Complex Epigenetic Regulation of Chemotherapy Resistance and Biohlogy in Esophageal Squamous Cell Carcinoma via MicroRNAs.
Complex Epigenetic Regulation of Chemotherapy Resistance and Biohlogy in Esophageal Squamous Cell Carcinoma via MicroRNAs.
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DOI：
10.3390/ijms19020499
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发表时间：
2018-02-07
影响因子：
5.6
通讯作者：
Hummel R
中科院分区：
文献类型：
--
作者：
Lindner K;Eichelmann AK;Matuszcak C;Hussey DJ;Haier J;Hummel R
背景：化疗耐药是食管鳞状细胞癌（ESCC）治疗的主要障碍。我们研究了特定microRNA在化疗耐药性和肿瘤生物学中的作用。研究方法：我们从耐药ESCC的特征性microRNA标签中选择了三种microRNA（hsa-miR-125 a-5 p、hsa-miR-130 a-3 p、hsa-miR-1226- 3 p）和hsa-miR-148 a-3 p。在6个ESCC细胞系中评估对化疗、粘附、迁移、凋亡和细胞周期的影响。使用Western印迹和荧光素酶技术进行靶分析。结果：miR-130 a-3 p在100%的细胞系中对顺铂敏感，miR-148 a-3 p在83%，miR-125 a-5 p在67%，miR-1226- 3 p在50%（p ≤ 0.04）。miR-130 a-3 p使83%的细胞系对5-FU敏感，miR-148 a-3 p/miR-125 a-5 p/miR-1226- 3 p仅为33%（p ≤ 0.015）。几种与耐药性相关的途径似乎在不同的层面上有针对性。Bcl-2被证实是miR-130 a-3 p和miR-148 a-3 p的直接靶点，p53被证实是miR-125 a-5 p的靶点。除miR-130 a-3 p外，所有microRNA均降低迁移和粘附，并增加凋亡。同时操作两种microRNA在50%（miR-125 a-5 p/miR-148 a-3 p）和75%（miR-148 a-3 p/miR-130 a-3 p）的细胞系中显示出对顺铂的加和增敏效应（p ≤ 0.006）。结论：我们的数据提供了强有力的证据表明，特定的microRNA签名负责耐药和侵袭性的ESCC。这些复杂过程的最终功能读数似乎比单个microRNA-靶标相互作用更重要。
Background: Resistance towards chemotherapy is a major obstacle in the treatment of esophageal squamous cell carcinoma (ESCC). We investigated the role of specific microRNAs in chemotherapy resistance and tumor biology. Methods: We selected three microRNAs from characteristic microRNA signatures of resistant ESCC (hsa-miR-125a-5p, hsa-miR-130a-3p, hsa-miR-1226-3p), and hsa-miR-148a-3p. Effects on chemotherapy, adhesion, migration, apoptosis and cell cycle were assessed in six ESCC cell lines. Target analyses were performed using Western blotting and luciferase techniques. Results: MiR-130a-3p sensitized cells towards cisplatin in 100% of cell lines, miR-148a-3p in 83%, miR-125a-5p in 67%, miR-1226-3p in 50% (p ≤ 0.04). MiR-130a-3p sensitized 83% of cell lines towards 5-FU, miR-148a-3p/miR-125a-5p/miR-1226-3p only 33% (p ≤ 0.015). Several resistance-relevant pathways seem to be targeted on various levels. Bcl-2 was confirmed as a direct target of miR-130a-3p and miR-148a-3p, and p53 as a target of miR-125a-5p. All microRNAs decreased migration and adhesion, except miR-130a-3p, and increased apoptosis. Simultaneous manipulation of two microRNAs exhibited additive sensitizing effects towards cisplatin in 50% (miR-125a-5p/miR-148a-3p), and 75% (miR-148a-3p/miR-130a-3p) of cell lines (p ≤ 0.006). Conclusion: Our data present strong evidence that specific microRNA signatures are responsible for drug resistance and aggressiveness of ESCC. Final functional readout of these complex processes appears to be more important than single microRNA-target interactions.
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影响因子：
50.3
作者：
Hu G;Chong RA;Yang Q;Wei Y;Blanco MA;Li F;Reiss M;Au JL;Haffty BG;Kang Y
通讯作者：
Kang Y
影响因子：
3.8
作者：
Kastl, L.;Brown, I.;Schofield, A. C.
通讯作者：
Schofield, A. C.
影响因子：
5.2
作者：
Jin C;Rajabi H;Kufe D
通讯作者：
Kufe D
影响因子：
4.8
作者：
Fujita, Yasunori;Kojima, Keitaro;Ito, Masafumi
通讯作者：
Ito, Masafumi
影响因子：
3.2
作者：
Hummel, Richard;Watson, David I.;Hussey, Damian J.
通讯作者：
Hussey, Damian J.