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 ΔNp63 α Silences a miRNA Program to Aberrantly Initiate a Wound-Healing Program That Promotes TGF β -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 anti-metastatic 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, DNp63a, remain largely undefined. Here, we report a distinct and TAp63-independent mechanism by which DNp63a-expressing cells within a TGFb-rich microenvironment become positively selected for metastatic dissemination. Orthotopic trans-plantation of DNp63a-expressing human osteosarcoma cells into athymic mice resulted in larger and more frequent lung metastases than transplantation of control cells. Mechanistic investigations revealed that DNp63a repressed miR-527 and miR-665, leading to the upregulation of two TGFb effectors, SMAD4 and TbRII (TGFBR2). Furthermore, we provide evidence that this mechanism reflects a fundamental role for DNp63a in the normal wound-healing response. We show that DNp63a-mediated repression of miR-527/665 controls a TGFb-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 .
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Submitted on : Tuesday, February 6, 2018 - 4:05:20 PM
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Lidia Rodriguez Calleja, Camille Jacques, François Lamoureux, Marc Baud 'Huin, Marta Tellez Gabriel, et al..  ΔNp63 α Silences a miRNA Program to Aberrantly Initiate a Wound-Healing Program That Promotes TGF β -Induced Metastasis. Cancer Research, American Association for Cancer Research, 2016, 76 (11), pp.3236 - 3251. ⟨10.1158/0008-5472.CAN-15-2317⟩. ⟨inserm-01702308⟩



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