In mouse mammary epithelial cells, CPEB1 mediates the apical localization of ZO-1 mRNA, which encodes a critical tight junction component. In mice lacking CPEB1 and in cultured cells from which CPEB has been depleted, randomly distributed ZO-1 mRNA leads to the loss of cell polarity. We have investigated whether this diminution of polarity results in an epithelial-to-mesenchyme (EMT) transition and possible increased metastatic potential. Here, we show that CPEB1-depleted mammary epithelial cells alter their gene expression profile in a manner consistent with an EMT and also become motile, which are made particularly robust when cells are treated with TGF-β, an enhancer of EMT. CPEB1-depleted mammary cells become metastatic to the lung following injection into mouse fat pads while ectopically-expressed CPEB1 prevents metastasis. Surprisingly, CPEB1 depletion causes some EMT/metastasis-related mRNAs to have shorter poly(A) tails while other mRNAs to have longer poly(A) tails. Matrix metalloproteinase 9 (MMP9) mRNA, which encodes a metastasis-promoting factor, undergoes poly(A) lengthening and enhanced translation upon CPEB reduction. Moreover, in human breast cancer cells that become progressively more metastatic, CPEB1 is reduced while MMP9 becomes more abundant. These data suggest that at least in part, CPEB1 regulation of MMP9 mRNA expression mediates metastasis of breast cancer cells.

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HighlightsIn mice, WFA-positive PNNs express aggrecan in selective brain regions.Appearance and glycosylation of aggrecan-positive PNNs is brain-region specific.Density of AB1031-, Cat-315-, and Cat-316-positive PNNs is brain-region specific.Localization of WFA-, AB1031-, Cat-315-, and Cat-316-positive molecules differ in PNNs.

Allogeneic hematopoietic cell transplantation (HCT) from HLA-haploidentical donors with post-transplantation high-dose cyclophosphamide (PT/Cy-haplo) now predominates worldwide. However, to our knowledge, no prospective study has compared immune reconstitution after PT/Cy-haplo with that after conventional HCT. The mechanism by which chronic graft-versus-host disease (GVHD) is inhibited by PT/Cy-haplo also remains unknown. We prospectively compared immune recovery patterns of lymphocyte subsets among four groups of adult patients with hematological disease who received HCT from either HLA-matched related or HLA-matched unrelated donors, cord blood transplantation, or reduced-dose PT/Cy-haplo. Counts of CD4+ T-cell subsets, CD8+ T-cell subsets, and NK cells on days 30 and 60 were often lower in PT/Cy-haplo than those in HLA-matched related HCT. The immune recovery pace in PT/Cy-haplo subsequently caught up with that of the other grafts. The regulatory T cells (Tregs) to conventional CD4+ T-cell (Tcon) ratio was significantly higher until day 90 in PT/Cy-haplo. In multivariate analysis, a higher Tregs-to-Tcon ratio on day 60 was significantly associated with a lower incidence of chronic GVHD (P < 0.01). The preservation of Tregs by PT/Cy in the early phase might have resulted in a lower incidence of chronic GVHD.

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