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Project description:Insufficient sleep and circadian disruption are associated with poor prognosis in cancer patients, yet how sleep deficiency (SD) disrupts circadian cellular biological process that promote tumor growth and development remains elusive. To investigate the effects of sleep deficiency on tumorigenesis, we evaluated the gene expression in the lung from KRASG12D/WT mice after sleep deficient treatment (7 weeks). Analyzing Gene Ontology (GO) Enrichment of significantly up-regulated genes from lung tumors of SD mice, we found that lipid metabolism processes were enriched in the top 20 GO terms. Lipid metabolomics results showed that SD dramatically stimulates fatty acid oxidation process during lung tumorigenesis. Moreover, genetic ablation of ACSL1, a key regulatory factor in FAO, marked reversed SD-promoted lung tumor development. In addition, SD triggered fatty acid oxidation to enhance cancer stem-like properties.
2025-10-01 | GSE216729 | GEO
Project description:Insufficient sleep and circadian disruption are associated with poor prognosis in cancer patients, yet how sleep deficiency (SD) disrupts circadian cellular biological process that promote tumor growth and development remains elusive. To investigate the effects of sleep deficiency on tumorigenesis, we evaluated the gene expression in the lung from KRASG12D/WT mice after sleep deficient treatment (7 weeks). Analyzing Gene Ontology (GO) Enrichment of significantly up-regulated genes from lung tumors of SD mice, we found that lipid metabolism processes were enriched in the top 20 GO terms. Lipid metabolomics results showed that SD dramatically stimulates fatty acid oxidation process during lung tumorigenesis. Moreover, genetic ablation of ACSL1, a key regulatory factor in FAO, marked reversed SD-promoted lung tumor development. In addition, SD triggered fatty acid oxidation to enhance cancer stem-like properties.
2025-10-01 | GSE216740 | GEO
Project description:Oncogenic fatty acid oxidation senses sleep deficiency-induced circadian disruption to promote tumorigenesis [circadian]
| PRJNA895059 | ENA
Project description:Oncogenic fatty acid oxidation senses sleep deficiency-induced circadian disruption to promote tumorigenesis
| PRJNA895077 | ENA
Project description:Oncogenic fatty acid oxidation senses sleep deficiency-induced circadian disruption to promote tumorigenesis [Ctrl vs SD]
| PRJNA895075 | ENA
Project description:ObjectivesLung cancer is the leading cause of cancer related deaths worldwide and mutation activating KRAS is one of the most frequent mutations found in lung adenocarcinoma. Identifying regulators of KRAS may aid in the development of therapies to treat this disease. The mitogen-induced gene 6, MIG-6, is a small adaptor protein modulating signaling in cells to regulate the growth and differentiation in multiple tissues. Here, we investigated the role of Mig-6 in regulating adenocarcinoma progression in the lungs of genetically engineered mice with activation of Kras.Materials and methodsUsing the CCSPCre mouse to specifically activate expression of the oncogenic KrasG12D in Club cells, we investigated the expression of Mig-6 in CCSPCreKrasG12D-induced lung tumors. To determine the role of Mig-6 in KrasG12D-induced lung tumorigenesis, Mig-6 was conditionally ablated in the Club cells by breeding Mig6f/f mice to CCSPCreKrasG12D mice, yielding CCSPCreMig-6d/dKrasG12D mice (Mig-6d/dKrasG12D).ResultsWe found that Mig-6 expression is decreased in CCSPCreKrasG12D-induced lung tumors. Ablation of Mig-6 in the KrasG12D background led to enhanced tumorigenesis and reduced life expectancy. During tumor progression, there was increased airway hyperplasia, a heightened inflammatory response, reduced apoptosis in KrasG12D mouse lungs, and an increase of total and phosphorylated ERBB4 protein levels. Mechanistically, Mig-6 deficiency attenuates the cell apoptosis of lung tumor expressing KRASG12D partially through activating the ErbB4 pathway.ConclusionsIn summary, Mig-6 deficiency promotes the development of KrasG12D-induced lung adenoma through reducing the cell apoptosis in KrasG12D mouse lungs partially by activating the ErbB4 pathway.
| S-EPMC5718380 | biostudies-literature
Project description:Circadian rhythms are 24-hr oscillations that control a variety of biological processes in living systems, including two hallmarks of cancer, cell division and metabolism. Circadian rhythm disruption by shift work is associated with greater risk for cancer development and poor prognosis, suggesting a putative tumor-suppressive role for circadian rhythm homeostasis. Using a genetically engineered mouse model of lung adenocarcinoma, we have characterized the effects of circadian rhythm disruption on lung tumorigenesis. We demonstrate that both physiologic perturbation (jet lag) and genetic mutation of the central circadian clock components decreased survival and promoted lung tumor growth and progression. The core circadian genes Per2 and Bmal1 were shown to have cell-autonomous tumor-suppressive roles in transformation and lung tumor progression. Loss of the central clock components led to increased c-Myc expression, enhanced proliferation, and metabolic dysregulation. Our findings demonstrate that both systemic and somatic disruption of circadian rhythms contribute to cancer progression.
