Metastasis-associated gene 1 (MTA1) enhances cisplatin resistance of malignant pleural mesothelioma by ATR-Chk1-mediated DNA repair.
Metastasis-associated gene 1 (MTA1) enhances cisplatin resistance of malignant pleural mesothelioma by ATR-Chk1-mediated DNA repair.
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转移相关基因 1 (MTA1) 通过 ATR-Chk1 介导的 DNA 修复增强恶性胸膜间皮瘤的顺铂耐药性
DOI：
10.21037/atm-21-941
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发表时间：
2021-04
影响因子：
--
通讯作者：
Tao M
中科院分区：
文献类型：
--
作者：
Xu C;Hu Y;Chen B;Li D;Liang R;Shen M;Wu M;Tao M
恶性胸膜间皮瘤（MPM）的化疗耐药性仍然是肿瘤学家面临的一个挑战。在我们之前的研究中，我们证明了转移相关基因1（MTA 1）的异常表达与MPM的致癌和转移相关。本研究的目的是探讨MTA 1在MPM中的作用机制及其与化疗耐药的关系。方法采用Western blotting和real-time PCR方法检测细胞的蛋白质和mRNA水平。通过慢病毒技术在MPM细胞系中用shRNA产生具有MTA 1敲低的稳定克隆。采用Cell Counting Kit-8法和结晶紫法测定细胞活力。免疫组化法检测MPM组织中MTA 1的表达。采用磷酸化组蛋白H3染色和流式细胞仪检测细胞周期。结果MPM中MTA 1蛋白表达上调，增强了MPM对顺铂的耐药性。顺铂通过抑制其泛素化稳定了MTA 1蛋白的表达，MTA 1通过参与共济失调毛细血管扩张症突变和rad 3相关检查点激酶1（ATR-Chk 1）通路的磷酸化，增强了G2/M细胞周期延迟，并调节和保护肿瘤基因组免受化疗药物的影响。结论MTA 1通过ATR-Chk 1介导的DNA损伤修复增强顺铂耐药，顺铂通过影响MTA 1的泛素化途径稳定MTA 1的表达。我们的研究结果表明，MTA 1可以作为一个新的治疗靶点，以克服MPM的化疗耐药性。
Background Malignant pleural mesothelioma (MPM) chemoresistance remains a challenge to oncologists. In our previous study, we demonstrated that the aberrant expression of metastasis-associated gene 1 (MTA1) is associated with carcinogenesis and metastasis in MPM. The aim of the present study was to investigate the mechanism of MTA1 and chemo-resistance in MPM. Methods Western blotting and real-time polymerase chain reaction were used to analyze the protein and mRNA levels. A stable clone with a knockdown of MTA1 was generated with shRNA via lentivirus technology in MPM cell lines. Cell Counting Kit-8 assay and crystal violet assay were used to measure cell viability. Immunochemical staining was employed to detect MTA1 expression in MPM tissues. The cell cycle of MPM cells was determined by phosphohistone H3 staining and flow cytometric analysis. Results The MTA1 protein was upregulated and enhanced cisplatin resistance in MPM. Cisplatin stabilized the expression of the MTA1 protein by inhibiting its ubiquitination, and MTA1 enhanced G2/M cell cycle delay and regulated and protected the tumor genome from chemotherapeutic drugs via participating in the phosphorylation of the ataxia telangiectasia mutated and rad3 related-checkpoint kinase 1 (ATR-Chk1) pathway. Conclusions These data suggest that MTA1 enhances cisplatin resistance by ATR-Chk1-mediated DNA damage repairment and cisplatin stabilizes MTA1 expression via affecting on the ubiquitination pathway of MTA1 in MPM. Our findings indicate that MTA1 could serve as a novel therapeutic target to overcome chemoresistance in MPM.
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影响因子：
3.8
作者：
Feng X;Zhang Q;Xia S;Xia B;Zhang Y;Deng X;Su W;Huang J
通讯作者：
Huang J
DOI：
10.1038/s41571-018-0114-z
发表时间：
2019-03
期刊：
Nature reviews. Clinical oncology
影响因子：
--
作者：
Pilié PG;Tang C;Mills GB;Yap TA
通讯作者：
Yap TA
影响因子：
5.2
作者：
Rundle S;Bradbury A;Drew Y;Curtin NJ
通讯作者：
Curtin NJ
DOI：
10.1158/1078-0432.ccr-15-0479
发表时间：
2015-11-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Karnitz LM;Zou L
通讯作者：
Zou L
影响因子：
21.3
作者：
Jazayeri, A;Falck, J;Jackson, SP
通讯作者：
Jackson, SP