Dataset Information

?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

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ΔNp63α Silences a miRNA Program to Aberrantly Initiate a Wound-Healing Program That Promotes TGFβ-Induced Metastasis.

Rodriguez Calleja Lidia L Jacques Camille C Lamoureux François F Baud'huin Marc M Tellez Gabriel Marta M Quillard Thibaut T Sahay Debashish D Perrot Pierre P Amiaud Jerome J Charrier Celine C Brion Regis R Lecanda Fernando F Verrecchia Franck F Heymann Dominique D Ellisen Leif W LW Ory Benjamin B

Cancer research 20160317 11

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, ΔNp63α, remain largely undefined. Here, we report a distinct a ...[more]

PMID: 26988989

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Project description:BackgroundThe balance of oral microbiomes is crucial to maintain oral health. Microecological imbalance can impair the function of mesenchymal stem cells (MSCs) and lead to delay wound healing. Probiotics is a promising prevention approach for the treatment of oral inflammatory diseases caused by a bacterial infection. However, the effect of probiotics on oral MSCs and wound healing is unclear. In the present study, we used one type of probiotics Lactobacillus reuteri extracts to determine whether bacterial extracts could regulate the functions of gingiva MSCs (GMSCs) and promote wound healing.MethodsLactobacillus reuteri was prepared with bacterial extracts using ultrasonic crushing apparatus. The effects of Lactobacillus reuteri extracts on GMSCs were tested using the cell scratch migration, alkaline phosphatase (ALP) activity, alizarin red staining, cell counting kit-8, real-time PCR, and western blot assays. To investigate the role of Lactobacillus reuteri extracts in the wound in mice, the wound position of bilateral mesial gingival of the maxillary first molar was established, the wound area with a size of 1?mm?×?2?mm and the full thickness gingiva was removed. Mice with wound were randomly distributed to two groups: injection of 0.9% NaCl (NS group) or injection of 50??g/ml bacterial extracts.ResultsWe discovered that 50??g/ml Lactobacillus reuteri extracts increased the capacities of migration, expression of stem cell markers, osteogenic differentiation, and proliferation of GMSCs. In addition, local injection of 50??g/ml bacterial extracts could promote wound-healing process in mice models. Mechanistically, we found that Lactobacillus reuteri extracts accelerated the process of wound healing via PI3K/AKT/?-catenin/TGF?1 pathway.ConclusionsThese data showed that Lactobacillus reuteri extracts could activate the potentials of GMSCs, thus promote wound healing. Our discovery provided the insight of the underlying mechanism activating functions of MSCs and identified Lactobacillus reuteri extracts as a potential therapeutic strategy for accelerating oral wound and potential application in the future dental clinic.

Dataset Information

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

Publications

ΔNp63α Silences a miRNA Program to Aberrantly Initiate a Wound-Healing Program That Promotes TGFβ-Induced Metastasis.

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