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Frameshift mutation of UVRAG, an autophagy-related gene, in gastric carcinomas with microsatellite instability. Hum Pathol

Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea.
Human pathology (Impact Factor: 2.77). 08/2008; 39(7):1059-63. DOI: 10.1016/j.humpath.2007.11.013
Source: PubMed

ABSTRACT

Alteration of autophagy is involved in tumor development. Beclin1, an important regulator of autophagy, acts as a tumor suppressor. Ultraviolet (UV) radiation resistance-associated gene (UVRAG) binds with Beclin1 and induces autophagy. There is a polyadenine tract in UVRAG gene (A10 in exon 8) that is a target for frameshift mutations in colorectal carcinomas with microsatellite instability (MSI). Functionally, colon cancer cells with the frameshift mutation of UVRAG show reduced autophagy formation and increased tumorigenicity. The aim of this study was to determine whether the frameshift mutations of UVRAG are also present in gastric carcinomas with MSI. For this, we analyzed human UVRAG exon 8 in 45 gastric carcinomas with MSI and 92 gastric carcinomas without MSI by a single-strand conformation polymorphism analysis. Overall, we detected 3 frameshift mutations of UVRAG in the polyadenine tract (3/45; 6.7%), and all of them were found in MSH-high (H) subtypes (3/32; 9.4%). The 3 mutations consisted of 2 c.708_709delA and 1 c.709delA which would result in premature stops of the UVRAG protein synthesis. The present data indicate that frameshift mutations in the polyadenine tract in UVRAG gene are present in gastric carcinomas as well and suggest that the affected gastric cancer cells with the mutations may have a reduced autophagy activity.

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    • "Indeed, centrosome aberrations are considered as a major contributing factor to CIN in cancer cells (Bornens, 2002; Fukasawa, 2007). UV-irradiation-resistance-associated gene (UVRAG) maps to a tumor susceptibility locus on human chromosome 11q13 that is frequently implicated in common human cancers, including breast, colorectal, and gastric cancers (Bekri et al., 1997; Goi et al., 2003; Ionov et al., 2004; Kim et al., 2008; Perelman et al., 1997). We and others have previously shown that UVRAG associates with Beclin1 and activates PI(3) kinase class III (PI(3)KC3) kinase in autophagy (Liang et al., 2006; Matsunaga et al., 2009; Takahashi et al., 2007b; Zhong et al., 2009). "
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    • "A missense mutation was also identified in UVRAG , a putative tumor suppressor that complements the ultraviolet sensitivity of xeroderma pigmentosum group C cells and also has a role in autophagy ( Kim et al . , 2008 ) . In addition , an 8 - to 12 - fold increase in copy number on chromosome 3p which contains four com - plete genes : RARB , TOP2B , NGLY1 , and KS ( OXSM ) and a four - to sixfold increase on chromosome 15 containing MKRN3 and NDN genes were noted . It is important to point out that this was the first instance that these amplified can"
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    • "Consistently, ectopic overexpression of BECN1 in colon cancer cell lines with low expression of this gene results in growth inhibition (Koneri et al. 2007). Subsequent to these studies, mutations in other autophagy-related genes including Atg2B, Atg5, Atg9B, Atg12, and UVRAG, have been documented in gastric and colorectal cancers (Kim et al. 2008; Kang et al. 2009). "
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