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. 2019 Jun 21;9:492. doi: 10.3389/fonc.2019.00492

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Copyright © 2019 Bourguignon.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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A proposed model for HA-CD44-mediated signaling activation in the regulation of miRNA-21, miR-302, and miR-10b production and oncogenesis in tumor cells. (A) The binding of HA to CD44 promotes JNK activity which, in turn, causes phosphorylation of c-Jun. Phosphorylated c-Jun then binds to the miR-21 promoter and induces miR-21 expression. HA binding to CD44 also causes Nanog interaction with Stat-3 and the microprocessor complex containing the RNase III (DROSHA) and the RNA helicase (p68). These Nanog-associated signaling complexes (containing Stat-3 and/or DROSHA and p68) then bind to miR-21 promoter region, resulting in miR-21 production leading to upregulation of IAP protein expression, tumor cell survival, and chemoresistance. (B) HA-CD44 interaction promotes miRNA-302 expression and chemoresistance: HA binding to CD44 promotes an association between CD44v3 and OCT4/SOX2/Nanog. Subsequently, OCT4/SOX2/Nanog complexes interact with the promoter region (containing OCT4-, SOX2-, and Nanog-binding sites) of the miR-302 cluster resulting in miR-302 cluster gene expression and mature miR-302 production. The resultant miR-302 then functions to induce IAP (cIAP-1, cIAP-2, and XIAP) expression, tumor cell growth, self-renewal, clone formation, tumor cell survival, and chemoresistance in tumor cells. (C) HA-CD44 interaction promotes miRNA-10b expression and tumor migration/invasion: HA binding to CD44 promotes c-Src phosphorylation (kinase activation), which, in turn, causes phosphorylation of Twist. Phosphorylated Twist then interacts with the E-box elements of mR-10b promoter, resulting in miR-10b gene expression, and mature miR-10b production. The binding of HA to CD44 also enhances DOT1L upregulation and DOT1L/H3K79 methylation-mediated epigenetic changes, resulting in methyl-H3K79 binding to miR-10b promoter, and miR-10b gene expression/production. The expressed miR-10b then promotes upregulation of RhoGTPase-mediated cytoskeleton activation leading to tumor cell migration and invasion. Red dot represents DOT1L/H3K79-mediated histone modifications (via epigenetic changes).