| S-EPMC5367626 | biostudies-literature
Project description:Rationale: The role of circadian clock in pituitary tumorigenesis remains elusive. Here we investigate whether and how circadian clock modulates the development of pituitary adenomas. Methods and Results: We found altered expression of pituitary clock genes in patients with pituitary adenomas. In particular, PER2 is prominently upregulated. Further, jetlagged mice with PER2 upregulation have accelerated growth of GH3 xenograft tumor. Conversely, loss of Per2 protects mice against developing estrogen-induced pituitary adenoma. Similar antitumor effect is observed for SR8278, a chemical that can decrease pituitary PER2 expression. RNA-seq analysis suggests involvement of cell cycle disturbance in PER2 regulation of pituitary adenoma. Subsequent in vivo and cell-based experiments validate that PER2 induces pituitary expression of Ccnb2, Cdc20 and Espl1 (three cell cycle genes) to facilitate cell cycle progression and inhibit apoptosis, thereby promoting pituitary tumorigenesis. Mechanistically, PER2 regulates the transcription of Ccnb2, Cdc20 and Espl1 through enhancing the transcriptional activity of HIF-1α. HIF-1α trans-activates Ccnb2, Cdc20 and Espl1 via direct binding to its specific response element in the gene promoters. Conclusion: PER2 integrates circadian disruption and pituitary tumorigenesis. These findings advance our understanding of crosstalk between circadian clock and pituitary adenomas and highlight the relevance of clock-based approaches in disease management.
| S-EPMC10196825 | biostudies-literature
Project description:Despite its involvement in most human cancers, MYC continues to pose a challenge as a readily tractable therapeutic target. Here we identify the MYC transcriptional cofactors TIP48 and TIP49 and MYC as novel binding partners of Mdm2-binding protein (MTBP), a functionally undefined protein that we show is oncogenic and overexpressed in many human cancers. MTBP associated with MYC at promoters and increased MYC-mediated transcription, proliferation, neoplastic transformation, and tumor development. In breast cancer specimens, we determined overexpression of both MYC and MTBP was associated with a reduction in 10-year patient survival compared with MYC overexpression alone. MTBP was also frequently co-amplified with MYC in many human cancers. Mechanistic investigations implicated associations with TIP48/TIP49 as well as MYC in MTBP function in cellular transformation and the growth of human breast cancer cells. Taken together, our findings show MTBP functions with MYC to promote malignancy, identifying this protein as a novel general therapeutic target in human cancer.
| S-EPMC4079748 | biostudies-literature
Project description:Background: Disruption of natural light cycles, as experienced by shift workers, is linked to enhanced cancer incidence. Several mouse models of cancer develop more severe disease when exposed to irregular light/dark cycles, supporting the connection between circadian disruption and increased cancer risk. Cryptochrome 2 (CRY2), a repressive component of the molecular circadian clock, facilitates turnover of the oncoprotein c-MYC, one mechanism that may link the molecular clock to tumorigenesis. In Eμ-MYC mice, which express transgenic c-MYC in B cells and develop aggressive lymphomas and leukemia, global Cry2 deletion reduces survival and enhances tumor formation. Lighting conditions that mimic the disruption experienced by shift workers dampen Cry2 transcripts in peripheral tissues of C57BL/6J mice. Although it is milder than homozygous deletion of Cry2, we hypothesized that reduced Cry2 rhythmicity could alter MYC protein accumulation and contribute to enhanced cancer risk caused by circadian disruption. We tested this hypothesis in MYC-driven lymphoma. Methods: We housed Eμ-MYC mice in light-tight boxes set to either control (continuous cycles of 12-hours of light followed by 12-hours of dark, LD12:12) or chronic jetlag (eight-hour light phase advances every two to three days, CJL) lighting conditions and assessed the impact of disrupted light cycles on survival and tumor formation in Eμ-MYC mice. Results: Environmental disruption of circadian rhythms did not alter tumor location, tumor growth, or survival in Eμ-MYC mice. Conclusions: Dampened rhythms of Cry2 following disruption of circadian light exposures is milder than deletion of Cry2. The lack of phenotype caused by altered circadian gene expression in contrast to enhanced tumorigenesis caused by homozygous deletion of Cry2 suggests that CRY2 dosage impacts this model. Importantly, these findings indicate that increased cancer risk associated with circadian disruption arises from one or more mechanisms that are not recapitulated here, and may be different in distinct tumor types.
| S-EPMC10558980 | biostudies-literature