Mutagenesis and Cancer Prevention Unit, IRCCS Ospedale Policlinico San Martino, Largo R. Benzi 10, Genoa, Italy.
Microrna. 2020;9(5):322-335. doi: 10.2174/2211536609666201209151659.
The chemoresistance of cancer cells is a multifactorial mechanism in which de-regulated apoptotic pathways, the oxidative response and cancer cell migration play a crucial role. A key player in the control of such pathways is the tumor suppressor gene TP53, also defined as the "guardian of the genome", encoding the P53 tetrameric transcription factor. P53, following cell injuries, can activate the transcription of several target genes crucial for the induction of apoptosis, cell cycle arrest, modulation of senescence, DNA repair, autophagy and metabolism. Importantly, TP53 gene is mutated in nearly 50% of human cancers, implying an altered expression of target genes in cancer cells. The presence of TP53 mutations can also affect the expression of several small noncoding RNAs (microRNAs or miRNAs) involved in the same regulation of the apoptotic signaling, cell cycle regulation and cell migration. In mutant P53 expressing tumors, some miRNAs resulted in being down-regulated, while others appeared to be up-regulated as demonstrated by in vitro and in vivo studies. Thus, the expression level of specific P53 responsive miRNAs could be used as a marker of cancer progression and therapy performance. In the present review, we will summarize the role of P53-related miRNAs and their clinical relevance in monitoring therapy outcome and progression of cancers with mutant P53.
癌细胞的化疗耐药性是一种多因素机制，其中失调的凋亡途径、氧化反应和癌细胞迁移起着至关重要的作用。调控这些途径的关键因素是肿瘤抑制基因 TP53，也被定义为“基因组的守护者”，它编码 P53 四聚体转录因子。P53 在细胞损伤后，可以激活对细胞凋亡、细胞周期阻滞、衰老调节、DNA 修复、自噬和代谢至关重要的几个靶基因的转录。重要的是，TP53 基因在近 50%的人类癌症中发生突变，这意味着癌症细胞中靶基因的表达发生改变。TP53 基因突变的存在也会影响参与凋亡信号、细胞周期调控和细胞迁移的同一调控的几个小非编码 RNA（microRNAs 或 miRNAs）的表达。在表达突变型 P53 的肿瘤中，一些 miRNA 被证明下调，而另一些 miRNA 似乎上调，这在体外和体内研究中都得到了证实。因此，特定 P53 反应性 miRNA 的表达水平可以作为癌症进展和治疗效果的标志物。在本综述中，我们将总结 P53 相关 miRNA 的作用及其在监测突变型 P53 癌症治疗效果和进展方面的临床相关性。
