Phenotypic similarities have long been recognized between subpopulations of glioma cells and neural stem cells. Many of these similar properties, including the robust abilities to self-renew, migrate and invade, are hallmarks of glioma cells that render them extremely aggressive. However, the molecular mechanisms underlying this character, particularly in glioma stem-like cells that drive this disease, remain poorly understood. Here we report the results of a differential miRNA expression screen that compared glioma cells and neural stem cells, where we found that miR-204 was markedly down-regulated in both types of cells. Mechanistic investigations revealed that miR-204 simultaneously suppressed self-renewal, stem cell associated phenotype and migration of glioma cells via targeting the stemness-governing transcriptional factor SOX4 and the migration-promoting receptor EphB2. Restoring miR-204 expression in glioma cells suppressed tumorigenesis and invasiveness in vivo and increased overall host survival. Further evaluation revealed that the miR-204 promoter was hypermethylated and that attenuating promoter methylation was sufficient to upregulate miR-204 in glioma cells. Together, our findings reveal miR-204 as a pivotal regulator of the development of stem cell-like phenotypes and cell motility in malignant glioma cells.

Oxygen vacancy creation in WO3 induces a synergetic catalytic effect between Pt atoms and def-WO3, thus bestowing excellent HER performances.

The surface reconstruction of cobalt phosphide nanosheets is investigated by an in situ electrochemical strategy for enhanced hydrogen evolution.

Paradoxically, during early tumor development in many cancer types, TGF-β acts as a tumor suppressor, whereas in the advanced stages of these cancers, increased TGF-β expression is linked to high metastasis and poor prognosis. These findings suggest that unidentified mechanisms may function to rewire TGF-β signaling toward its prometastatic role in cancer cells. Our current study using non-small-cell lung carcinoma (NSCLC) cell lines, animal models, and clinical specimens demonstrates that suppression of SMAD2, with SMAD3 function intact, switches TGF-β-induced transcriptional responses to a prometastatic state. Importantly, we identified chaperonin containing TCP1 subunit 6A (CCT6A) as an inhibitor and direct binding protein of SMAD2 and found that CCT6A suppresses SMAD2 function in NSCLC cells and promotes metastasis. Furthermore, selective inhibition of SMAD3 or CCT6A efficiently suppresses TGF-β-mediated metastasis. Our findings provide a mechanism that directs TGF-β signaling toward its prometastatic arm and may contribute to the development of therapeutic strategies targeting TGF-β for NSCLC.

Fe−N−C electrocatalysts have been demonstrated to be the most promising substitutes for benchmark Pt/C catalysts for the oxygen reduction reaction (ORR). Herein, we report that N‐doped carbon materials with trace amounts of iron (0–0.08 wt. %) show excellent ORR activity and durability comparable and even superior to those of Pt/C in both alkaline and acidic media without significant contribution by the metal sites. Such an N‐doped carbon (denoted as N‐HPCs) features a hollow and hierarchically porous architecture, and more importantly, a noncovalently bonded N‐deficient/N‐rich heterostructure providing the active sites for oxygen adsorption and activation owing to the efficient electron transfer between the layers. The primary Zn‐air battery using N‐HPCs as the cathode delivers a much higher power density of 158 mW cm−2, and the maximum power density in the H2−O2 fuel cell reaches 486 mW cm−2, which is comparable to and even better than those using conventional Fe−N−C catalysts at cathodes.

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Highlights d Low-dose sorafenib safely suppresses NASH progression in mice d Low-dose sorafenib resolves NASH in monkeys without detectable toxicities d AMPK activation is required for the therapeutic effects of sorafenib in NASH d Sorafenib activates AMPK by acting as a mitochondrial uncoupler

Despite the importance of AKT overactivation in tumor progression, results from clinical trials of various AKT inhibitors remain suboptimal, suggesting that AKT-driven tumor metastasis needs to be further understood. Herein, based on long non-coding RNA (lncRNA) profiling induced by active AKT, we identify that VAL (Vimentin associated lncRNA, LINC01546), which is directly induced by AKT/STAT3 signaling, functions as a potent pro-metastatic molecule and is essential for active AKT-induced tumor invasion, metastasis and anoikis resistance in lung adenocarcinoma (LAD). Impressively, chemosynthetic siRNAs against VAL shows great therapeutic potential in AKT overactivation-driven metastasis. Interestingly, similar to activated AKT in LAD cells, although unable to induce epithelial-mesenchymal transition (EMT), VAL exerts potent pro-invasive and pro-metastatic effects through directly binding to Vimentin and competitively abrogating Trim16-depedent Vimentin polyubiquitination and degradation. Taken together, our study provides an interesting demonstration of a lncRNA-mediated mechanism for active AKT-driven EMT-independent LAD metastasis and indicates the great potential of targeting VAL or Vimentin stability as a therapeutic approach.