Wild-type and mutant p53 differentially modulate miR-124/iASPP feedback following pohotodynamic therapy in human colon cancer cell line.
Wild-type and mutant p53 differentially modulate miR-124/iASPP feedback following pohotodynamic therapy in human colon cancer cell line.
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人结肠癌细胞系光动力治疗后野生型和突变型 p53 差异调节 miR-124/iASPP 反馈
DOI：
10.1038/cddis.2017.477
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发表时间：
2017-10-12
影响因子：
9
通讯作者：
Liang Y
中科院分区：
文献类型：
--
作者：
Liu K;Chen W;Lei S;Xiong L;Zhao H;Liang D;Lei Z;Zhou N;Yao H;Liang Y
结直肠癌（Colorectal cancer，CRC）是最常见的消化系统恶性肿瘤。p53突变在癌症中起重要作用，在CRC中经常观察到，并提出了巨大的挑战。据报道，p53突变减弱了基于photofrin的光动力疗法（PDT）的抑制作用。p53突变诱导的功能获得带来了致癌因子（包括miRNA）的功能障碍。我们的研究发现，PDT抑制CRC细胞活力，缩小肿瘤体积，延长生存时间，所有这些都可以通过p53突变或缺失来减弱。p53突变或缺失后，几种miRNA表达水平下调，其中miR-124下调最强烈，而iASPP表达上调。p53与miR-124的启动子结合，促进其表达，进而抑制iASPP的表达，从而放大PDT对野生型p53细胞的抑制作用。在p53突变或缺失的细胞中，这种结合不再促进miR-124表达，iASPP表达增加，最终导致PDT后CRC细胞活力的提高。p53突变或缺失细胞中miR和iASPP的相互调节可能是PDT治疗CRC过程中p53突变或缺失介导治疗抵抗的重要途径。
Colorectal cancer (CRC) is a most common digestive system malignant tumor. p53 mutation has essential role in cancers and is frequently observed in CRC and presents a huge challenge. p53 mutation has been reported to attenuate the inhibitory effect of photofrin-based photodynamic therapy (PDT). p53 mutation-induced gain of function brings up the dysfunction of carcinogenic factors, including miRNAs. Our research found that PDT suppressed CRC cell viability, reduced the tumor size and prolonged the survival time, all of which could be attenuated by p53 mutation or deletion. After p53 mutation or deletion, several miRNA expression levels were downregulated, among which miR-124 was the most strongly downregulated, whereas iASPP expression was upregulated. p53 binds to the promoter of miR-124 to promote its expression and then inhibited iASPP expression, so as to amplify the inhibitory effect of PDT on wild-type p53 cells. In p53-mutant or-deleted cells, this binding no longer worked to promote miR-124 expression, and iASPP expression increased, finally resulted in promoted CRC cell viability upon PDT. The interactive modulation among miR and iASPP in p53-mutant or-deleted cells may serve as a crucial pathway, which mediates therapy resistance when p53 is mutated or deleted, in the process of PDT treatment of CRC.
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影响因子：
5.6
作者：
Kushibiki T;Hirasawa T;Okawa S;Ishihara M
通讯作者：
Ishihara M
影响因子：
4.2
作者：
Kudo, Itsuhiro;Esumi, Mariko;Ikeda, Minoru
通讯作者：
Ikeda, Minoru
影响因子：
6.4
作者：
Bond, Catherine E.;Umapathy, Aarti;Whitehall, Vicki L. J.
通讯作者：
Whitehall, Vicki L. J.
影响因子：
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作者：
Heinzelmann-Schwarz, V;Fedier, A;Fink, D
通讯作者：
Fink, D
影响因子：
1.6
作者：
Kim, Seung Tae;Ha, Sang Yun;Park, Young Suk
通讯作者：
Park, Young Suk