Transmembrane B cell lymphoma 2-associated X protein inhibitor motif-containing (TMBIM) 6, a Ca2+ channel-like protein, is highly upregulated in several cancer types. Here, we show that TMBIM6 is closely associated with survival in patients with cervical, breast, lung, and prostate cancer. TMBIM6 deletion or knockdown suppressed primary tumor growth. Further, mTORC2 activation was up-regulated by TMBIM6 and stimulated glycolysis, protein synthesis, and the expression of lipid synthesis genes and glycosylated proteins. Moreover, ER-leaky Ca2+ from TMBIM6, a unique characteristic, was shown to affect mTORC2 assembly and its association with ribosomes. In addition, we identified that BIA compound, a suggestive TMBIM6 antagonist, prevented TMBIM6 binding to mTORC2, decreased mTORC2 activity, and also regulated TMBIM6-leaky Ca2+, further suppressing tumor formation and progression in cancer xenograft models. This previously unknown signaling cascade in which mTORC2 activity is enhanced via the interaction with TMBIM6 provides effective therapeutic targets for various malignancies.
TMBIM6/BI-1 contributes to cancer progression through assembly with mTORC2 and AKT activation.
Specimen part, Cell line
View SamplesTime-course analysis of adipocyte gene expression profiles response to high fat diet. The hypothesis tested in the present study was that in diet-induced obesity, early activation of TLR-mediated inflammatory signaling cascades by CD antigen genes, leads to increased expression of pro-inflammatory cytokines and chemokines, resulting in chronic low-grade inflammation. Early changes in collagen genes may trigger the accumulation of ECM components, promoting fibrosis in the later stages of diet-induced obesity. New therapeutic approaches targeting visceral adipose tissue genes altered early by HFD feeding may help ameliorate the deleterious effects of a diet-induced obesity.
Time-course microarrays reveal early activation of the immune transcriptome and adipokine dysregulation leads to fibrosis in visceral adipose depots during diet-induced obesity.
Age, Specimen part, Treatment, Time
View SamplesThe treatment strategy of rectal cancer has substantially changed in recent decades. Historically postoperative chemoradiotherapy (CRT) was considered to be the first-line therapy for stage II and III rectal cancers. However, the preoperative CRT is now considered to be the optimal therapy regimen for locally advanced rectal ancer due to its improved local control, reduced toxicity, and increased rate of sphincter preservation. Our study established a clinically practical multi-class prediction model by adopting a novel strategy that applies two separate prediction models (MI and TO predictor) sequentially to a patient to predict the response. For promising clinical practice, we validated our model in a published dataset, which is completely independent dataset from ours. This study suggests a clinically plausible prediction model that correctly infers the preoperative CRT response of patients with high accuracy based on 163 gene signatures we identified.
No associated publication
Sex, Age
View SamplesDrug-induced alterations in transcriptional regulation play a central role in establishing the persistent neuroplasticities that occur during drug addiction. Additionally, changes in gene expression associated with drug administration provide valuable insight into the molecular basis of drug abuse. The molecular mechanisms that underlie susceptibility to psychostimulant addiction remain unknown. Identifying the common gene transcriptional responses to psychostimulants can provide a mechanistic insight to elucidate the molecular nature of drug dependence.
Neuronal development genes are key elements mediating the reinforcing effects of methamphetamine, amphetamine, and methylphenidate.
Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Methylome analysis reveals alterations in DNA methylation in the regulatory regions of left ventricle development genes in human dilated cardiomyopathy.
Sex, Specimen part
View SamplesCore diet-induced obesity networks were constructed using Ingenuity pathway analysis (IPA) based on 332 high-fat diet responsive genes identified in liver by time-course microarray analysis (8 time-points over 24 weeks) of high-fat diet fed mice compared to normal diet fed mice. IPA identified five core diet-induced obesity networks with time-dependent gene expression changes in liver. When we merged core diet-induced obesity networks, Tlr2, Cd14 and Ccnd1 emerged as hub genes associated with both liver steatosis and inflammation and were altered in a time-dependent manner. Further protein-protein interaction network analysis revealed Tlr2, Cd14 and Ccnd1 were inter-related through the ErbB/insulin signaling pathway. Dynamic changes occur in molecular networks underlying diet-induced obesity. Tlr2, Cd14 and Ccnd1 appear to be hub genes integrating molecular interactions associated with the development of NASH. Therapeutics targeting hub genes and core diet-induced obesity networks may help ameliorate diet-induced obesity and NASH.
