Circadian disruption enhances HSF1 signaling and tumorigenesis in Kras-driven lung cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA799045 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17682068.fastq.gz | Fastqsanger.gz | |||
| SRR17682069.fastq.gz | Fastqsanger.gz | |||
| SRR17682070.fastq.gz | Fastqsanger.gz | |||
| SRR17682071.fastq.gz | Fastqsanger.gz | |||
| SRR17682072.fastq.gz | Fastqsanger.gz |
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Project description:Disrupted circadian rhythmicity is a prominent feature of modern society and has been designated as a probable carcinogen by the World Health Organization. However, the biological mechanisms that connect circadian disruption and cancer risk remain largely undefined. We demonstrate that exposure to chronic circadian disruption (chronic jetlag, CJL) increases tumor formation in a mouse model of KRAS-driven lung cancer. Molecular characterization of tumors and tumor-bearing lung tissues revealed that CJL enhances the expression of heat shock factor 1 (HSF1) target genes. Consistently, exposure to CJL disrupted the highly rhythmic nuclear trafficking of HSF1 in the lung, resulting in an enhanced accumulation of HSF1 in the nucleus. HSF1 has been shown to promote tumorigenesis in other systems, and we find that pharmacological inhibition of HSF1 reduces the growth of KRAS-mutant human lung cancer cells. These findings implicate HSF1 as a molecular link between circadian disruption and enhanced tumorigenesis.
2022-02-01 | GSE194097 | GEO
Project description:Disrupted circadian rhythmicity is a prominent feature of modern society and has been designated as a probable carcinogen by the World Health Organization. However, the biological mechanisms that connect circadian disruption and cancer risk remain largely undefined. We demonstrate that exposure to chronic circadian disruption [chronic jetlag (CJL)] increases tumor burden in a mouse model of KRAS-driven lung cancer. Molecular characterization of tumors and tumor-bearing lung tissues revealed that CJL enhances the expression of heat shock factor 1 (HSF1) target genes. Consistently, exposure to CJL disrupted the highly rhythmic nuclear trafficking of HSF1 in the lung, resulting in an enhanced accumulation of HSF1 in the nucleus. HSF1 has been shown to promote tumorigenesis in other systems, and we find that pharmacological or genetic inhibition of HSF1 reduces the growth of KRAS-mutant human lung cancer cells. These findings implicate HSF1 as a molecular link between circadian disruption and enhanced tumorigenesis.
| S-EPMC9519049 | biostudies-literature
Project description:Oncogenic STAT3 functions are known in various malignancies. We found that STAT3 plays an unexpected tumor suppressive role in KRAS-mutant non-small-cell-lung cancer (NSCLC). In mice, tissue-specific inactivation of Stat3 resulted in increased Kras (G12D)-driven NSCLC initiation and malignant progression leading to markedly reduced survival. Clinically, low STAT3 expression levels correlate with poor survival in human lung adenocarcinoma patients with smoking history. Consistently, KRAS-mutant lung tumors showed reduced STAT3 levels. Mechanistically, we show that STAT3 controls NFκB-induced IL-8-expression by sequestering NFκB in the cytoplasm while IL-8 in turn regulates myeloid tumor infiltration and tumor vascularization thereby promoting tumor progression. These results identify a novel STAT3-NFκB-IL-8 axis in KRAS-mutant NSCLC with therapeutic and prognostic relevance WT: Control lung; KRAS: Lung tumors expressing KRAS G12D; KRAS STAT3 KO: Lung tumors expressing KRAS G12D- STAT3 deficient; tumors of four mice pooled per sample
2015-02-05 | E-GEOD-52798 | biostudies-arrayexpress
Project description:Non-small cell lung cancer (NSCLC), the most frequent subtype of lung cancer, remains a highly lethal malignancy and one of the leading causes of cancer deaths worldwide. Mutant KRAS is the prevailing oncogenic driver of lung adenocarcinoma, the most common histological form of NSCLC. In this study, we examined the role of PKCe, an oncogenic kinase highly expressed in NSCLC and other cancers, in KRAS-driven tumorigenesis. Notably, database analysis revealed an association between PKCe expression and poor outcome in lung adenocarcinoma patients specifically having KRAS mutation. By generating a PKCe-deficient, conditionally activatable allele of oncogenic Kras (LSL-Kras G12D ;PKCe -/- mice) we were able to demonstrate the requirement of PKCe for Kras-driven lung tumorigenesis in vivo, which is consistent with the impaired transformed growth observed in PKCe-deficient KRAS-dependent NSCLC cells. Moreover, PKCe-knockout mice were found to be less susceptible to lung tumorigenesis induced by benzo[a]pyrene, a carcinogen that induces mutations in Kras. Mechanistic analysis using RNA-Seq revealed little overlapping for PKCe and KRAS in the control of genes/biological pathways relevant in NSCLC, suggesting that a permissive role of PKCe in KRAS-driven lung tumorigenesis may involve non-redundant mechanisms. Our results thus highlight the relevance and potential of targeting PKCe for lung cancer therapeutics.
