文章：

TMPRSS2-ERG通过抑制癌基因诱导的衰老促进前列腺癌的发生

TMPRSS2-ERG promotes the initiation of prostate cancer by suppressing oncogene-induced senescence 

原文发布日期：2022-04-07 

英文摘要：

ERG translocations are commonly involved in the initiation of prostate neoplasia, yet previous experimental approaches have not addressed mechanisms of oncogenic inception. Here, in a genetically engineered mouse model, combining TMPRSS2-driven ERG with KrasG12D led to invasive prostate adenocarcinomas, while ERG or KrasG12D alone were non-oncogenic. In primary prostate luminal epithelial cells, following inducible oncogenic Kras expression or Pten depletion, TMPRSS2-ERG suppressed oncogene-induced senescence, independent of TP53 induction and RB1 inhibition. Oncogenic KRAS and TMPRSS2-ERG synergized to promote tumorigenesis and metastasis of primary luminal cells. The presence of TMPRSS2-ERG compared to a wild-type background was associated with a stemness phenotype and with relatively increased RAS-induced differential gene expression for MYC and mTOR-regulated pathways, including protein translation and lipogenesis. In addition, mTOR inhibitors abrogated ERG-dependent senescence resistance. These studies reveal a previously unappreciated function whereby ERG expression primes preneoplastic cells for the accumulation of additional gene mutations by suppression of oncogene-induced senescence. 

摘要翻译： 

ERG易位通常参与前列腺肿瘤发生的起始过程，但以往的实验方法未能揭示致癌起始的分子机制。本研究通过基因工程小鼠模型发现，将TMPRSS2驱动的ERG与KrasG12D结合会诱发浸润性前列腺腺癌，而单独表达ERG或KrasG12D均不具致癌性。在原代前列腺腔上皮细胞中，诱导致癌性Kras表达或Pten缺失后，TMPRSS2-ERG能够抑制癌基因诱导的衰老，该过程不依赖TP53诱导和RB1抑制。致癌性KRAS与TMPRSS2-ERG通过协同作用促进原代腔上皮细胞的肿瘤发生和转移。与野生型背景相比，TMPRSS2-ERG的存在与干细胞表型相关，并相对增强RAS诱导的MYC和mTOR调控通路（包括蛋白质翻译和脂肪生成）的差异基因表达。此外，mTOR抑制剂可消除ERG依赖的衰老抵抗。这些研究揭示了一个先前未被认识的功能：ERG表达通过抑制癌基因诱导的衰老，使癌前细胞为积累额外基因突变创造条件。

原文链接：

TMPRSS2-ERG promotes the initiation of prostate cancer by suppressing oncogene-induced senescence