affected genes within common deleted loci of hepatocellular carcinoma, we conducted transcriptional mapping by highresolution cDNA microarray analysis. In 20 hepatocellular carcinoma cell lines and 20 primary tumors studied, consistent downregulations of novel transcripts were highlighted throughout the entire genome and within sites of frequent losses. The array-derived candidates including fibrinogen gamma peptide (FGG, at 4q31.3), vitamin D binding protein (at 4q13.3), fibrinogen-like 1 (FGL1, at 8p22), metallothionein 1G (MT1G, at 16q12.2) and alpha-2-plasmin inhibitor (SERPINF2, at 17p13) were confirmed by quantitative reverse transcriptionpolymerase chain reaction, which also indicated a more profound downregulation of FGL1, MT1G and SERPINF2 relative to reported tumor-suppressor genes, such as DLC1 (8p22), E-cadherin (16q22.1) and TP53 (17p13.1). In primary hepatocellular carcinoma examined, a significant repression of MT1G by more than 100-fold was indicated in 63% of tumors compared to the adjacent nonmalignant liver (P ¼ 0.0001). Significant downregulations of FGG, FGL1 and SERPINF2 were also suggested in 30, 23 and 33% of cases, respectively, compared to their nonmalignant counterparts (Po0.016). In summary, transcriptional mapping by microarray indicated a number of previously undescribed downregulated genes in hepatocellular carcinoma, and highlighted potential candidates within common deleted regions. Keywords: hepatocellular carcinoma; deletion hotspots; cDNA array; transcriptional mapping Hepatocellular carcinoma currently ranks the fifth most common malignancy worldwide. 1,2 It carries a high cancer morbidity and mortality because by the time of clinical presentation, more than 80% of patients are at the advance inoperable stage. 2,3 The low efficacy of current screening regime by serum alpha-fetoprotein measurements and transabdominal ultrasound imaging has rendered most patients not being diagnosed in time for curative surgery.Thus, underpinning the genetic events associated with hepatocellular carcinoma is expected to improve our understanding on liver carcinogenesis and also potentially provide biomarkers that are of diagnosis and prognostic values.Molecular studies using loss of heterozygosity analysis and comparative genomic hybridization have revealed recurrent chromosomal changes in hepatocellular carcinoma including losses on 1p, 4q, 6q, 8p, 11q, 13q, 16q and 17p. [4][5][6] As diminutions on 4q, 8p, 16q and 17p have been described in the nontumorous cirrhotic nodules and early preneoplastic liver dysplasia, these changes have been further implicated in the early carcinogenetic events of hepat...

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RASSF1A is a target tumor suppressor from 3p21.3 in nasopharyngeal carcinoma

Cited by 99 publications

References 22 publications

An Update on Epstein-Barr Virus and Nasopharyngeal Carcinogenesis

An Update on Epstein-Barr Virus and Nasopharyngeal Carcinogenesis

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

Positional expression profiling indicates candidate genes in deletion hotspots of hepatocellular carcinoma

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