璧勮涓績 > 浜у搧鏂囩尞闆?> Molecular Cell Biology (167)

  鉁旀湰綃囪鏂囦嬌鐢ㄥ崕鑱斾駭鍝侊細Experimental Accessories  
 Plos One. 2013; 8(6): e65489. doi: 10.1371/journal.pone.0065489.
 BAK and NOXA Are Critical Determinants of Mitochondrial Apoptosis Induced by Bortezomib in Mesothelioma 
 Sara Busacca, Alex D. Chacko, Astero Klabatsa, Kenneth Arthur, Michael Sheaff,vignesh K. Gunasekharan, Julia J. Gorski, Mohamed El-tanani, V. Courtney Broaddus, Giovanni Gaudino, Dean A. Fennell
  Abstract
Based on promising preclinical efficacy associated with the 20S proteasome inhibitor bortezomib in malignant pleural mesothelioma (MPM), two phase II clinical trials have been initiated (EORTC 08052 and ICORG 05鈥?0). However, the potential mechanisms underlying resistance to this targeted drug in MPM are still unknown. Functional genetic analyses were conducted to determine the key mitochondrial apoptotic regulators required for bortezomib sensitivity and to establish how their dysregulation may confer resistance. The multidomain proapoptotic protein BAK, but not its orthologue BAX, was found to be essential for bortezomib-induced apoptosis in MPM cell lines. Immunohistochemistry was performed on tissues from the ICORG-05 phase II trial and a TMA of archived mesotheliomas. Loss of BAK was found in 39% of specimens and loss of both BAX/BAK in 37% of samples. However, MPM tissues from patients who failed to respond to bortezomib and MPM cell lines selected for resistance to bortezomib conserved BAK expression. In contrast, c-Myc dependent transactivation of NOXA was abrogated in the resistant cell lines. In summary, the block of mitochondrial apoptosis is a limiting factor for achieving efficacy of bortezomib in MPM, and the observed loss of BAK expression or NOXA transactivation may be relevant mechanisms of resistance in the clinic.
   

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  鉁旀湰綃囪鏂囦嬌鐢ㄥ崕鑱斾駭鍝侊細Human OneArray  
 Oncoscience. doi:10.18632/oncoscience.285.
 In silico and experimental analyses predict the therapeutic value of an EZH2 inhibitor GSK343 against hepatocellular carcinoma through the induction of metallothionein genes
 
 
 
  Abstract
There are currently no effective molecular targeted therapies for hepatocellular carcinoma (HCC), the third leading cause of cancer-related death worldwide. Enhancer of zeste homolog 2 (EZH2), a histone H3 lysine 27 (H3K27)-specific methyltransferase, has been emerged as novel anticancer target. Our previous study has demonstrated that GSK343, an S-adenosyl-L-methionine (SAM)-competitive inhibitor of EZH2, induces autophagy and enhances drug sensitivity in cancer cells including HCC. In this study, an in silico study was performed and found that EZH2 was overexpressed in cancerous tissues of HCC patients at both gene and protein levels. Microarray analysis and in vitro experiments indicated that the anti-HCC activity of GSK343 was associated with the induction of metallothionein (MT) genes. In addition, the negative association of EZH2 and MT1/MT2A genes in cancer cell lines and tissues was found in public gene expression database. Taken together, our findings suggest that EZH2 inhibitors could be a good therapeutic option for HCC, and induction of MT genes was associated with the anti-HCC activity of EZH2 inhibitors.
   

  鉁旀湰綃囪鏂囦嬌鐢ㄥ崕鑱斾駭鍝侊細Human OneArray  
 Bmc Bioinformatics. doi: 10.1186/s12859-015-0848-x.
 Gene expression profiling identifies candidate biomarkers for active and latent tuberculosis
 
 
 
