The Neuronal MicroRNA miR-326 Acts in a Feedback Loop with Notch and Has Therapeutic Potential against Brain Tumors

Abstract

Little is known of microRNA interactions with cellular pathways. Few reports have associated microRNAs with the Notch pathway, which plays key roles in nervous system development and in brain tumors. We previously implicated the Notch pathway in gliomas, the most common and aggressive brain tumors. While investigating Notch mediators, we noted microRNA-326 was upregulated following Notch-1 knockdown. This neuronally expressed microRNA was not only suppressed by Notch but also inhibited Notch proteins and activity, indicating a feedback loop. MicroRNA-326 was downregulated in gliomas via decreased expression of its host gene. Transfection of microRNA-326 into both established and stem cell-like glioma lines was cytotoxic, and rescue was obtained with Notch restoration. Furthermore, miR-326 transfection reduced glioma cell tumorigenicity in vivo. Additionally, we found microRNA-326 partially mediated the toxic effects of Notch knockdown. This work demonstrates a microRNA-326/Notch axis, shedding light on the biology of Notch and suggesting microRNA-326 delivery as a therapy.

The role of micro-RNA in the regulation of signal pathways in gliomas

“…Как оказалось, miR-326 гипоактивирована в глиомах за счёт сниженной экспрессии гена-"хозяина" этой miR -ARRB1. MiR-326 ингибирует NOTCH1 и NOTCH2, и при этом сама способна репрессироваться NOTCH [35]. MiR-33a необходима для поддержания способности к росту и пролиферации опухоль-инициирующих клеток при глиобластоме, она демонстрирует повышенные уровни экспрессии при сравнении с другими клетками глиомы и ассоциирована с худшим прогнозом для пациентов.…”

“…Cниженная экспрессия гена-"хозяина" часто приводит к снижению уровня miR-326. Введение miR-326 может являться новой стратегией терапии [35]. miR-326 ингибируется PI3-киназным каскадом [21] [ [20][21][22], [35], [37] miR-675-5p, ген которой находится внутри гена длинной некодирующей РНК Н19, играет роль в развитии ответа на гипоксию и гипоксия-опосредованном ангиогенезе [81] [81], [82] короткая длина зрелых микро-РНК ограничивает дизайн проб [101].…”

Evaluation of plasma microRNA levels to predict insensitivity of patients with advanced lung adenocarcinomas to pemetrexed and platinum

“…miR-326 is a suppressor of the Hedgehog, Notch and mitogen-activated protein kinase signaling pathways that are associated with brain tumors (61)(62)(63), and may block expression of multidrug resistance-associated proteins in breast cancer (64). Low expression levels of miR-326 are correlated with poor OS in patients with pathological grade III-IV glioma (65).…”

The Role of microRNAs in Gliomas and Their Potential Applications for Diagnosis and Treatment

“…It has recently been shown that miRNAs play important roles in gliomas [8][9][10][11][12][13][14][15][16][17][18][19] . A number of miRNAs, such as miR-21, miR-221, miR-222, miR-10b, and the miR-26a cluster 15,19 , together with the genes cyclin-dependent kinase 4 (CDK4) and CENTG1, are upregulated in gliomas and appear to act in an oncogenic fashion.…”