Melatonin, an indolamine produced and secreted predominately by the pineal gland, exhibits a variety of physiological functions, possesses antioxidant and antitumor properties. In this study, we have shown that pharmacologic concentration (1mm) of melatonin significantly reduced cell migration and invasion of T98G and U251 glioma cells after 24-hr treatment and inhibited expression of matrix metalloproteinase 2 (MMP 2) and MMP 9. The melatonin inhibition of cell migration and invasion was associated with its reduction of intracellular basal free radical generation. Melatonin at pharmacologic concentration also inhibited the constitutive activation of the reactive oxygen species downstream transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Furthermore, pyrrolidine dithiocarbamate, a NF-κB-specific inhibitor, at 10μm displayed anti-migration and invasion effects and inhibition of MMP 2 and MMP 9 expression resembling that of melatonin. Taken together, it is concluded that inhibition of migration and invasion of glioma cells by melatonin is associated with the latter in its inhibition of oxidative stress pathway. This suggests a potential therapeutic application of melatonin in the treatment of glioma.

Architectural integrity of the mitotic spindle is required for efficient chromosome congression and accurate chromosome segregation to ensure mitotic fidelity. Tumour suppressor PTEN has multiple functions in maintaining genome stability. Here we report an essential role of PTEN in mitosis through regulation of the mitotic kinesin motor EG5 for proper spindle architecture and chromosome congression. PTEN depletion results in chromosome misalignment in metaphase, often leading to catastrophic mitotic failure. In addition, metaphase cells lacking PTEN exhibit defects of spindle geometry, manifested prominently by shorter spindles. PTEN is associated and co-localized with EG5 during mitosis. PTEN deficiency induces aberrant EG5 phosphorylation and abrogates EG5 recruitment to the mitotic spindle apparatus, leading to spindle disorganization. These data demonstrate the functional interplay between PTEN and EG5 in controlling mitotic spindle structure and chromosome behaviour during mitosis. We propose that PTEN functions to equilibrate mitotic phosphorylation for proper spindle formation and faithful genomic transmission.

The POU family transcription factor OCT4 is required for maintaining the pluripotency of embryonic stem cells and for generating induced pluripotent stem cells. Although OCT4 is clearly shown to be expressed in some pluripotent germ cell tumours, its expression in human somatic tumours remains controversial. Some studies have shown that OCT4 is expressed in adult stem cells, somatic cancers and, further, cancer stem cells, while other studies failed to make such an observation. It is thus important to ascertain whether OCT4 is expressed in human somatic tumours. By using RT-PCR and sequencing analysis, three OCT4 pseudogenes, viz. OCT4-pg1, OCT4-pg3 and OCT4-pg4 but excluding the OCT4 gene, were found to be expressed in two types of human solid tumours, glioma and breast carcinoma, from which cancer stem cells had earlier been isolated. The protein expression of these pseudogenes was further demonstrated by immunochemistry and western blotting. Along with this, it was shown that OCT4 pseudogenes lacked OCT4-like activities. The expression of OCT4 splicing variant and various pseudogenes at both the mRNA and protein levels in human somatic tumours might call into question the reliability of the results regarding OCT4 expression and function in tumourigenesis. Hence, in investigations of OCT4 expression in cancers and stem cells, different approaches with appropriate controls would be desirable to exclude possibility of false-positive results.

Summary Faithful DNA replication and accurate chromosome segregation are the key machineries of genetic transmission. Disruption of these processes represents a hallmark of cancer and often results from loss of tumor suppressors. PTEN is an important tumor suppressor frequently mutated or deleted in human cancer. Loss of PTEN has been associated with aneuploidy and poor prognosis in cancer patients. In mice, Pten deletion or mutation drives genomic instability and development of various tumors with high penetrance. PTEN deficiency induces DNA replication stress, confers stress tolerance, and disrupts mitotic spindle architecture, leading to accumulation of structural and numerical chromosome instability. Therefore, PTEN guards the genome by controlling multiple processes of chromosome inheritance. Here we summarize current studies that reveal the PTEN function in promoting high-fidelity transmission of genetic information. We also discuss the PTEN pathways of genome maintenance and highlight potential targets for cancer treatment.

