國家衛生研究院 NHRI:Item 3990099045/7111
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    题名: A novel interaction of nucleophosmin with BCL2-Associated X protein regulating death evasion and drug sensitivity in human hepatoma cells
    作者: Lo, SJ;Fan, LC;Tsai, YF;Lin, KY;Huang, HL;Wang, TH;Liu, H;Chen, TC;Huang, SF;Chang, CJ;Lin, Y, Jr.;Yung, BYM;Hsieh, SY
    贡献者: Institute of Molecular and Genomic Medicine
    摘要: Death evasion is crucial for both carcinogenesis and resistance to anticancer therapies. Recently we identified nucleophosmin (NPM) as a key factor counteracting death stimuli in human hepatocellular carcinoma (HCC) cells. Here we report the identification of a novel NPM-BCL2-associated X protein (BAX) pathway orchestrating death evasion in human HCC cells. Silencing of NPM expression significantly sensitized HCC cells, particularly those bearing inactivated p53 (Huh7, Hep3B, and Mahlavu), to UV irradiation, mitomycin C, doxorubicin, cisplatin, sorafenib, and lapatinib. This sensitizing effect was not further changed as p53 expression had been simultaneously silenced. Following cell stress, NPM and BAX were induced and exported out of nucleoli and nucleus, respectively. BAX was translocated to cytoplasm in cells with relatively high NPM level, or accumulated in the mitochondria in cells with relatively low NPM level and undergoing apoptosis. Subcellular fractionation revealed that silencing of NPM expression greatly enhanced mitochondrial translocation and oligomerization of BAX in Huh7 and Mahlavu cells. In situ proximity ligation assays and reciprocal co-immunoprecipitation evidenced direct interaction between NPM and BAX in the cytoplasm. Silencing of BAX expression abolished the sensitization effect exerted by silencing of NPM in HCC cells. Clinically, upregulation of NPM was significantly associated with advanced tumor stage and poor prognosis. Conclusion: Via directly blockading BAX mitochondrial translocation and activation, NPM helps human HCC cells evade death induction independently of p53-mediated cell death. Silencing of NPM significantly sensitized HCC cells to anticancer therapies. NPM is a potential co-target in combination with other therapies for HCC particularly harboring inactivated p53. Our findings are of clinical significance, since NPM upregulation and p53 mutations are usually found in advanced human cancers, including HCC.
    日期: 2013-05
    關聯: Hepatology. 2013 May;57(5):1893-1905.
    Link to: http://dx.doi.org/10.1002/hep.26209
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0270-9139&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000318162200025
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=84876738157
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