國家衛生研究院 NHRI:Item 3990099045/11546
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    题名: Hydroxysteroid 11-Beta dehydrogenase 1 overexpression with copy-number gain and missense mutations in primary gastrointestinal stromal tumors
    其它题名: Hydroxysteroid 11-β Dehydrogenase 1 Overexpression with Copy-Number Gain and Missense Mutations in Primary Gastrointestinal Stromal Tumors
    作者: Li, CF;Liu, TT;Wang, JC;Yu, SC;Chen, YY;Fang, FM;Li, WS;Huang, HY
    贡献者: National Institute of Cancer Research
    摘要: The lipid-metabolizing enzymes remain underexplored in gastrointestinal stromal tumors (GISTs). Through transcriptomic reappraisal, hydroxysteroid 11-beta dehydrogenase-1 (HSD11B1) was identified as a top-upregulated, progression-associated gene. To validate the clinical relevance of HSD11B1, the informative results of Sanger sequencing (n = 58), mRNA quantification by branched-chain DNA in situ hybridization assay (n = 70), copy number assay by fluorescent in situ hybridization (n = 350), and immunohistochemistry (n = 350) were correlated with clincopathological variables, KIT/PDGFRA/BRAF genotypes, and disease-free survival (DFS). HSD11B1 was stably silenced to explore its oncogenic function. HSD11B1 mRNA varied between high-risk and non-high-risk groups (p = 0.009) and positively correlated with HSD11B1 immunoexpression (r = 0.783, p < 0.001). HSD11B1 copy-number gain (CNG), including polysomy (5.4%) and amplification (12%), associated with HSD11B1 overexpression (p < 0.001). Predominantly involving the homodimer interface-affecting exon 6 or exon 7, missense HSD11B1 mutations (17.2%) were related to high risk (p = 0.044), age >/=70 years (p = 0.007), and shorter DFS among relapsed cases (p = 0.033). CNG was related to unfavorable KIT/PDGFRA/BRAF genotypes (p = 0.015), while HSD11B1 overexpression was preferential in non-gastric cases (p < 0.001). Both abnormalities strongly associated with risk levels (both p < 0.001) and shorter univariate DFS (both p < 0.0001), and HSD11B1 CNG remained prognostically independent (p < 0.001) with a 3-fold increased hazard ratio. In vitro, HSD11B1 knockdown significantly inhibited proliferation and caused G2/M arrest. In conclusion, HSD11B1 overexpression may occur owing to CNG, confer a pro-proliferative function, and predict a worse prognosis in GISTs.
    日期: 2018-11-01
    關聯: Journal Of Clinical Medicine. 2018 Nov 1;7(11):Article number 408.
    Link to: http://dx.doi.org/10.3390/jcm7110408
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=2077-0383&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000451311900031
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85076958512
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