Summary Transforming growth factor-β (TGF-β) functions as a tumor suppressor in pre-malignant cells but as a metastasis promoter in cancer cells. The dichotomous functions of TGF-β are proposed to be dictated by different partners of its downstream effectors Smads. However, the mechanism for the contextual changes of Smad partners remained undefined. Here, we demonstrate that 14-3-3ζ destabilizes p53, a Smad partner in pre-malignant mammary epithelial cells, by downregulating 14-3-3σ, thus turning off TGF-β’s tumor suppression function. Conversely, 14-3-3ζ stabilizes Gli2 in breast cancer cells, and Gli2 partners with Smads to activate PTHrP and promote TGF-β-induced bone metastasis. The 14-3-3ζ-driven contextual changes of Smad partners from p53 to Gli2 may serve as biomarkers and therapeutic targets of TGF-β-mediated cancer progression.

There is an urgent need to develop optimized experimental models to examine human implantation. These studies aimed to (i) establish a human endometrium-like three-dimensional (3D) culture system, and (ii) examine the attachment of trophoblast-like Jar spheroids to the culture. In the present work, 3D endometrial cultures were constructed with fibrin-agarose as matrix scaffold, and using epithelial and stromal cells from both human primary cultures and established cell lines. An attachment assay between trophoblast cells and the 3D culture was developed. Epithelial cells (cytokeratin(+)) concentrated on top of the matrix forming a monolayer, and stromal cells (vimentin(+)) resided within the matrix, resembling the normal endometrial structure. The capability of primary epithelial cells to form glands spontaneously was observed. Human trophoblast cells (Jar cells) were hCG(+) by immunostaining, allowed to form spheroids, and confirmed to secrete hCG into the medium. Time-dependent experiments demonstrated a high rate of attachment of Jar spheroids to the epithelium, and adhesion was strongly related to the various cell types present in the 3D culture. An architecturally and functionally competent 3D endometrial culture system was established, that coupled with Jar spheroids mimicking trophoblast cells, provides a unique in vitro model for the study of certain aspects of human implantation.

miR-375 interacts with five conserved target sites in the CIP2A coding region, whereas the CIP2A 3′ UTR is not conserved across mammalian species. Reexpression of the tumor suppressor miR-375 in cancer cells represses the expression of CIP2A, resulting in a decrease in the MYC protein level and leading to reduced cell proliferation, migration, and invasion.

The current outbreak of coronavirus disease 2019 (COVID-19), which was first reported in December 2019, spreads across the globe rapidly and has been declared as pandemic on 11 March 2020 by the World Health Organization. 1-4 COVID-19 is caused by a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and associates with substantial morbidity and mortality. 2-8 As of 19 July 2020, more than 14.0 million cases have been confirmed and over 600,000 deaths. The clinical manifestations of COVID-19 are heterogeneous, ranging from asymptomatic to severe disease and even death. 9,10 Currently, no specific antiviral drug proved by randomized controlled trials or vaccine is available for the prevention and treatment of COVID-19. 8,10,11 A key challenge for clinicians is to identify risk and protective factors for COVID-19 to improve outcomes. A number of epidemiological studies have identified older age, male gender, black and minority ethnicity, and various comorbidities including hypertension,