Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA327171 | ENA |
REPOSITORIES: ENA
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Project description:Thyroid transcription factor-1 (TTF-1), also known as NKX2-1, plays a role as a lineage-survival oncogene in lung adenocarcinoma with double-edged sword characteristics. Although previous studies steadily accumulated evidence for roles of TTF-1 in the transcriptional regulation of protein-coding genes, very little is known about its regulatory relationship with miRNAs. In this study, we have identified miR-532-5p as a novel transcriptional target of TTF-1 by an integrative approach, which was designed to extract maximal information from expression profiles of both patient tumors in vivo and TTF-1-inducible cell lines in vitro. Consequently, we have found that miR-532-5p is directly regulated by TTF-1 through its binding to a genomic region 8 kb upstream of miR-532-5p, which appeared to impose transcriptional regulation independent of that of CLCN5, a protein-coding gene harboring miR-532-5p in its intron 3. Further, we have also identified KRAS and MKL2 as novel direct targets of miR-532-5p. Introduction of miR-532-5p mimics markedly induced apoptosis in KRAS-mutant as well as KRAS wildtype lung adenocarcinoma cell lines. Interestingly, miR-532-5p affected the MEK-ERK pathway signaling specifically in cell lines sensitive to siKRAS treatment, while the miR-532-5p-mediated effects were clearly phenocopied by repressing expression or inhibiting function of MKL2 regardless of KRAS mutation status. In summary, our findings demonstrate that miR-532-5p is as novel transcriptional target of TTF-1 and plays a tumor suppressive role by targeting KRAS and MKL2 in lung adenocarcinoma. Novel therapeutic strategies using miR-532-5p or an MKL2 inhibitor may prove effective against this hard-to-cure cancer irrespective of the dependence on KRAS-mediated signaling.
2017-06-21 | GSE83836 | GEO
Project description:Thyroid transcription factor-1 (TTF-1), also known as NKX2-1, plays a role as a lineage-survival oncogene in lung adenocarcinoma with double-edged sword characteristics. Although previous studies steadily accumulated evidence for roles of TTF-1 in the transcriptional regulation of protein-coding genes, very little is known about its regulatory relationship with miRNAs. In this study, we have identified miR-532-5p as a novel transcriptional target of TTF-1 by an integrative approach, which was designed to extract maximal information from expression profiles of both patient tumors in vivo and TTF-1-inducible cell lines in vitro. Consequently, we have found that miR-532-5p is directly regulated by TTF-1 through its binding to a genomic region 8 kb upstream of miR-532-5p, which appeared to impose transcriptional regulation independent of that of CLCN5, a protein-coding gene harboring miR-532-5p in its intron 3. Further, we have also identified KRAS and MKL2 as novel direct targets of miR-532-5p. Introduction of miR-532-5p mimics markedly induced apoptosis in KRAS-mutant as well as KRAS wildtype lung adenocarcinoma cell lines. Interestingly, miR-532-5p affected the MEK-ERK pathway signaling specifically in cell lines sensitive to siKRAS treatment, while the miR-532-5p-mediated effects were clearly phenocopied by repressing expression or inhibiting function of MKL2 regardless of KRAS mutation status. In summary, our findings demonstrate that miR-532-5p is as novel transcriptional target of TTF-1 and plays a tumor suppressive role by targeting KRAS and MKL2 in lung adenocarcinoma. Novel therapeutic strategies using miR-532-5p or an MKL2 inhibitor may prove effective against this hard-to-cure cancer irrespective of the dependence on KRAS-mediated signaling.
2017-06-21 | GSE83837 | GEO
Project description:Thyroid transcription factor-1 (TTF-1), also known as NKX2-1, plays a role as a lineage-survival oncogene in lung adenocarcinoma with double-edged sword characteristics. Although previous studies steadily accumulated evidence for roles of TTF-1 in the transcriptional regulation of protein-coding genes, very little is known about its regulatory relationship with miRNAs. In this study, we have identified miR-532-5p as a novel transcriptional target of TTF-1 by an integrative approach, which was designed to extract maximal information from expression profiles of both patient tumors in vivo and TTF-1-inducible cell lines in vitro. Consequently, we have found that miR-532-5p is directly regulated by TTF-1 through its binding to a genomic region 8 kb upstream of miR-532-5p, which appeared to impose transcriptional regulation independent of that of CLCN5, a protein-coding gene harboring miR-532-5p in its intron 3. Further, we have also identified KRAS and MKL2 as novel direct targets of miR-532-5p. Introduction of miR-532-5p mimics markedly induced apoptosis in KRAS-mutant as well as KRAS wildtype lung adenocarcinoma cell lines. Interestingly, miR-532-5p affected the MEK-ERK pathway signaling specifically in cell lines sensitive to siKRAS treatment, while the miR-532-5p-mediated effects were clearly phenocopied by repressing expression or inhibiting function of MKL2 regardless of KRAS mutation status. In summary, our findings demonstrate that miR-532-5p is as novel transcriptional target of TTF-1 and plays a tumor suppressive role by targeting KRAS and MKL2 in lung adenocarcinoma. Novel therapeutic strategies using miR-532-5p or an MKL2 inhibitor may prove effective against this hard-to-cure cancer irrespective of the dependence on KRAS-mediated signaling.
