Lung adenocarcinoma subtypes definable by lung development-related miRNA expression profiles in association with clinicopathologic features
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Takashi Takahashi
PROVIDER: E-GEOD-51855 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Accumulation of genetic and epigenetic changes alters regulation of a web of interconnected genes including miRNAs, which confer hallmark capabilities and characteristic cancer features. In this study, the miRNA and mRNA expression profiles of 126 non-small cell lung cancer specimens were analyzed, with special attention given to the diversity of lung adenocarcinomas. Of those, 76 adenocarcinomas were classified into two major subtypes, developing lung-like and adult lung-like, based on their distinctive miRNA expression profiles resembling those of either developing or adult lungs, respectively. A systems biology-based approach using a Bayesian network and nonparametric regression was employed to estimate the gene regulatory circuitry functioning in patient tumors in order to identify subnetworks enriched for genes with differential expression between the two major subtypes. miR-30d and miR-195, identified as hub genes in such subnetworks, had lower levels of expression in the developing lung-like subtype, while introduction of miR-30d or miR-195 into the lung cancer cell lines evoked shifts of mRNA expression profiles towards the adult lung-like subtype. Conversely, the influence of miR-30d and miR-195 was significantly different between the developing lung- and adult lung-like subtypes in our analysis of the patient dataset. In addition, RRM2, a child gene of the miR-30d-centered subnetwork, was found to be a direct target of miR-30d. Together, our findings reveal the existence of two miRNA expression profile-defined lung adenocarcinoma subtypes with distinctive clinicopathologic features and also suggest the usefulness of a systems biology-based approach to gain insight into the altered regulatory circuitry involved in cancer development. Microarray analysis using a Whole Human Genome 4 x 44K Microarray G4112F (Agilent) was conducted.
2014-06-19 | E-GEOD-51852 | biostudies-arrayexpress
Project description:Accumulation of genetic and epigenetic changes alters regulation of a web of interconnected genes including miRNAs, which confer hallmark capabilities and characteristic cancer features. In this study, the miRNA and mRNA expression profiles of 126 non-small cell lung cancer specimens were analyzed, with special attention given to the diversity of lung adenocarcinomas. Of those, 76 adenocarcinomas were classified into two major subtypes, developing lung-like and adult lung-like, based on their distinctive miRNA expression profiles resembling those of either developing or adult lungs, respectively. A systems biology-based approach using a Bayesian network and nonparametric regression was employed to estimate the gene regulatory circuitry functioning in patient tumors in order to identify subnetworks enriched for genes with differential expression between the two major subtypes. miR-30d and miR-195, identified as hub genes in such subnetworks, had lower levels of expression in the developing lung-like subtype, while introduction of miR-30d or miR-195 into the lung cancer cell lines evoked shifts of mRNA expression profiles towards the adult lung-like subtype. Conversely, the influence of miR-30d and miR-195 was significantly different between the developing lung- and adult lung-like subtypes in our analysis of the patient dataset. In addition, RRM2, a child gene of the miR-30d-centered subnetwork, was found to be a direct target of miR-30d. Together, our findings reveal the existence of two miRNA expression profile-defined lung adenocarcinoma subtypes with distinctive clinicopathologic features and also suggest the usefulness of a systems biology-based approach to gain insight into the altered regulatory circuitry involved in cancer development. Microarray analysis using a Whole Human Genome 4 x 44K Microarray G4112F (Agilent) was conducted to examine changes in expression of 400 genes in SiGN network by transfection of Pre-miR-30d, Pre-miR-195 or Pre-miR-NC#2 (Ambion) in SK-LC-7 cells, which were then harvested at 72 hours after transfection.
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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.
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Project description:Accumulating evidence indicates that altered miRNA expression is crucially involved in lung cancer development, but only little has been elucidated about how MYC, an archetypical oncogene, is regulated by miRNAs, especially through a mechanism involving the MYC cofactor(s). In this study, we aimed at identifying miRNAs involved in the regulation of MYC transcriptional activity in lung cancers. To this end, we have taken an integrative approach with combinatorial usage of miRNA and mRNA expression profile datasets of patientsâ?? tumor tissues as well as those of MYC-inducible cell lines in vitro. We report here that in addition to miRNAs previously reported to be directly regulating or regulated by MYC including let-7 and miR-17-92, our strategy allowed us to identify miR-342-3p as the one capable of indirectly regulating MYC activity through direct repression of a MYC-cooperating molecule, E2F1. Furthermore, the miR-342-3p module activity, which we defined as a gene set reflecting experimentally substantiated influence of miR-342-3p on mRNA expression, was found to be inversely correlated with MYC activity reflected in the MYC module activity in three independent datasets of lung adenocarcinoma patients obtained by the Directorâ??s Challenge Consortium of the United States (P=1.94x10-73), the National Cancer Center of Japan (P=9.05x10-34) and our own in this study (P=3.37x10-6). Our integrative approach thus appears to be useful to elucidate inter-regulatory relationships between miRNAs and a protein coding-gene of interest, even those present in tumor tissues in patients, which still remains a challenge to better understand the pathogenesis of this devastating disease. Microarray analysis using a SurePrint G3 Human GE 8 x 60K Microarray G4851A (Agilent) was conducted. Tai, MeiChee
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Project description:Accumulating evidence indicates that altered miRNA expression is crucially involved in lung cancer development, but only little has been elucidated about how MYC, an archetypical oncogene, is regulated by miRNAs, especially through a mechanism involving the MYC cofactor(s). In this study, we aimed at identifying miRNAs involved in the regulation of MYC transcriptional activity in lung cancers. To this end, we have taken an integrative approach with combinatorial usage of miRNA and mRNA expression profile datasets of patientsâ tumor tissues as well as those of MYC-inducible cell lines in vitro. We report here that in addition to miRNAs previously reported to be directly regulating or regulated by MYC including let-7 and miR-17-92, our strategy allowed us to identify miR-342-3p as the one capable of indirectly regulating MYC activity through direct repression of a MYC-cooperating molecule, E2F1. Furthermore, the miR-342-3p module activity, which we defined as a gene set reflecting experimentally substantiated influence of miR-342-3p on mRNA expression, was found to be inversely correlated with MYC activity reflected in the MYC module activity in three independent datasets of lung adenocarcinoma patients obtained by the Directorâs Challenge Consortium of the United States (P=1.94x10-73), the National Cancer Center of Japan (P=9.05x10-34) and our own in this study (P=3.37x10-6). Our integrative approach thus appears to be useful to elucidate inter-regulatory relationships between miRNAs and a protein coding-gene of interest, even those present in tumor tissues in patients, which still remains a challenge to better understand the pathogenesis of this devastating disease. Microarray analysis using a SurePrint G3 Human GE 8 x 60K Microarray G4851A (Agilent) was conducted.
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