MIR21 Drives Resistance to Heat Shock Protein 90 Inhibition in Cholangiocarcinoma.
MIR21 Drives Resistance to Heat Shock Protein 90 Inhibition in Cholangiocarcinoma.
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DOI：
10.1053/j.gastro.2017.10.043
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发表时间：
2018-03
期刊：
影响因子：
29.4
通讯作者：
Braconi C
中科院分区：
文献类型：
--
作者：
Lampis A;Carotenuto P;Vlachogiannis G;Cascione L;Hedayat S;Burke R;Clarke P;Bosma E;Simbolo M;Scarpa A;Yu S;Cole R;Smyth E;Mateos JF;Begum R;Hezelova B;Eltahir Z;Wotherspoon A;Fotiadis N;Bali MA;Nepal C;Khan K;Stubbs M;Hahne JC;Gasparini P;Guzzardo V;Croce CM;Eccles S;Fassan M;Cunningham D;Andersen JB;Workman P;Valeri N;Braconi C
胆管癌（CCA）对化疗耐药，因此需要新的治疗药物。我们进行了筛选，以确定对CCA有活性的小分子化合物。microRNA 21（MIR 21或miRNA 21）的水平在CCA中增加。我们研究了miRNA 21是否介导CCA细胞和类器官对HSP 90抑制剂的抗性。我们对484种小分子化合物进行了高通量筛选，以确定那些降低6种人类CCA细胞系活力的化合物。我们测试了HSP 90抑制剂对MIR 21基因破坏的细胞、与MIR 21抑制剂孵育的细胞以及具有MIR 21诱导型表达的稳定细胞系的影响。我们从患者获得CCA活检，将其培养为类器官（患者源性类器官）。我们评估了它们的结构，突变和基因表达模式，对培养物中化合物的反应，以及作为小鼠皮下异种移植肿瘤生长时的反应。具有IDH 1和PBRM 1突变的细胞对组蛋白去乙酰化酶抑制剂具有最高水平的敏感性。HSP 90抑制剂在所有细胞系中均有效，与突变无关。细胞对HSP 90抑制剂的敏感性与MIR 21的基线水平呈负相关。MIR 21的破坏增加了细胞对HSP 90抑制剂的敏感性。表达转基因MIR 21的CCA细胞比转染对照载体的细胞对HSP 90抑制剂更具抗性;这些细胞中MIR 21的失活恢复了对这些试剂的敏感性。MIR 21显示靶向DnaJ热休克蛋白家族（Hsp 40）成员B5（DNAJB 5）。在过表达MIR 21的CCA细胞中转基因表达DNAJB 5使它们对HSP 90抑制剂重新敏感。患者来源的类器官对HSP 90抑制剂的敏感性，在培养中和作为小鼠异种移植肿瘤生长时，取决于miRNA的表达21。miRNA 21似乎通过降低DNAJB 5的水平来介导CCA细胞对HSP 90抑制剂的抗性。HSP 90抑制剂可能被开发用于治疗CCA，miRNA 21可能是对这些药物敏感的标志物。
Cholangiocarcinomas (CCA) are resistant to chemotherapy, so new therapeutic agents are needed. We performed a screen to identify small-molecule compounds that are active against CCAs. Levels of microRNA 21 (MIR21 or miRNA21) are increased in CCAs. We investigated whether miRNA21 mediates resistance of CCA cells and organoids to HSP90 inhibitors. We performed a high-throughput screen of 484 small-molecule compounds to identify those that reduced viability of 6 human CCA cell lines. We tested the effects of HSP90 inhibitors on cells with disruption of the MIR21 gene, cells incubated with MIR21 inhibitors, and stable cell lines with inducible expression of MIR21. We obtained CCA biopsies from patients, cultured them as organoids (patient-derived organoids). We assessed their architecture, mutation and gene expression patterns, response to compounds in culture, and when grown as subcutaneous xenograft tumors in mice. Cells with IDH1 and PBRM1 mutations had the highest level of sensitivity to histone deacetylase inhibitors. HSP90 inhibitors were effective in all cell lines, irrespective of mutations. Sensitivity of cells to HSP90 inhibitors correlated inversely with baseline level of MIR21. Disruption of MIR21 increased cell sensitivity to HSP90 inhibitors. CCA cells that expressed transgenic MIR21 were more resistant to HSP90 inhibitors than cells transfected with control vectors; inactivation of MIR21 in these cells restored sensitivity to these agents. MIR21 was shown to target the DnaJ heat shock protein family (Hsp40) member B5 (DNAJB5). Transgenic expression of DNAJB5 in CCA cells that overexpressed MIR21 re-sensitized them to HSP90 inhibitors. Sensitivity of patient-derived organoids to HSP90 inhibitors, in culture and when grown as xenograft tumors in mice, depended on expression of miRNA21. miRNA21 appears to mediate resistance of CCA cells to HSP90 inhibitors by reducing levels of DNAJB5. HSP90 inhibitors might be developed for the treatment of CCA and miRNA21 might be a marker of sensitivity to these agents.
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影响因子：
13.5
作者：
Braconi, Chiara;Huang, Nianyuan;Patel, Tushar
通讯作者：
Patel, Tushar
影响因子：
64.5
作者：
Gao D;Vela I;Sboner A;Iaquinta PJ;Karthaus WR;Gopalan A;Dowling C;Wanjala JN;Undvall EA;Arora VK;Wongvipat J;Kossai M;Ramazanoglu S;Barboza LP;Di W;Cao Z;Zhang QF;Sirota I;Ran L;MacDonald TY;Beltran H;Mosquera JM;Touijer KA;Scardino PT;Laudone VP;Curtis KR;Rathkopf DE;Morris MJ;Danila DC;Slovin SF;Solomon SB;Eastham JA;Chi P;Carver B;Rubin MA;Scher HI;Clevers H;Sawyers CL;Chen Y
通讯作者：
Chen Y
影响因子：
25.7
作者：
Claperon, Audrey;Mergey, Martine;Fouassier, Laura
通讯作者：
Fouassier, Laura
影响因子：
65.1
作者：
Banales, Jesus M.;Cardinale, Vincenzo;Alvaro, Domenico
通讯作者：
Alvaro, Domenico
影响因子：
3.7
作者：
Braconi C;Swenson E;Kogure T;Huang N;Patel T
通讯作者：
Patel T