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Modulation of LIN28B/Let-7 Signaling by Propranolol Contributes to Infantile Hemangioma Involution

2018; Lippincott Williams & Wilkins; Volume: 38; Issue: 6 Linguagem: Inglês

10.1161/atvbaha.118.310908

1524-4636

Ezinne F. Mong, Kemal M. Akat, John Canfield, John H. Lockhart, Jeffrey VanWye, Andrew Matar, John C.M. Tsibris, June K. Wu, Thomas Tuschl, Hana Totary-Jain,

Islanding Detection in Power Systems

Objective— Infantile hemangiomas (IHs) are the most common benign vascular neoplasms of infancy, characterized by a rapid growth phase followed by a spontaneous involution, or triggered by propranolol treatment by poorly understood mechanisms. LIN28/let-7 axis plays a central role in the regulation of stem cell self-renewal and tumorigenesis. However, the role of LIN28B/let-7 signaling in IH pathogenesis has not yet been elucidated. Approach and Results— LIN28B is highly expressed in proliferative IH and is less expressed in involuted and in propranolol-treated IH samples as measured by immunofluorescence staining and quantitative RT-PCR. Small RNA sequencing analysis of IH samples revealed a decrease in microRNAs that target LIN28B, including let-7, and an increase in microRNAs in the mir-498(46) cistron. Overexpression of LIN28B in HEK293 cells induced the expression of miR-516b in the mir-498(46) cistron. Propranolol treatment of induced pluripotent stem cells, which express mir-498(46) endogenously, reduced the expression of both LIN28B and mir-498(46) and increased the expression of let-7. Furthermore, propranolol treatment reduced the proliferation of induced pluripotent stem cells and induced epithelial–mesenchymal transition. Conclusions— This work uncovers the role of the LIN28B/let-7 switch in IH pathogenesis and provides a novel mechanism by which propranolol induces IH involution. Furthermore, it provides therapeutic implications for cancers in which the LIN28/let-7 pathway is imbalanced.