  Abstract
Background Tuberculosis (TB) is a serious infectious disease in that 90 % of those latently infected with Mycobacterium tuberculosis present no symptoms, but possess a 10 % lifetime chance of developing active TB. To prevent the spread of the disease, early diagnosis is crucial. However, current methods of detection require improvement in sensitivity, efficiency or specificity. In the present study, we conducted a microarray experiment, comparing the gene expression profiles in the peripheral blood mononuclear cells among individuals with active TB, latent infection, and healthy conditions in a Taiwanese population. Results Bioinformatics analysis revealed that most of the differentially expressed genes belonged to immune responses, inflammation pathways, and cell cycle control. Subsequent RT-PCR validation identified four differentially expressed genes, NEMF, ASUN, DHX29, and PTPRC, as potential biomarkers for the detection of active and latent TB infections. Receiver operating characteristic analysis showed that the expression level of PTPRC may discriminate active TB patients from healthy individuals, while ASUN could differentiate between the latent state of TB infection and healthy condidtion. In contrast, DHX29 may be used to identify latently infected individuals among active TB patients or healthy individuals. To test the concept of using these biomarkers as diagnostic support, we constructed classification models using these candidate biomarkers and found the Naïve Bayes-based model built with ASUN, DHX29, and PTPRC to yield the best performance. Conclusions Our study demonstrated that gene expression profiles in the blood can be used to identify not only active TB patients, but also to differentiate latently infected patients from their healthy counterparts. Validation of the constructed computational model in a larger sample size would confirm the reliability of the biomarkers and facilitate the development of a cost-effective and sensitive molecular diagnostic platform for TB.
   

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  鉁旀湰綃囪鏂囦嬌鐢ㄥ崕鑱斾駭鍝侊細Experimental Accessories  
 Journal Of Virology. 2012, 86(15):8041-9. doi: 10.1128/JVI.00808-12.
 Defective Antiviral Responses of Induced Pluripotent Stem Cells to Baculoviral Vector Transduction
 
 
 Chen Gy, Hwang Sm, Su Hj, Kuo Cy, Luo Wy, Lo Kw, Huang Cc, Chen Cl, Yu Sh, Yu-chen Hu
  Abstract
Genetic engineering of induced pluripotent stem cells (iPSCs) is important for their clinical applications, and baculovirus (BV) holds promise as a gene delivery vector. To explore the feasibility of using BV for iPSCs transduction, in this study we first examined how iPSCs responded to BV. We determined that BV transduced iPSCs efficiently, without inducing appreciable negative effects on cell proliferation, apoptosis, pluripotency, and differentiation. BV transduction slightly perturbed the transcription of 12 genes involved in the Toll-like receptor (TLR) signaling pathway, but at the protein level BV elicited no well-known cytokines (e.g., interleukin-6 [IL-6], tumor necrosis factor alpha [TNF-], and beta interferon [IFN-]) except for IP-10. Molecular analyses revealed that iPSCs expressed no TLR1, -6, -8, or -9 and expressed merely low levels of TLR2, -3, and -4. In spite of evident expression of such RNA/DNA sensors as RIG-I and AIM2, iPSCs barely expressed MDA5 and DAI (DNA-dependent activator of IFN regulatory factor [IRF]). Importantly, BV transduction of iPSCs stimulated none of the aforementioned sensors or their downstream signaling mediators (IRF3 and NF-B). These data together confirmed that iPSCs responded poorly to BV due to the impaired sensing and signaling system, thereby justifying the transduction of iPSCs with the baculoviral vector.
   

  鉁旀湰綃囪鏂囦嬌鐢ㄥ崕鑱斾駭鍝侊細Experimental Accessories  
 Plos One. 2012, 7(8):e43304. doi: 10.1371/journal.pone.0043304.
 Luteolin Induces microRNA-132 Expression and Modulates Neurite Outgrowth in PC12 Cells
 
 
 Lian-fang Lin, Szu-ping Chiu, Ming-jiuan Wu, Pei-yi Chen, Jui-hung Yen
  Abstract
Luteolin, a food-derived flavonoid, has been reported to exert neurotrophic properties that are associated with its capacity to promote neuronal survival and neurite outgrowth. In this study, we report for the first time that luteolin induces the persistent expression of microRNA-132 (miR-132) in PC12 cells. The correlation between miR- 132 knockdown and a decrease in luteolin-mediated neurite outgrowth may indicate a mechanistic link by which miR-132 functions as a mediator for neuritogenesis. Furthermore, we find that luteolin led to the phosphorylation and activation of cAMP response element binding protein (CREB), which is associated with the up-regulation of miR-132 and neurite outgrowth. Moreover, luteolin-induced CREB activation, miR-132 expression and neurite outgrowth were inhibited by adenylate cyclase, protein kinase A (PKA) and MAPK/ERK kinase 1/2 (MEK1/2) inhibitors but not by protein kinase C (PKC) or calcium/calmodulin-dependent protein kinase II (CaMK II) inhibitors. Consistently, we find that luteolin treatment increases ERK phosphorylation and PKA activity in PC12 cells. These results show that luteolin induces the up-regulation of miR-132, which serves as an important regulator for neurotrophic actions, mainly acting through the activation of cAMP/PKA- and ERK-dependent CREB signaling pathways in PC12 cells.
   

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