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The molecular pathogenesis of glioblastoma indicates that RTK/Ras/PI3K, RB and TP53 pathways are critical for human gliomagenesis. Here, several transgenic zebrafish lines with single or multiple deletions of nf1, tp53 and rb1 in astrocytes, were established to genetically induce gliomagenesis in zebrafish. In the mutant with a single deletion, we found only the nf1 mutation low-efficiently induced tumour incidence, suggesting that the Nf1 pathway is critical for the initiation of gliomagenesis in zebrafish. Combination of mutations, nf1;tp53 and rb1;tp53 combined knockout fish, showed much higher tumour incidences, high-grade histology, increased invasiveness, and shortened survival time. Further bioinformatics analyses demonstrated the alterations in RTK/Ras/PI3K, cell cycle, and focal adhesion pathways, induced by abrogated nf1, tp53, or rb1, were probably the critical stepwise biological events for the initiation and development of gliomagenesis in zebrafish. Gene expression profiling and histological analyses showed the tumours derived from zebrafish have significant similarities to the subgroups of human gliomas. Furthermore, temozolomide treatment effectively suppressed gliomagenesis in these glioma zebrafish models, and the histological responses in temozolomide-treated zebrafish were similar to those observed in clinically treated glioma patients. Thus, our findings will offer a potential tool for genetically investigating gliomagenesis and screening potential targeted anti-tumour compounds for glioma treatment., Luo et al. genetically induce gliomagenesis in zebrafish by generating zebrafish lines with single or multiple deletions of nf1, tp53, and rb1 in astrocytes, and characterize the lines at the morphological, histological and molecular levels.

Diabetic cardiomyopathy can cause cardiac dysfunction and eventually lead to heart failure and sudden death. Long noncoding RNA (lncRNA) Gas5 has been reported to play a function in cardiomyocyte. Here we studied the function of Gas5 on newborn mouse cardiomyocyte (NMC) apoptosis to detect its molecular mechanism. High-glucose treatment was implemented to induce the apoptosis of NMC in this study. And terminal deoxynucleotidyl transferase dUTP nick-end labeling assay, JC-1 assay, and flow cytometry analysis were conducted to know about the apoptosis of NMC when Gas5 and Tcf3 were silenced. Meanwhile, RNA pull-down assay and luciferase reporter assay were conducted to verify the binding of RNAs. Finally, rescue assay was implemented to evaluate the influence on apoptosis situation affected by competing endogenous RNA pathways. Tcf3 was found to bind to the Gas5 promoter to activate the expression of Gas5. Meanwhile, Gas5 and Tcf3 were both found to promote the apoptosis of NMC. Also, mmu-miR-320-3p could bind to Gas5 and Tcf3. Moreover, the Gas5/miR-320-3p/Tcf3 pathway was found to modulate the apoptosis of NMC. In conclusion, Tcf3-activated lncRNA Gas5 regulates NMC apoptosis in diabetic cardiomyopathy.

Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance is a major obstacle in the treatment of non-small cell lung cancer (NSCLC). Epigenetic alterations have been shown to be involved in NSCLC oncogenesis; however, their function in EGFR-TKI resistance remains uncharacterized. Here, we found that an EHMT2 inhibitor, UNC0638, can significantly inhibit cell growth and induce apoptosis in EGFR-TKI-resistant NSCLC cells. Additionally, we also found that EHMT2 expression and enzymatic activity levels were elevated in EGFR-TKI-resistant NSCLC cells. Moreover, we determined that genetic or pharmacological inhibition of EHMT2 expression enhanced TKI sensitivity and suppressed migration and tumor sphere formation in EGFR-TKI-resistant NSCLC cells. Further investigation revealed that EHMT2 contributed to PTEN transcriptional repression and thus facilitated AKT pathway activation. The negative relationship between EHMT2 and PTEN was confirmed by our clinical study. Furthermore, we determined that combination treatment with the EHMT2 inhibitor and Erlotinib resulted in enhanced antitumor effects in a preclinical EGFR-TKI-resistance model. We also found that high EHMT2 expression along with low PTEN expression can predict poor overall survival in patients with NSCLC. In summary, our findings showed that EHMT2 facilitated EGFR-TKI resistance by regulating the PTEN/AKT pathway in NSCLC cells, suggesting that EHMT2 may be a target in the clinical treatment of EGFR-TKI-resistant NSCLC.

As the key factor of the polarity protein complex, Par6 not only regulates polarization processes, but also plays important roles in tumor metastasis and progression in many epithelium malignancy tumors. Here, we showed that Par6 is an essential component in glioma tumorigenesis. Our results indicated the aberrant expression of Par6 in malignant glioma tissues and cell lines. We found that the regulation of Par6 expression induces cell proliferation and tumor growth in vivo and in vitro. Additionally, RNA-seq revealed the effects of Par6 were associated with cyclin D1-regulated cell cycle progression in glioma cells. Moreover, our results demonstrated that the regulation of Par6 can enhance the activation of Akt/PI3K signaling pathway, and subsequently upregulate the expression level of GSK-3β protein, which then regulate cyclin D1-mediated cell cycle regulation. Furthermore, we found that TGF-β-induced the upregulation of Par6 expression may be involved in this process. The pathological analysis confirmed the correlation between Par6 expression and the prognosis in human glioma tissues, suggesting the regulation of Par6 expression regulates glioma tumorigenesis and progression. Thus, our findings showed that Par6 might be a potential biomarker for the diagnosis and providing a therapeutic strategy for the treatment of malignant glioma.

Graphene quantum dots (GQDs) are well-known for its potential applications for bioimaging, biosensor, and drug carrier in biomedicine. GQDs are well characteristic of intrinsic peroxidase-like catalytic activity, which is proven effective in scavenging the free radicals, such assuperoxide anion, hydrogen peroxide, and hydroxyl radical. GQDs are also well praised for its low in vivo and in vitro toxicity. Here, we found that nitrogen-doped GQDs (N-GQDs) can strongly disturb redox-sensitive system via the selective inhibition of endogenous antioxidant enzyme activities in zebrafish. The enzyme activities or transcription levels of a battery of hemoproteins including catalase (CAT), superoxide dismutase (SOD), respiratory chain complex I, complex Ⅲ, hemoglobin (Hb), and myeloperoxidase (MPO), were significantly suppressed by N-GQDs. We also found that N-GQDs activated the cytochrome P450 monooxygenase (e.g. cyp1a) and the associated aryl-hydrocarbon receptor repressors (ahrr1 and ahrr2) in zebrafish embryos. Compared to the ultrasmall graphene oxide (USGO), N-GQDs exhibited stronger fluorescent permeability and tissue-specific bio-accumulative effects. Taken together, our findings highlighted that exposure to N-GQDs can disrupt endogenous antioxidant enzyme activities, possibly via the competitive inhibition of electron transfer process. Our results in this study provided solid data for biosafety evaluations of various types of GQDs, and created an alert for the future biomedical applications of N-GQDs.