Recent studies demonstrated that the molecules secreted from astrocytes play important roles in the cell fate determination of neural stem cells (NSCs). However, the exact molecules involved and its possible mechanisms in the process remain largely unknown. In this study, astrocyte-conditioned medium (ACM) obtained from astrocytes unstimulated or stimulated by lipopolysaccharide was prepared to treat NSCs. The results showed that both the proliferation and differentiation of NSCs treated with stimulated ACMs were significantly increased compared with those treated with unstimulated ACM. Interleukin-6 (IL-6) antibody neutralization of the ACMs decreased NSC proliferation and astrogliogenesis, while NSC neurogenesis was increased. In contrast, recombinant IL-6 cytokine increased NSC proliferation and astrogliogenesis, but decreased neurogenesis. Furthermore, the expression of phosphorylated signal transducer and activator of transcription 3 (p-stat3) protein as well as serial of basic helix-loop-helix transcription factors (bHLH) mRNA in NSCs exposed to stimulated ACMs significantly increased, respectively. The expression levels of p-stat3 protein and bHLH mRNA of NSCs were significantly altered after adding anti-IL-6 antibody or recombinant IL-6, respectively. The data suggest that IL-6 secreted from activated astrocytes participates in ACM-induced proliferation and differentiation of NSCs via the phosphorylation of stat3 signals and the expression of bHLH transcription factors.

Our observations demonstrate a novel mechanistic insight into a critical role of GRIM-19 in HCC invasive potential.

It has become increasingly clear that there are notable parallels between normal development and tumorigenesis. Glioma is a classic model that links between tumorigenesis and development. We evaluated the expression of GRIM-19, a novel gene essential for normal development, in various grades of gliomas and several human glioma cell lines. We showed that GRIM-19 mRNA and protein expression were markedly lower in gliomas than in control brain tissues and negatively correlated with the malignancy of gliomas. Downregulation of GRIM-19 in glioma cells significantly enhanced cell proliferation and migration, whereas overexpression of GRIM-19 showed the opposite effects. We also showed that the activation of signal transducer and activator of transcription 3 (STAT3) and the expression of many STAT3-dependent genes were regulated by the expression of

Chronic inflammation is thought to contribute to the early pathogenesis of Alzheimer's disease (AD). However, the precise mechanism by which inflammatory cytokines promote the formation and deposition of Aβ remains unclear. Available data suggest that applications of inflammatory cytokines onto isolated neurons do not promote the formation of Aβ, suggesting an indirect mechanism of action. Based on evidence astrocyte derived extracellular vesicles (astrocyte derived EVs) regulate neuronal functions, and data that inflammatory cytokines can modify the molecular cargo of astrocyte derived EVs, we sought to determine if IL‐1β promotes the formation of Aβ indirectly through actions of astrocyte derived EVs on neurons. The production of Aβ was increased when neurons were exposed to astrocyte derived EVs shed in response to IL‐1β (astrocyte derived EV‐IL‐1β). The mechanism for this effect involved an enrichment of Casein kinase 1 (CK1) in astrocyte derived EV‐IL‐1β. This astrocyte derived CK1 was delivered to neurons where it formed a complex with neuronal APC and GSK3 to inhibit the β‐catenin degradation. Stabilized β‐catenin translocated to the nucleus and bound to Hnrnpc gene at promoter regions. An increased cellular concentration of hnRNP C promoted the translation of APP by outcompeting the translational repressor fragile X mental retardation protein (FMRP) bound to APP mRNA. An increased amount of APP protein became co‐localized with BACE1 in enlarged membrane microdomains concurrent with increased production of Aβ. These findings identify a mechanism whereby inflammation promotes the formation of Aβ through the actions of astrocyte derived EV‐IL‐1β on neurons.