Auboeuf Didier
Univ Lyon, ENS de Lyon, Univ Claude Bernard, CNRS UMR 5239, INSERM U1210, Laboratory of Biology and Modelling of the Cell, Lyon, France.
Transcription. 2016 Oct 19;7(5):164-187. doi: 10.1080/21541264.2016.1221491.
Understanding the molecular mechanisms behind the capacity of cancer cells to adapt to the tumor microenvironment and to anticancer therapies is a major challenge. In this context, cancer is believed to be an evolutionary process where random mutations and the selection process shape the mutational pattern and phenotype of cancer cells. This article challenges the notion of randomness of some cancer-associated mutations by describing molecular mechanisms involving stress-mediated biogenesis of mRNA-derived small RNAs able to target and increase the local mutation rate of the genomic loci they originate from. It is proposed that the probability of some mutations at specific loci could be increased in a stress-specific and RNA-depending manner. This would increase the probability of generating mutations that could alleviate stress situations, such as those triggered by anticancer drugs. Such a mechanism is made possible because tumor- and anticancer drug-associated stress situations trigger both cellular reprogramming and inflammation, which leads cancer cells to express molecular tools allowing them to "attack" and mutate their own genome in an RNA-directed manner.
了解癌细胞适应肿瘤微环境和抗癌疗法背后的分子机制是一项重大挑战。在这种情况下，癌症被认为是一个进化过程，随机突变和选择过程塑造了癌细胞的突变模式和表型。本文通过描述涉及应激介导的mRNA衍生小RNA生物合成的分子机制，对一些癌症相关突变的随机性概念提出了挑战，这些小RNA能够靶向并提高它们所源自的基因组位点的局部突变率。有人提出，特定位点的某些突变概率可能以应激特异性和RNA依赖性方式增加。这将增加产生能够缓解应激情况（如抗癌药物引发的应激情况）的突变的概率。这样一种机制之所以成为可能，是因为肿瘤和抗癌药物相关的应激情况会引发细胞重编程和炎症，这导致癌细胞表达分子工具，使其能够以RNA定向的方式“攻击”并突变自身基因组。
