Genomic characterization of DICER1-associated neoplasms uncovers novel molecular classes
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE214568 | GEO | 2023/02/08
REPOSITORIES: GEO
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Project description:Ovarian cancer (OC) remains the leading cause of death in patients with gynecological malignancy. An improved understanding of the genomics has led to the separation of OC into histologically and molecularly defined subgroups. Based on molecular profiling in OC patients, subtype with a reactivated tumor stroma presented the worst prognosis, emphasizing the importance of tumor microenvironment especially stromal fibroblasts in fueling OC progression. Dicer1 is well recognized as the microRNA (miR) synthesis machinery, playing a crucial role in cellular maturation and development, and was generally considered to be a tumor suppressor gene that inhibited tumor initiation and metastasis. Dicer1 expression pattern and exact biological function was seldom studied in the stromal compartment. There was a recent study demonstrating that Dicer1 was involved in mouse embryonic fibroblast (MEF) development and maturation. Therefore, we are inspired to explore the expression and function of Dicer1 in stromal fibroblasts of OC patients. In this study, mRNA and microRNA gene expression profiling were conducted for MRC5-CAFs after silencing of Dicer1. By comparing the expression data of MRC5-CAFs transfected with control siRNA (si-Ctrl) or with Dicer1 specific siRNA (si-Dicer1) for 72 hr, we identified a set of differential expressed mRNA and microRNA in MRC5-CAFs after Dicer1 knockdown. This study was the first to investigate Dicer1 influence of stromal fibroblast gene expression and the underlying regulation mechanism, which held great importance in complementing our understanding of Dicer1 in OC initiation and development, and raises potent therapeutical targets in controlling OC metastasis We used microarrays to profile the microRNA expression of MRC5-CAFs before and after Dicer1 knockdown, in order to identify microRNA alteration exerted by Dicer1 in the context of stromal fibroblasts.
2018-04-10 | GSE97937 | GEO
Project description:Ovarian cancer (OC) remains the leading cause of death in patients with gynecological malignancy. An improved understanding of the genomics has led to the separation of OC into histologically and molecularly defined subgroups. Based on molecular profiling in OC patients, subtype with a reactivated tumor stroma presented the worst prognosis, emphasizing the importance of tumor microenvironment especially stromal fibroblasts in fueling OC progression. Dicer1 is well recognized as the microRNA (miR) synthesis machinery, playing a crucial role in cellular maturation and development, and was generally considered to be a tumor suppressor gene that inhibited tumor initiation and metastasis. Dicer1 expression pattern and exact biological function was seldom studied in the stromal compartment. There was a recent study demonstrating that Dicer1 was involved in mouse embryonic fibroblast (MEF) development and maturation. Therefore, we are inspired to explore the expression and function of Dicer1 in stromal fibroblasts of OC patients. In this study, mRNA and microRNA gene expression profiling were conducted for MRC5-CAFs after silencing of Dicer1. By comparing the expression data of MRC5-CAFs transfected with control siRNA (si-Ctrl) or with Dicer1 specific siRNA (si-Dicer1) for 72 hr, we identified a set of differential expressed mRNA and microRNA in MRC5-CAFs after Dicer1 knockdown. This study was the first to investigate Dicer1 influence of stromal fibroblast gene expression and the underlying regulation mechanism, which held great importance in complementing our understanding of Dicer1 in OC initiation and development, and raises potent therapeutical targets in controlling OC metastasis We used microarrays to profile the mRNA expression of MRC5-CAFs before and after Dicer1 knockdown, in order to identify molecular alteration exerted by Dicer1 in the context of stromal fibroblasts.
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Project description:DICER1 canonically regulates micro(mi)RNA-mediated epithelial-to-mesenchymal transition (EMT) in lung adenocarcinomas (LUADs). We discovered that KRAS/ERK pathway phosphorylates DICER1 causing its nuclear translocation; phosphomimetic Dicer1 contributes to tumorigenesis in mice. Mechanisms through which phospho-DICER1 regulates tumor progression remain undefined. Here, we show that phospho-DICER1 is expressed in invasive human LUADs and promotes late-stage tumor progression in mice with oncogenic Kras, independent of miRNAs and EMT. Strikingly, in mice, we observed that the AT2 tumor cells with phospho-DICER1 express endodermal (gastric) genes and display an open chromatin state such that there are sub-populations of tumors cells with alveolar-endodermal or only endodermal identity. Importantly, we also observed expression of gastric genes in human LUADs with phospho-DICER1. Mechanistically, we identify a chromatin-DICER1 nuclear complex comprised of Mediator complex subunit 12, CBX1, MACROH2A.1 and transcriptional regulators. Together, we propose that phosphorylated-nuclear DICER1 leads to lineage reprogramming of AT2 tumor cells to mediate lung cancer progression.