Time-dependent network analysis reveals molecular targets underlying the development of diet-induced obesity and non-alcoholic steatohepatitis.
Age, Specimen part
View SamplesTo identify a set of genes related to radioresistance, we analyzed the time-series gene expression profiles of radioresistant H1299 and radiosensitive H460 lung cancer cells in response to 2 Gy of ionizing radiation (IR) by performing quadratic regression (QR) analysis. Out of the 21,331 genes, we selected 6,538 genes by QR analysis from the gene expression profile of H460 cells and 6,086 genes from that of H1299 cells. Most of the genes identified in the H460 cells were classified into continuously up- or down-regulated groups, while the major QR groups were transiently changed groups in the H1299 cell line. From gene ontology analysis of the major QR groups, the DNA damage response was commonly enriched in both cell lines. DNA repair-related genes such as ATM, ATR, TP53BP1, BRCA1, MRE11, NBN and RAD50 were particularly up-regulated in H1299 cells. Suppression of these DNA repair-related genes using siRNA made H1299 cells radiosensitive to ionizing radiation. The data suggest that differential responses to DNA damage confer radioresistance to cancer cells, and provide potential novel targets for sensitizing radiotherapy.
No associated publication
Cell line
View SamplesPediatric medulloblastoma is considered a highly heterogeneous disease, and a new strategy of risk stratification to optimize therapeutic outcomes is required. We aimed to investigate a new risk-stratification approach based on expression profiles of medulloblastoma cohorts. We analyzed gene expression profiles of 30 primary medulloblastomas and detected strong evidence that poor survival outcome was significantly associated with mRNA expression profiles of 17p loss. However, it was not supported in independent cohorts from previously published data (n=100). We speculated that this controversy might come from complex conditions of two important prognostic determinants, loss of tumor suppressors (chromosome 17p) and high expression of oncogenes, c-myc (MYC) or N-myc (MYCN). Simultaneous consideration of these two factors led to a new subgrouping of patients, exhibiting obviously different survival expectancies between the subgroups. Patients with up-regulated WNT signalings were always pre-defined as an independent subgroup, which ultimately removed confounding effect arising from contradictory outcome, favorable prognosis of WNT medulloblastomas despite their high MYC/MYCN expression level. We also found that age is a significant prognostic marker after adjusting for 17p and MYC/MYCN status. Diminished survival in age <3 years was more substantial in groups with high expression of MYC/MYCN or 17p loss, indicating survival outcome might be coordinately affected by these three factors. We suggest a more tailored and easily applicable subgrouping system based on expression profiles of chromosome 17p and MYC/MYCN, while separating WNT medulloblastoma as an independent subgroup, which could provide the basis for a novel risk-stratification strategy in pediatric medulloblastoma.
Prognostic classification of pediatric medulloblastoma based on chromosome 17p loss, expression of MYCC and MYCN, and Wnt pathway activation.
Sex, Specimen part
View SamplesAlterations in DNA methylation and gene expression have been implicated in the development of human dilated cardiomyopathy (DCM). In this study, we analyzed DNA methylomes (Infinium 450K HumanMethylation BeadChip) and transcriptomes (Infinium HT-12 v4) to characterize differentially methylated probes (DMPs) and differentially expressed genes (DEGs) between the left and right ventricles of human DCM.
Methylome analysis reveals alterations in DNA methylation in the regulatory regions of left ventricle development genes in human dilated cardiomyopathy.
Sex, Specimen part
View SamplesWe focused on whether transposon mutagenesis in Brucella abortus could induce difference in the trascriptional responses of RAW 264.7 cell infection model compared to the wild strain infected RAW 264.7 cells.
No associated publication
Cell line, Time
View Samples