Endometrial cancer is the most common gynecological cancer in the United States. We wanted to identify epigenetic aberrations involving microRNAs (miRNAs), whose genes become hypermethylated in endometrial primary tumors. By integrating known miRNA sequences from the miRNA database (miRBase) with DNA methylation data from methyl-CpG-capture sequencing, we identified 111 differentially methylated regions (DMRs) associated with CpG islands (CGIs) and miRNAs. Among them, 22 DMRs related to 29 miRNAs and within 8 kb of CGIs were hypermethylated in endometrial tumors but not in normal endometrium. miR-137 was further validated in additional endometrial primary tumors. Hypermethylation of miR-137 was found in both endometrioid and serous endometrial cancer (P < 0.01), and it led to the loss of miR-137 expression. Treating hypermethylated endometrial cancer cells with epigenetic inhibitors reactivated miR-137. Moreover, genetic overexpression of miR-137 suppressed cancer cell proliferation and colony formation in vitro. When transfected cancer cells were implanted into nude mice, the cells that overexpressed miR-137 grew more slowly and formed smaller tumors (P < 0.05) than vector transfectants. Histologically, xenograft tumors from cancer cells expressing miR-137 were less proliferative (P < 0.05), partly due to inhibition of EZH2 and LSD1 expression (P < 0.01) in both the transfected cancer cells and tumors. Reporter assays indicated that miR-137 targets EZH2 and LSD1. These results suggest that miR-137 is a tumor suppressor that is repressed in endometrial cancer because the promoter of its gene becomes hypermethylated.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, debilitating disease with unknown etiopathogenesis. Previous reports have reported that long non-coding RNAs (lncRNAs) were involved in various pathophysiological processes. However, the role of lncRNAs in IPF has not been fully described. We aimed to explore the relationship between miR-15a and lncRNA PFAR and its function in pulmonary fibrosis. Biological information analysis and luciferase were used to identify targeted binding of lncRNA PFAR and miR-15a. Western blot, quantitative reverse transcription-PCR (qRT-PCR) and immunofluorescence staining were conducted to detect fibrosis-related factors. Fibroblasts proliferation were analyzed using 5-ethynyl-2′-deoxyuridine (EdU) staining and fibroblasts migration ability were measured using wound-healing scratch assay. We identified that lncRNA PFAR has a binding site with miR-15a and luciferase reporter assays demonstrated their combinative relationship. Our results showed that silencing PFAR attenuated TGF-β1 induced fibrogenesis in primary lung fibroblasts. And miR-15a antagonized the function of PFAR and inhibited PFAR induced extracellular collagen deposition, fibroblasts proliferation, migration and differentiation. In conclusion, our results revealed that PFAR functions as a competitive endogenous RNA (ceRNA) by acting as a sponge for miR-15a, revealing a potential regulatory network involving PFAR and miR-15a with a role in the modulation of YAP1-Twist expression. This mechanism may contribute to a better understanding of pulmonary fibrosis pathogenesis and treatment method.

Innate immune cells in the tumor microenvironment have been proposed to control the transition from benign to malignant stages. In many cancers, increased infiltration of natural killer (NK) cells associates with good prognosis. Although the mechanisms that enable NK cells to restrain colorectal cancer (CRC) are unclear, the current study suggests the involvement of Smad4. We found suppressed Smad4 expression in circulating NK cells of untreated metastatic CRC patients. Moreover, NK cell-specific Smad4 deletion promoted colon adenomas in DSS-treated ApcMin/+ mice and adenocarcinomas in AOM/DSS-treated mice. Other studies have shown that Smad4 loss or weak expression in colonic epithelium associates with poor survival in CRC patients. Therefore, targeting Smad4 in both colonic epithelium and NK cells could provide an excellent opportunity to manage CRC. Toward this end, we showed that dietary intervention with black raspberries (BRBs) increased Smad4 expression in colonic epithelium in patients with FAP or CRC and in the two CRC mouse models. Also, benzoate metabolites of BRBs, such as hippurate, upregulated Smad4 and Gzmb expression that might enhance the cytotoxicity of primary human NK cells. Of note, increased levels of hippurate is a metabolomic marker of a healthy gut microbiota in humans, and hippurate also has antitumor effects. In conclusion, our study suggests a new mechanism for the action of benzoate metabolites derived from plant-based foods. This mechanism could be exploited clinically to upregulate Smad4 in colonic epithelium and NK cells, thereby delaying CRC progression.

We previously reported that SOX4 is overexpressed in endometrial cancer and that it partially contributes to hypermethylation of miR-129-2 and miR-203. The current study seeks to identify methylation and expression levels of the SOX gene family in endometrial carcinomas. Methylation levels of the 16 SOX gene family members were measured by combining bisulfite restriction analysis (COBRA), MassARRAY, and pyrosequencing assays of cell lines and endometrial cancer samples. Gene expression was determined by RT-qPCR. The methylation level of the SOX11 locus

The behaviors of Na+ and H2O in cyclic peptide nanotube (CPN) under different conditions are important for their applications. In this study, a series of driving forces has been applied to Na+ and H2O constrained in the self-assembled nanotube of {cyclo[(-D-Ala-L-Ala)4-]}10, to understand the influence on the transport properties and behaviors of Na+ and H2O using steered molecular dynamics (SMD). The results show that H2O need less driving force (0.4 kcal mol−1 Å−1) to migrate in the nanotube than that of Na+ (2.3 kcal mol−1 Å−1). Under the same driving force, the transport speed of H2O is about 135 times faster than that of Na+. The instantaneous velocity curves reveal that water adopts a kind of irregular hopping transport mode which does not change with the driving force, while Na+ transports in an obvious hopping mode changing with driving force in three different types. Particularly, the instantaneous velocity curves of Na+ under the driving force of 3.2–5.2 kcal mol−1 Å are roughly similar to the pulse signal, which is of great significance to the treatment of human diseases and the detection of electrolytes. The transport resistance mainly comes from electrostatic interaction. Results in this work show that cyclic octa-peptide nanotubes have excellent performance sensitive to external driving forces and are good potential materials for drug design, biosensors, ion transmembrane transport and ion probe for the detection of Na+ in organisms.