Background: Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer that develops in the pleural and outer layer of tissues surrounding the lungs. MPM is primarily caused by occupational exposure to asbestos and results in a poor prognosis. Effective therapeutics as well as early diagnostics for the MPM are still lacking. To identify potential diagnostic biomarkers for MPM, we performed bioinformatics analysis of public database. Methods: Utilizing databases from Cancer Cell Line Encyclopedia (CCLE) and Gene Expression Omnibus (GEO), we identified several potential candidates that could act as MPM biomarkers. We carried out additional molecular analyses of these potential markers using MPM patient tissue samples via quantitative polymerase chain reaction. Results: We identified Lysyl oxidase (LOX), Lysyl oxidase homologs 1&2 (LOXL1& LOXL2) Zinc Finger Protein, FOG Family Member 2 (ZFPM2) as potential diagnostic biomarkers for MPM. In this study, we found that the LOX family and ZFPM2 showed comparable diagnostic ability to Fibulin-3 or mesothelin (MSLN) and would be better potential biomarkers than Sulfatase 1 (SULF1), Thrombospondin 2 (THBS2) and Cadherin 11 (CDH11). Conclusions: LOX family and ZPFM2 were identified as novel MPM diagnostic biomarkers which could strengthen MPM clinical diagnostic capabilities.
We previously reported that CD133, as a putative cancer stem cell marker, plays an important role in cell proliferation and invasion in colon cancer. To understand the role of CD133 expression in colon cancer, we evaluated the inhibitory effect of CD133 in colon cancer cells. In this study, we generated CD133 knockout colon cancer cells (LoVo) using the CRISPR-Cas9 gene editing system. CD133 + colon cancer cells (LoVo) were infected with the lentiviral vector carrying CD133 gRNA and purified cell by culturing single cell colonies. CD133 knockout cells was validated by western blot and flow cytometry analysis. In functional study, we observed a significant reduction in cell proliferation and colony formation in CRISPR-Cas9 mediated CD133 knockout cells in compare with control (P < 0.001). We also found the anticancer effect of stattic was dependent on CD133 expression in colon cancer cells. Although CD133 knockout cells could not completely block the tumorigenic property, they showed remarkable inhibitory effects on the ability of cell migration and invasion (P < 0.001). In addition, we examined the epithelial mesenchymal transition (EMT)-related protein expression by western blot. The result clearly showed a loss of vimentin expression in CD133 knockout cells. Therefore, CRISPR-Cas9 mediated CD133 knockout can be an effective treatment modality for CD133 + colon cancer through reducing the characteristics of cancer stem cells.
For survival, it is crucial for eating behaviours to be sequenced through two distinct seeking and consummatory phases. Heterogeneous lateral hypothalamus (LH) neurons are known to regulate motivated behaviours, yet which subpopulation drives food seeking and consummatory behaviours have not been fully addressed. Here, in male mice, fibre photometry recordings demonstrated that LH leptin receptor (LepR) neurons are correlated explicitly in both voluntary seeking and consummatory behaviours. Further, micro-endoscope recording of the LHLepR neurons demonstrated that one subpopulation is time-locked to seeking behaviours and the other subpopulation time-locked to consummatory behaviours. Seeking or consummatory phase specific paradigm revealed that activation of LHLepR neurons promotes seeking or consummatory behaviours and inhibition of LHLepR neurons reduces consummatory behaviours. The activity of LHLepR neurons was increased via Neuropeptide Y (NPY) which acted as a tonic permissive gate signal. Our results identify neural populations that mediate seeking and consummatory behaviours and may lead to therapeutic targets for maladaptive food seeking and consummatory behaviours.
Agouti-related protein (AgRP) has been believed to be the main driver of feeding behaviors ever since its discovery. However, recent studies using fiber photometry and optogenetics proved that feeding behaviors are not directly driven by AgRP neurons (temporal discrepancy between neuronal activity and behavior). To resolve this paradox, we conducted novel multi-phase feeding experiments to scrutinize the dynamics of AgRP. Fiber photometry study showed that AgRP neurons start to deactivate even before the initiation of the food search phase. Using optogenetics, we could prove that the feeding behavior induced by AgRP neuron activation had substantial temporal delay and the feeding behavior was sustained for substantial time even after cessation of optogenetic activation. These results indicate that AgRP neurons are not the direct driver of feeding behavior and another downstream neuron is the driver of feeding behavior. Leptin receptor (LepR) neurons in the lateral hypothalamus (LH). LH LepR neurons were activated before voluntary food search behavior initiation and showed robust increase after food approach behavior. Artificial activation of LH LepR neurons drives food search and food approach behavior. In accordance, chemogenetic activation of LepR neurons increased food search and food approach behaviors. Lastly, slice calcium imaging results showed the possibility that NPY from the AgRP neurons could be the downstream neuromodulator of AgRP neuron, driving LH LepR neuron activation. Overall, our study shows that AgRP neurons are not the direct drivers of feeding behavior, whereas LH LepR neurons directly drive sustained food seeking behavior.
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