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Project description:Co-chaperone Aha1 activates HSP90 ATPase to promote the folding of client proteins. However, the client proteins of Aha1 are largely unknown. By employing ascorbate peroxidase (APEX) based proximity labeling, we identified 32 proximity proteins of HSP90 that are modulated by genetic depletion of Aha1. Among them, Dicer1 is one of the top-ranked proteins, which were further confirmed by streptavidin pull-down followed by Western blot analysis, demonstrating the reliability of the approach. Flag pull-down result showed interactions between endogenous HSP90 and Dicer1 and Aha1. The Dicer1 level is regulated synergistically by Aha1 and HSP90. Maturation-dependent interaction results showed a preferential binding of Aha1 and HSP90 to nascently translated Dicer1. Reconstitution of Aha1-depleted cells with WT Aha1 restored Dicer1 level, while the HSP90-binding-defective E67K mutant exhibited partial restoration. Moreover, knockdown of Aha1 and inhibition of HSP90 can diminish the levels of mature miRNA, let-7b and mir-30a. Overall, our study uncovers, for the first time, Dicer1 and transporter proteins as clients of Aha1 and HSP90.
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Project description:DICER1 canonically regulates micro(mi)RNA-mediated epithelial-to-mesenchymal transition (EMT) in lung adenocarcinomas (LUADs). We discovered that KRAS/ERK pathway phosphorylates DICER1 causing its nuclear translocation; phosphomimetic Dicer1 contributes to tumorigenesis in mice. Mechanisms through which phospho-DICER1 regulates tumor progression remain undefined. Here, we show that phospho-DICER1 is expressed in invasive human LUADs and promotes late-stage tumor progression in mice with oncogenic Kras, independent of miRNAs and EMT. Strikingly, in mice, we observed that the AT2 tumor cells with phospho-DICER1 express endodermal (gastric) genes and display an open chromatin state such that there are sub-populations of tumors cells with alveolar-endodermal or only endodermal identity. Importantly, we also observed expression of gastric genes in human LUADs with phospho-DICER1. Mechanistically, we identify a chromatin-DICER1 nuclear complex comprised of Mediator complex subunit 12, CBX1, MACROH2A.1 and transcriptional regulators. Together, we propose that phosphorylated-nuclear DICER1 leads to lineage reprogramming of AT2 tumor cells to mediate lung cancer progression.
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Project description:DICER1 canonically regulates micro(mi)RNA-mediated epithelial-to-mesenchymal transition (EMT) in lung adenocarcinomas (LUADs). We discovered that KRAS/ERK pathway phosphorylates DICER1 causing its nuclear translocation; phosphomimetic Dicer1 contributes to tumorigenesis in mice. Mechanisms through which phospho-DICER1 regulates tumor progression remain undefined. Here, we show that phospho-DICER1 is expressed in invasive human LUADs and promotes late-stage tumor progression in mice with oncogenic Kras, independent of miRNAs and EMT. Strikingly, in mice, we observed that the AT2 tumor cells with phospho-DICER1 express endodermal (gastric) genes and display an open chromatin state such that there are sub-populations of tumors cells with alveolar-endodermal or only endodermal identity. Importantly, we also observed expression of gastric genes in human LUADs with phospho-DICER1. Mechanistically, we identify a chromatin-DICER1 nuclear complex comprised of Mediator complex subunit 12, CBX1, MACROH2A.1 and transcriptional regulators. Together, we propose that phosphorylated-nuclear DICER1 leads to lineage reprogramming of AT2 tumor cells to mediate lung cancer progression.
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Project description:We report the generation and characterization of DICER1-deficient hESCs. We uncover an unexpected requirement for DICER1 as well as essential pro-survival roles of members of the mir-302- 367 and mir-371- 373 clusters in hESCs. Our work provides a robust platform for interrogating microRNA function in hESC and differentiation.
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Project description:We developed a genetically engineered conditional compound heterozygous Dicer1 mouse strain that fully recapitulates the bi-allelic mutations of DICER1 in DICER1 syndrome-associated cancers. Embryonic activation of bi-allelic Dicer1 mutations, driven by the anti-Müllerian hormone receptor 2 (Amhr2)-driven Cre strain (Amhr2+/cre), drove cancer development from oviduct. mRNA sequencing was performed to compare the mRNA expression profiles between tumor and normal oviduct.
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