Reversal of Triple-Negative Breast Cancer EMT by miR-200c Decreases Tryptophan Catabolism and a Program of Immunosuppression.
Reversal of Triple-Negative Breast Cancer EMT by miR-200c Decreases Tryptophan Catabolism and a Program of Immunosuppression.
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DOI：
10.1158/1541-7786.mcr-18-0246
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发表时间：
2019-01
期刊：
影响因子：
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通讯作者：
Richer JK
中科院分区：
文献类型：
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作者：
Rogers TJ;Christenson JL;Greene LI;O'Neill KI;Williams MM;Gordon MA;Nemkov T;D'Alessandro A;Degala GD;Shin J;Tan AC;Cittelly DM;Lambert JR;Richer JK
色氨酸-2，3-双加氧酶（TDO 2）是色氨酸催化途径中的限速酶，在三阴性乳腺癌（TNBC）中由炎症信号和锚定非依赖性条件诱导。与雌激素受体阳性（ER+）乳腺癌相比，TNBC表达极低水平的microRNA-200（miR-200）家族。在正常上皮细胞和ER+乳腺癌和细胞系中，高水平的家族成员miR-200 c用于靶向和抑制参与上皮向间充质转化（EMT）的基因。为了鉴定允许TNBC表达TDO 2和在更分化的ER+乳腺癌中不表达的其他蛋白质的机制，在TNBC细胞系中恢复了miRNA-200 c。数据表明，miR-200 c靶向TDO 2直接导致免疫抑制代谢物犬尿氨酸的产生减少。此外，除了逆转经典的EMT特征外，miR-200 c还抑制了许多编码免疫抑制因子的基因，包括PD-L1/2，HMOX 1和GDF 15。miR-200 c的恢复揭示了一种机制，即TNBC劫持了一种基因表达程序，让人想起滋养层细胞用来抑制母体免疫系统以确保妊娠期间胎儿耐受的基因表达程序。了解肿瘤源性免疫抑制因子的调节将有助于开发新的治疗策略，以补充当前的免疫疗法，从而降低TNBC患者的死亡率。
Tryptophan-2,3-dioxygenase (TDO2), a rate-limiting enzyme in the tryptophan catabolism pathway, is induced in triple-negative breast cancer (TNBC) by inflammatory signals and anchorage-independent conditions. TNBC express extremely low levels of the microRNA-200 (miR-200) family compared to estrogen receptor-positive (ER+) breast cancer. In normal epithelial cells and ER+ breast cancers and cell lines, high levels of the family member, miR-200c serve to target and repress genes involved in epithelial-to-mesenchymal transition (EMT). To identify mechanism(s) that permit TNBC to express TDO2 and other proteins not expressed in the more well-differentiated ER+ breast cancers, miRNA-200c was restored in TNBC cell lines. The data demonstrate that miR-200c targeted TDO2 directly resulting in reduced production of the immune-suppressive metabolite kynurenine. Furthermore, in addition to reversing a classical EMT signature, miR-200c repressed many genes encoding immune-suppressive factors including PD-L1/2, HMOX1, and GDF15. Restoration of miR-200c revealed a mechanism whereby TNBC hijacks a gene expression program reminiscent of that used by trophoblasts to suppress the maternal immune system to ensure fetal tolerance during pregnancy. Knowledge of the regulation of tumor-derived immune-suppressive factors will facilitate development of novel therapeutic strategies that complement current immunotherapy to reduce mortality for TNBC patients.