2017-06-21 | GSE83838 | GEO
Project description:TTF-1-regulated miR-532-5p targets KRAS and MKL2 oncogenes and induces apoptosis in lung adenocarcinoma
| PRJNA327170 | ENA
Project description:TTF-1-regulated miR-532-5p targets KRAS and MKL2 oncogenes and induces apoptosis in lung adenocarcinoma [pts]
| PRJNA327285 | ENA
Project description:TTF-1-regulated miR-532-5p targets KRAS and MKL2 oncogenes and induces apoptosis in lung adenocarcinoma [cell line]
| PRJNA327284 | ENA
Project description:Adenocarcinoma is the most common histologic subtype of lung cancer, which is the leading cause of cancer death. We and others previously identified TTF-1, a lineage-specific transcription factor required for branching morphogenesis and physiological lung functions, as a lineage-survival oncogene in lung adenocarcinoma. However, how TTF-1 mediates survival signals remains elusive. Here we show that TTF-1 induces receptor tyrosine kinase-like orphan receptor 1 (ROR1), which in turn mediates TTF-1 survival signaling in lung adenocarcinoma. Inhibition of ROR1 impaired prosurvival signaling through the PI3K-AKT pathway and induced nuclear accumulation of FOXO1. These were found to be imposed, at least in part, through PTEN inactivation via c-Src, while ROR1 was shown to physically interact with and phosphorylate c-Src. ROR1 inhibition also elicited marked p38 activation, provoking ill-balance between prosurvival and proapoptotic signaling, and consequential “oncogenic shock.” In addition, we found that ROR1 is crucially involved in EGFR- and MET-mediated prosurvival signaling. ROR1 knockdown effectively induced apoptosis in lung adenocarcinoma cell lines with acquired EGFR TKI resistance conferred by a secondary T790M EGFR mutation, or HGF-elicited MET signaling and resultant switching of the addicted receptor tyrosine kinases (RTKs). Taken together, our findings indicate that ROR1 RTK is a very promising molecular target for development of a novel therapeutic means to treat this hard-to-cure cancer. Dye-swap experiment, vector control vs. stable TTF-1 transfectant of HPL1D, immortalized human peripheral lung epithelial cell line.
2011-12-31 | E-GEOD-25830 | biostudies-arrayexpress
Project description:To characterize gene expression changes induced by oncogenes implicated in human lung adenocarcinoma, we analyzed the whole transcriptome of NIH3T3 cells expressing mutant EGFR (exon 19 deletion) or wild-type EGFR. Expression levels of several genes from this list were validated by quantitative RT-PCR using the same RNA samples.
2017-10-03 | GSE104494 | GEO
Project description:Mutations of the proto-oncogene KRas, together with the inactivation of the onco-suppressor genes APC and TP53, are considered to have an important role both in the carcinogenesis and in the colorectal tumor progression. The oncogene K-ras has activating mutations, especially in codon 12, in about 40% to 50% of colorectal carcinomas (Andreyev et al., 1998). The mechanism by which oncogenic K-ras alone contribuites to tumor progression in colon cancer is largely unknown. To this end, we have developed a model system where the colorectal adenocarcinoma cell line Colo741 has been stably trasfected with the Kras-G12V or Kras-G12D mutated oncogenes. Our results demonstrate how expression profiling data can be used to interpret changes in cellular characteristics induced by transfection and hence provide some clues as to the mechanisms by which different activated K-Ras impair processes mediated by endogenous wild-type KRas proteins. We made for the production of cell clones that could be utilized as useful in vitro models. The adenocarcinoma cell line Colo741 has been chosen to produce stable transfectants for two mutant forms of KRas2 (Gly12Val and Gly12Asp) and the wild-type coding sequence (as experiment control). After the transfection, the cells have been selected (with G418), cloned (by limited dilutions) and screened (by RT-PCR). The total RNAs, Dnase-treated, from five cell clones per condition, have been pooled. The samples, constituted by biotin-labeled cRNA, derived from a pool of five cell clones obtained from transfection of the adenocarcinoma cell line Colo741 with either pcDNA3.1-KRas2(Wt) or pcDNA3.1-KRas2(Gly12Val) or pcDNA3.1KRas2(Gly12Asp). They were hybridized to a Human Gene 1.0 ST array (Affymetrix). Two technical replicates have been performed for each condition.
2008-12-17 | E-GEOD-12398 | biostudies-arrayexpress
Project description:In order to determine the serum microRNAs profile from middle-old aged patients with acute ischemic stroke and investigate possible diagnostic value of these differential microRNAs.The blood samples of 117 IS patients and 82 healthy people were collected. Differential miRNAs in serum from IS and control were screened with miRNA microarray analysis, and the expression of selected miRNAs were validated by quantitative reverse-transcriptase polymerase chain reaction assays (qRT-PCR). Results: We discovered 115 differentially expressed miRNAs, among which miR-32-3p, miR-106-5p, miR-532-5p were found be related to IS for the first time. Conclusions: In the present study, we identified the changed expression pattern of miRNAs in IS. Serum miR-32-3p, miR-106-5p, miR-1246 and miR-532-5p may serve as potential diagnostic biomarkers for IS.
2015-08-12 | GSE60319 | GEO