Definition of three minimal deleted regions by comprehensive allelotyping and mutational screening of FHIT,p16INK4A, and p19ARF genes in nasopharyngeal carcinoma

Ko, Jenq‐Yuh; Lee, Tso-Ching; Hsiao, Chin‐Fu; Lin, Guan-Lu; Yen, Sang‐Hue; Chen, Kuang Y.; Hsiung, Chao A.; Chen, Pei‐Jer; Hsu, Mow‐Ming; Jou, Yuh–Shan

doi:10.1002/cncr.10406

Cited by 22 publications

(15 citation statements)

References 68 publications

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“…Two genomic loci encoding miR-138 (miR-138-1 and miR-138-2) have been identified. The miR-138-1 gene is located at chromosome 3p21, where allelic loss is frequently detected in nasopharyngeal cancer (41, 42). MiR-138 is frequently downregulated in several cancer types.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-138 Modulates DNA Damage Response by Repressing Histone H2AX Expression

Wang

Huang

et al. 2011

Molecular Cancer Research

143

140

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Precise regulation of DNA damage response is crucial for cellular survival after DNA damage, and its abrogation often results in genomic instability in cancer. Phosphorylated histone H2AX (γH2AX) forms nuclear foci at sites of DNA damage and facilitates DNA damage response and repair. MicroRNAs are short, non-protein-encoding RNA molecules, which post-transcriptionally regulate gene expression by repressing translation of and/or degrading mRNA. How microRNAs modulate DNA damage response is largely unknown. In this study, we developed a cell-based screening assay utilizing ionizing radiation-induced γH2AX foci formation in a human osteosarcoma cell line, U2OS, as the readout. By screening a library of human microRNA mimics, we identified several microRNAs that inhibited γH2AX foci formation. Among them, miR-138 directly targeted the histone H2AX 3′-UTR, reduced histone H2AX expression and induced chromosomal instability after DNA damage. Overexpression of miR-138 inhibited homologous recombination and enhanced cellular sensitivity to multiple DNA damaging agents (cisplatin, camptothecin, and ionizing radiation). Reintroduction of histone H2AX in miR-138 overexpressing cells attenuated miR-138-mediated sensitization to cisplatin and camptothecin. Our study suggests that miR-138 is an important regulator of genomic stability and a potential therapeutic agent to improve the efficacy of radiotherapy and chemotherapy with DNA damaging agents.

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Section: Discussionmentioning

confidence: 99%

MicroRNA-138 Modulates DNA Damage Response by Repressing Histone H2AX Expression

Wang

Huang

et al. 2011

Molecular Cancer Research

143

140

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“…The microsatellite markers were purchased from PE Applied Biosystems (Foster City, CA) and from the set of Multi-Colored Fluorescent Human MapPairs Markers (version 8) of Research Genetics (Huntsville, Alabama). The protocols of PCR reaction, markers pooling, and gel electrophoresis were based on the protocols provided by the manufacturers with slight modifications (34).…”

Section: Methodsmentioning

confidence: 99%

Clustering of Minimal Deleted Regions Reveals Distinct Genetic Pathways of Human Hepatocellular Carcinoma

et al. 2004

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Systematic scan and statistical analysis of loss of heterozygosity (LOH) has been widely used to define chromosomal aberrations in various cancers for cloning of tumor suppressor genes and for development of prognostic markers. However, the establishment of novel strategies is needed, so that the nonrandom but heterogeneous chromosomal aberration data could provide significant insights into our understanding of molecular pathogenesis of cancers.

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“…There are many Alu repeat sequences in the proximal telomere of the fragile site FRA3B, including the highly unstable repeat sequence (TAA) 15 [10][11][12]. Thus, it can be inferred that under the influence of external carcinogens, breakage and fissuring may occur at the FRA3B site, leading to abnormal DNA repair and rearrangement, ultimately resulting in FHIT gene complexes such as MSI and LOH [13]. In our study, the average frequencies of FHIT gene LOH and MSI in GC were 32.4% and 26.4%, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…This affects catabolism of Ap3A and Ap4A. Accumulated intracellular Ap3A and Ap4A can then repress cell apoptosis, and induce carcinomatous cellular changes [19,20].…”

Section: Relationship Between Fhit Gene Loh Msi and Clinicopathologimentioning

confidence: 99%

MSI/LOH and extron expression of the FHIT gene in gastric carcinoma

et al. 2007

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We detected loss of heterozygosity (LOH) and microsatellite instabilities (MSI), as well as extron expression of the fragile histidine triad (FHIT) gene in gastric carcinoma (GC), in order to evaluate their association with clinicopathological processes in gastric carcinogenesis. LOH and MSI of the FHIT were detected by using PCR at 4 microsatellite loci: D3S 1300, D3S 4103, D3S 1481, D3S 1234 in cancer tissues from 50 patients with primary GC, with normal mucosa acting as matched controls. FHIT transcripts were detected by nested RT-PCR in 30 cases of GC and their products were sequenced. Results show that the average frequencies of LOH and MSI of the FHIT gene in GC were 32.4% and 26.4%, respectively. There was no correlation between LOH and MSI of the FHIT gene in GC and the histological characteristics of gastric carcinoma (Bormann's or Lauren's classification). LOH of the FHIT gene in GC was related to depth invasiveness, and its frequency in GC where serosa was penetrated was significantly higher than that in GC without serosa penetration (73.5% vs 37.5%, P < 0.05). The frequency of MSI in GC without lymph node metastasis was significantly higher than that in GC with lymph node metastasis (66.7% vs 34.3%, P < 0.05). Aberrant transcripts were found in 11/30 GC tissues. Sequencing analysis of the aberrant fragments found a RT-PCR product missing exons 5-7 in one case of GC, and another product missing exons 4-7. Four of 10 (40.0%) cases of primary GC showed absent or decreased expression of the FHIT protein as compared to their matched normal tissues. The findings in this study suggest that LOH and MSI of FHIT gene may induce aberrant extron expression, which might play a role in gastric carcinogenesis.

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Definition of three minimal deleted regions by comprehensive allelotyping and mutational screening of FHIT,p16^INK4A, and p19^ARF genes in nasopharyngeal carcinoma

Cited by 22 publications

References 68 publications

MicroRNA-138 Modulates DNA Damage Response by Repressing Histone H2AX Expression

MicroRNA-138 Modulates DNA Damage Response by Repressing Histone H2AX Expression

Clustering of Minimal Deleted Regions Reveals Distinct Genetic Pathways of Human Hepatocellular Carcinoma

MSI/LOH and extron expression of the FHIT gene in gastric carcinoma

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