2020-07-31 | GSE149205 | GEO
Project description:We investigated the impacts of environmental circadian disruption on placental gene expression (E15.5) in a C57BL/6J mouse (Mus musculus) model. A number of transcripts showed sex-specific patterns of expression and several transcripts were differentially expressed in placenta from mice developmentally exposed to circadian disruption compared to mice exposed to control light.
2021-08-18 | GSE169266 | GEO
Project description:Oncogenic STAT3 functions are known in various malignancies. We found that STAT3 plays an unexpected tumor suppressive role in KRAS-mutant non-small-cell-lung cancer (NSCLC). In mice, tissue-specific inactivation of Stat3 resulted in increased Kras (G12D)-driven NSCLC initiation and malignant progression leading to markedly reduced survival. Clinically, low STAT3 expression levels correlate with poor survival in human lung adenocarcinoma patients with smoking history. Consistently, KRAS-mutant lung tumors showed reduced STAT3 levels. Mechanistically, we show that STAT3 controls NFκB-induced IL-8-expression by sequestering NFκB in the cytoplasm while IL-8 in turn regulates myeloid tumor infiltration and tumor vascularization thereby promoting tumor progression. These results identify a novel STAT3-NFκB-IL-8 axis in KRAS-mutant NSCLC with therapeutic and prognostic relevance
2015-02-05 | GSE52798 | GEO
Project description:KRAS induces lung tumorigenesis through microRNAs modulation
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Project description:Circadian rhythm disruption is associated with skeletal muscle dysfunction within the blind Mexican Cavefish
2023-01-13 | MSV000091062 | MassIVE
Project description:Disruption of circadian clocks exacerbates various diseases, in part likely due to impaired stress resistance. It is unclear how nearly lethal stresses affect circadian clocks. We found that near-lethal doses of reactive oxygen species (ROS)-induced critical oxidative stress (cOS) at the branch point of life and death resets circadian clocks, synergistically evoking protective responses for cell survival. The cOS-triggered clock resetting and pro-survival responses are mediated by transcription factor, central clock-regulatory BMAL1 and heat shock stress-responsive (HSR) HSF1. Casein kinase II (CK2) M-bM-^@M-^Smediated phosphorylation regulates dimerization and function of BMAL1 and HSF1 to control the cOS-evoked responses. The core cOS-responsive transcriptome includes CK2-orchestrated crosstalk between the circadian, HSR, NFM-NM-:B-mediated anti-apoptotic, and Nrf2-mediated anti-oxidant pathways. This novel circadian-adaptive signaling system likely plays fundamental protective roles in ROS-inducible disorders, various diseases, and death. Gene expression was measured 4h, 20h and 32h after treatment with 5 mM H2O2 for 10 min.
2013-11-09 | E-GEOD-47955 | biostudies-arrayexpress
Project description:Disruption of circadian clocks exacerbates various diseases, in part likely due to impaired stress resistance. It is unclear how nearly lethal stresses affect circadian clocks. We found that near-lethal doses of reactive oxygen species (ROS)-induced critical oxidative stress (cOS) at the branch point of life and death resets circadian clocks, synergistically evoking protective responses for cell survival. The cOS-triggered clock resetting and pro-survival responses are mediated by transcription factor, central clock-regulatory BMAL1 and heat shock stress-responsive (HSR) HSF1. Casein kinase II (CK2) –mediated phosphorylation regulates dimerization and function of BMAL1 and HSF1 to control the cOS-evoked responses. The core cOS-responsive transcriptome includes CK2-orchestrated crosstalk between the circadian, HSR, NFκB-mediated anti-apoptotic, and Nrf2-mediated anti-oxidant pathways. This novel circadian-adaptive signaling system likely plays fundamental protective roles in ROS-inducible disorders, various diseases, and death.
2013-11-09 | GSE47955 | GEO