Functional evidence for a nasopharyngeal carcinoma tumor suppressor gene that maps at chromosome 3p21.3

Cheng, Yue; Poulos, Nicholas E.; Lung, Maria Li; Hampton, Garret M.; Bao-xiang, OU; Lerman, Michael I.; Stanbridge, Eric J.

doi:10.1073/pnas.95.6.3042

Cited by 101 publications

(137 citation statements)

References 39 publications

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“…The presence of a functional tumor suppressor activity encompassing this region (Cheng et al, 1998) supports such a hypothesis. Homozygous deletions have been described in this region both in vitro and in vivo (Todd et al, 1997), but no mutations of any of the genes in this deleted region have been reported with high frequency in carcinomas in (Haber and Harlow, 1997;Sager, 1997).…”

Section: Discussionmentioning

confidence: 63%

“…The telomeric breakpoint resides approximately 4 kb centromeric to the HYAL1 open reading frame, and overlaps with the centromeric region of the SCLC deletions. In addition to the chromosomal aberrations, the region encompassing 3p21.3 has functional tumor suppressor activity in vivo as determined by monochromosome mediated transfer in a nasopharyngeal carcinoma line (Cheng et al, 1998). Despite the frequency of homozygous deletions on 3p21.3 in various carcinomas, no mutations have been reported with high frequency in any of the candidate genes examined to date.…”

Section: Introductionmentioning

confidence: 99%

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HYAL1LUCA-1, a candidate tumor suppressor gene on chromosome 3p21.3, is inactivated in head and neck squamous cell carcinomas by aberrant splicing of pre-mRNA

et al. 2000

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The hyaluronidase ®rst isolated from human plasma, Hyal-1, is expressed in many somatic tissues. The Hyal-1 gene, HYAL1, also known as LUCA-1, maps to chromosome 3p21.3 within a candidate tumor suppressor gene locus de®ned by homozygous deletions and by functional tumor suppressor activity. Hemizygosity in this region occurs in many malignancies, including squamous cell carcinomas of the head and neck. We have investigated whether cell lines derived from such malignancies expressed Hyal-1 activity, using normal human keratinocytes as controls. Hyal-1 enzyme activity and protein were absent or markedly reduced in six of seven carcinoma cell lines examined. Comparative genomic and¯uorescence in situ hybridization identi®ed chromosomal deletions of one allele of HYAL1 in six of seven cell lines. Initial RT ± PCR analyses demonstrated marked discrepancies between levels of HYAL1 mRNA and protein. Despite repeated sequence analyses, no mutations were found. However, two species of transcripts were identi®ed when primers were used that included the 5' untranslated region. The predominant mRNA species did not correlate with protein translation and contained a retained intron. A second spliced form lacking this intron was found only in cell lines that produced Hyal-1 protein. Inactivation of HYAL1 in these tumor lines is a result of incomplete splicing of its pre-mRNA that appears to be epigenetic in nature.

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Section: Discussionmentioning

confidence: 63%

Section: Introductionmentioning

confidence: 99%

HYAL1LUCA-1, a candidate tumor suppressor gene on chromosome 3p21.3, is inactivated in head and neck squamous cell carcinomas by aberrant splicing of pre-mRNA

et al. 2000

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“…The exogenous chromosome 3 of MCH8.12, with a discrete deletion in the 3p24.2-3p22 region, and MCH12.10 containing an exogenous chromosome 3 harboring a significant deletion in 3pter-3p22 region were used. These cell line complementary DNAs were hybridized against their matched tumorigenic tumor segregants arising after selection in the mice (Cheng et al, 1998). Microarrays were scanned in a GenePix 4000A.…”

Section: Npc Tissue Specimensmentioning

confidence: 99%

“…NotI chromosome 3-specific microarray profiling is useful for screening for genes inactivated by deletion and/or hypermethylation. Comparative hybridization of tumorigenic NPC cell lines versus an immortalized nasopharyngeal (NP) epithelial cell line and also of previously established and characterized tumor-suppressive chromosome 3 microcell hybrids (MCHs) versus tumorigenic MCH tumor segregants (Cheng et al, 1998) can be used to identify chromosome 3 candidate tumor-suppressor gene (TSGs). A candidate gene, Fibulin-2 (FBLN2), which showed frequent methylation or deletion in NPC cell lines and tumor segregants, was thus, identified.…”

Section: Introductionmentioning

confidence: 99%

Anti-angiogenic and tumor-suppressive roles of candidate tumor-suppressor gene, Fibulin-2, in nasopharyngeal carcinoma

et al. 2011

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“…Microcells were prepared from the mouse A 9 microcell hybrid MCH903.1, which contain a normal human chromosome 3 with a neo selective marker (Cheng et al, 1998) and fused with the UOK 121 cells. Stable clones were selected using 600 mg/ml G418.…”

Section: Chromosome 3 Transfer Into Uok 121 Cellsmentioning

confidence: 99%

Analysis of aberrant methylation of the VHL gene by transgenes, monochromosome transfer, and cell fusion

Kuzmin

Geil

et al. 1999

Oncogene

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Several tumor suppressor genes were shown to be inactivated by a process involving aberrant de novo methylation of their GC-rich promoters which is usually associated with transcriptional repression. The mechanisms underlying this process are poorly understood. In particular this abnormal methylation may be caused and/ or maintained by either de®ciency of some trans-acting factor(s) or by various malfunctions acting in cis. Here we studied the nature of aberrant methylation of the von Hippel-Lindau (VHL) disease tumor suppressor gene in a human clear cell renal carcinoma cell line, UOK 121, that contains a silent hypermethylated endogenous VHL allele. First, we transfected unmethylated VHL transgenes, driven by the VHL promoter, into UOK 121 cells. Next, to exclude possible position e ects that may in¯uence methylation of the introduced VHL genes, we transferred a single chromosome 3, carrying an apparently normal hypomethylated VHL allele into the UOK 121 cells. Finally, we created somatic cell hybrids between UOK 121 and UMRC 6 cells containing a mutant VHL-expressing hypomethylated allele. In these three experiments both the methylation of the VHL promoter and the transcriptional status of the introduced and endogenous VHL alleles remained unchanged. Our results demonstrate that the putative trans-acting factors present in the UOK 121 and UMRC 6 cells are unable to induce changes in methylation pattern of the VHL alleles in all cell lines and hybrids studied. Taken together, the results indicate that cis-speci®c local features are pivotal in maintaining and perpetuating aberrant methylation of the VHL CpG island. Contribution of some putative trans-acting factors cannot be excluded during a period when the aberrant VHL methylation pattern was ®rst generated.

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Functional evidence for a nasopharyngeal carcinoma tumor suppressor gene that maps at chromosome 3p21.3

Cited by 101 publications

References 39 publications

HYAL1LUCA-1, a candidate tumor suppressor gene on chromosome 3p21.3, is inactivated in head and neck squamous cell carcinomas by aberrant splicing of pre-mRNA

HYAL1LUCA-1, a candidate tumor suppressor gene on chromosome 3p21.3, is inactivated in head and neck squamous cell carcinomas by aberrant splicing of pre-mRNA

Anti-angiogenic and tumor-suppressive roles of candidate tumor-suppressor gene, Fibulin-2, in nasopharyngeal carcinoma

Analysis of aberrant methylation of the VHL gene by transgenes, monochromosome transfer, and cell fusion

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