?Np63? Silences a miRNA Program to Aberrantly Initiate a Wound-Healing Program That Promotes TGF?-Induced Metastasis.

ABSTRACT: Primary cancer cell dissemination is a key event during the metastatic cascade, but context-specific determinants of this process remain largely undefined. Multiple reports have suggested that the p53 (TP53) family member p63 (TP63) plays an antimetastatic role through its minor epithelial isoform containing the N-terminal transactivation domain (TAp63). However, the role and contribution of the major p63 isoform lacking this domain, ?Np63?, remain largely undefined. Here, we report a distinct and TAp63-independent mechanism by which ?Np63?-expressing cells within a TGF?-rich microenvironment become positively selected for metastatic dissemination. Orthotopic transplantation of ?Np63?-expressing human osteosarcoma cells into athymic mice resulted in larger and more frequent lung metastases than transplantation of control cells. Mechanistic investigations revealed that ?Np63? repressed miR-527 and miR-665, leading to the upregulation of two TGF? effectors, SMAD4 and T?RII (TGFBR2). Furthermore, we provide evidence that this mechanism reflects a fundamental role for ?Np63? in the normal wound-healing response. We show that ?Np63?-mediated repression of miR-527/665 controls a TGF?-dependent signaling node that switches off antimigratory miR-198 by suppressing the expression of the regulatory factor, KSRP (KHSRP). Collectively, these findings reveal that a novel miRNA network involved in the regulation of physiologic wound-healing responses is hijacked and suppressed by tumor cells to promote metastatic dissemination. Cancer Res; 76(11); 3236-51. ©2016 AACR.

SUBMITTER: Rodriguez Calleja L 

PROVIDER: S-EPMC4891241 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature