A growing body of evidence suggests that the dysregulation of long noncoding RNA is increasingly linked to many human diseases. Maternally expressed gene 3 ( MEG3) is one such gene thought to be affected. In the placenta of patients with preeclampsia, there is reduced expression of MEG3; however, its role and the mechanism involved are not clear. Therefore, we examined the expression of MEG3, epithelial-mesenchymal transition (EMT) markers (E-cadherin and N-cadherin), and TGF-β/smad signaling pathway genes ( TGF-β1, smad3, and smad7) in the placental tissues of 20 patients with preeclampsia and 20 healthy patients. We further observed the impact of MEG3 on the invasion and migration functions of human trophoblast cells and the effects on EMT and TGF-β/smad signaling pathways in an Human trophoblast cell-8 (HTR-8)Vneo cell line. The expression of MEG3 was lower in tissues from patients with preeclampsia having an EMT decline, as well as a messenger RNA expression of smad7. The expression of TGF-β1 and smad3 were higher in patients with preeclampsia. In HTR-8/SVneo cells with overexpressed MEG3, the invasion and migration functions were enhanced and accompanied by higher EMT and a significantly increased expression of smad7. Our data indicate that MEG3 is closely associated with the pathogenesis of preeclampsia and thus associated with changes in the EMT of placental trophoblast cells. These results indicate that MEG3 regulation of trophoblast cell EMT via the TGF-β pathway inhibitor smad7 may be the molecular mechanism involved in the pathogenesis of preeclampsia.
Endometrioid endometrial carcinoma (EEC) is the most dominant subtype of endometrial cancer. Aberrant transcriptional regulation has been implicated in EEC. Herein, we characterized mRNA and miRNA transcriptomes by RNA sequencing in EEC to investigate potential molecular mechanisms underlying the pathogenesis. Total mRNA and small RNA were simultaneously sequenced by next generation sequencing technology for 3 pairs of stage I EEC and adjacent non-tumorous tissues. On average, 52,716,765 pair-end 100 bp mRNA reads and 1,669,602 single-end 50 bp miRNA reads were generated. Further analysis indicated that 7 miRNAs and 320 corresponding target genes were differentially expressed in the three stage I EEC patients. Six of all the seven differentially expressed miRNAs were targeting on eleven differentially expressed genes in the cell cycle pathway. Real-time quantitative PCR in sequencing samples and other independent 21 pairs of samples validated the miRNA-mRNA differential co-expression, which were involved in cell cycle pathway, in the stage I EEC. Thus, we confirmed the involvement of hsa-let-7c-5p and hsa-miR-99a-3p in EEC and firstly found dysregulation of hsa-miR-196a-5p, hsa-miR-328-3p, hsa-miR-337-3p, and hsa-miR-181c-3p in EEC. Moreover, synergistic regulations among these miRNAs were detected. Transcript sequence variants such as single nucleotide variant (SNV) and short insertions and deletions (Indels) were also characterized. Our results provide insights on dysregulated miRNA-mRNA co-expression and valuable resources on transcript variation in stage I EEC, which implies the new molecular mechanisms that underlying pathogenesis of stage I EEC and supplies opportunity for further in depth investigations.
Isoflavone derivatives were synthesized via intramolecular cyclization of 3-(2-bromophenyl)-3-oxopropanal derivatives, using CuI as the catalyst, 2-picolinic acid (¼ pyridine-2-carboxylic acid) as the ligand, K 2 CO 3 as the base, and DMF as the solvent, in up to 96% yield. The synthesis is functional grouptolerant. Some methodologies for the preparation of these isoflavones have been already developed [7 -11]. However, the reported methods suffer from hazardous materials or harsh reaction conditions. Transition metal-catalyzed coupling reactions have emerged as a powerful tool for the formation of CÀC [12] and CÀX [13] (X ¼ N, O, S) bonds. Maiti and Buchwald had successfully developed an efficient and complementary set of Cu-and Pd-based catalyst systems for the selective O-and N-arylation of unprotected amino phenols using aryl halides [14]. Together with our previous efforts [15] to construct heterocycles via CuI-catalyzed intramolecular cyclization reactions, these prompted us to investigate the feasibility of a synthesis strategy featuring a Cucatalyzed cyclization reaction of the 3-(2-bromophenyl)-3-oxo-2-phenylpropanal derivatives (Scheme).
Cyclin-dependent kinase 4 (CDK4) is a member of cyclin-dependent kinase family which regulates G1 to S cell cycle transition. CDK4 activity is increased in many tumor types. Here, we report a negative automodulatory feedback loop between CDK4 and miR-16 that regulates cell cycle progression in nasopharyngeal carcinoma (NPC). By miRNA array and real-time PCR, we identified upregulation of tumor suppressor miR-16a, which inhibited cell cycle progression and sensitized NPC cells to chemotherapy. CDK4 knockdown reduced the expression of c-Myc, the latter of which directly suppresses the miR-16 expression by directly binding to the miR-16 promoter. Moreover, we found that miR-16 upregulation could reduce CDK4 expression by repressing CCND1 and thus forms a feedback loop via the CDK4/c-Myc/miR-16/CCND1 pathway. Finally, miR-16 was negatively correlated with CDK4 expression in NPC biopsies. In summary, our results define a double-negative feedback loop involving CDK4 and miR-16 mediated by c-Myc that modulates NPC cell growth and chemotherapy sensitivity.
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