No abstract

Jagged1 (JAG1) is a Notch ligand that contact-dependently activates Notch receptors and regulates cancer progression. The JAG1 intracellular domain (JICD1) is generated from JAG1, such as the formation of NOTCH1 intracellular domain (NICD1), however, the role of JICD1 in tumorigenicity has not been comprehensively elucidated. Herein, we revealed that JICD1 induced astrocytes to acquire several cancer stem cell properties, including tumor formation, invasiveness, stemness, and resistance to chemotherapy and radiotherapy. The transcriptome, ChIP-sequencing, and proteomic analyses revealed that JICD1 increased SOX2 expression by forming a transcriptional complex with DDX17, SMAD3, and TGIF2. Furthermore, JICD1-driven tumorigenicity was directly regulated by SOX2. Therefore, our results demonstrated that, like NICD1, JICD1 acts as a transcriptional cofactor in the formation of the DDX17/SMAD3/TGIF2 transcriptional complex, leading to oncogenic transformation.

Glioblastoma (GBM) is the most aggressive and malignant brain tumor, resulting in a poor prognosis. The current therapy for GBM consists in concurrent radiation and chemotherapy following removal of the tumor. Although the therapy prolongs patient survival, recurrence often occurs. The major cause of tumor recurrence is thought to be GBM stem cells (GSCs), which aid the development of chemo-radiotherapy resistance, and can self-renew and aberrantly differentiate. Therefore, GSCs should be targeted to eradicate the tumor and prevent recurrence. Transcriptomic analysis has categorized GBM into proneural (PN), mesenchymal and classical subtypes, and the outcome of recurrence and prognosis markedly depends on subtype. To identify specific GSC markers, the present study analyzed public microarray and RNA-seq data and identified dihydropyrimidinase-related protein 5 (DRP5) as a candidate GSC marker. DRP5 is known to mediate semaphorin 3A signaling and is involved in the regulation of neurite outgrowth and axon guidance during neuronal development. In the present study, DRP5 was specifically upregulated in the PN-subtype GSCs and served crucial roles in maintaining GSC properties, including tumor sphere formation, stem cell marker expression and xenograft tumor growth. Furthermore, bioinformatics analysis revealed that DRP5 expression was positively correlated with signatures of stemness, including Notch, Hedgehog and Wnt/β-catenin expression, which are also known to be positively correlated with PN-subtype gene signatures. Conversely, DRP5 expression was negatively correlated with NF-κB and signal transducer and activator of transcription 3 stemness signatures, which are negatively correlated with PN-subtype gene signatures. Taken together, these findings suggested that DRP5 was specifically expressed in PN-subtype GSCs and may be used as a functional marker of PN-subtype GSCs.

The oncogenic role of nuclear LIM domain only 2 (LMO2) as a transcriptional regulator is well established, but its function in the cytoplasm is largely unknown. Here, we identified LMO2 as a cytoplasmic activator for signal transducer and activator of transcription 3 (STAT3) signaling in glioma stem cells (GSCs) through biochemical and bioinformatics analyses. LMO2 increases STAT3 phosphorylation by interacting with glycoprotein 130 (gp130) and Janus kinases (JAKs). LMO2-driven activation of STAT3 signaling requires the LDB1 protein and leads to increased expression of an inhibitor of differentiation 1 (ID1), a master regulator of cancer stemness. Our findings indicate that the cytoplasmic LMO2-LDB1 complex plays a crucial role in the activation of the GSC signaling cascade via interaction with gp130 and JAK1/2. Thus, LMO2-LDB1 is a bona fide oncogenic protein complex that activates either the JAK-STAT signaling cascade in the cytoplasm or direct transcriptional regulation in the nucleus.

Background In animals, weaning stress is the first and most critical stress. Weaning can negatively affect the growth performance of animals physically, psychologically, and pathologically. Our previous studies on the HT-29 cell line and early-weaned rats demonstrated that adequate sophorolipid (SPL) supplementation in feed could enhance the mucin-producing and wound healing capacities of the gut defense system by modulating gut microbiota. Methods We conducted an experiment with one hundred forty 21-day-old early weaned piglets (L x Y x D). They were allocated into 4 treatment and 7 replications (4 pigs per pen) according to their initial body weight. Body weight and feed intake were measured biweekly during experimental period. After 6 weeks, 28 pigs were randomly selected and sacrificed to collect plasma, jejunum, and cecal content samples. Results Dietary SPL supplementation at 5 and 10 mg/kg quadratically increased the average daily gain during the experimental period in the treatment groups when compared with the control group. The albumin levels of piglets fed with the SPL supplemented diet were downregulated to the normal range. Moreover, in feed, SPL supplementation at 5 and 10 mg/kg improved jejunal histological indices and gene expression levels related to mucin secretion and local inflammation markers. Consistent with these results, adequate SPL supplementation (5 and 10 mg/kg) increased the population of Prevotella, a beneficial bacterium, and its short-chain fatty acid production in the ceca of piglets. Conclusions The occurrence of diarrhea after weaning in piglets could be reduced by feeding a 10 ppm of SPL supplemented diet which improves the gut defense system by improving the microbial population and enhancing mucin layer integrity.