Department of Microbiology, New York University Grossman School of Medicine, New York, NY 10016.
New York University Perlmutter Cancer Center, New York University Grossman School of Medicine, New York, NY 10016.
Proc Natl Acad Sci U S A. 2023 Apr 11;120(15):e2207898120. doi: 10.1073/pnas.2207898120. Epub 2023 Apr 4.
Breast cancer (BC) metastasis involves cancer stem cells (CSCs) and their regulation by micro-RNAs (miRs), but miR targeting of the translation machinery in CSCs is poorly explored. We therefore screened miR expression levels in a range of BC cell lines, comparing non-CSCs to CSCs, and focused on miRs that target translation and protein synthesis factors. We describe a unique translation regulatory axis enacted by reduced expression of miR-183 in breast CSCs, which we show targets the eIF2Bδ subunit of guanine nucleotide exchange factor eIF2B, a regulator of protein synthesis and the integrated stress response (ISR) pathway. We report that reduced expression of miR-183 greatly increases eIF2Bδ protein levels, preventing strong induction of the ISR and eIF2α phosphorylation, by preferential interaction with P-eIF2α. eIF2Bδ overexpression is essential for BC cell invasion, metastasis, maintenance of metastases, and breast CSC expansion in animal models. Increased expression of eIF2Bδ, a site of action of the drug ISRIB that also prevents ISR signaling, is essential for breast CSC maintenance and metastatic capacity.
乳腺癌（BC）转移涉及癌症干细胞（CSCs）及其受 microRNA（miRs）的调控，但 CSCs 中转录机制的 miR 靶向作用尚未得到充分探索。因此，我们在一系列 BC 细胞系中筛选了 miR 的表达水平，将非 CSCs 与 CSCs 进行了比较，并将重点放在靶向翻译和蛋白质合成因子的 miR 上。我们描述了一个独特的翻译调控轴，在乳腺癌 CSCs 中 miR-183 的表达减少，我们发现它靶向鸟嘌呤核苷酸交换因子 eIF2B 的 eIF2Bδ 亚基，这是蛋白质合成和整合应激反应（ISR）途径的调节剂。我们报告说，miR-183 的表达减少大大增加了 eIF2Bδ 蛋白水平，通过与 P-eIF2α 的优先相互作用，防止了 ISR 的强烈诱导和 eIF2α 的磷酸化。eIF2Bδ 的过表达对于 BC 细胞侵袭、转移、转移的维持以及动物模型中的乳腺癌 CSC 扩增是必不可少的。ISRIB 的作用部位 eIF2Bδ 的表达增加，也可防止 ISR 信号，这对于维持乳腺癌 CSC 和转移能力是必不可少的。
