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Kinetic comparative analysis of gene expression in whole adrenal glands from Znrf3 cKO and control mice

ABSTRACT: Unlike most cancers, adrenocortical carcinomas (ACC) are more frequent in women than men, but the underlying mechanisms of this sexual dimorphism remain elusive. Here, we show that inactivation of Znrf3 in steroidogenic cells of the mouse adrenal cortex is associated with sexually dimorphic tumour progression. Although female knockouts develop metastatic carcinomas at 18 months, adrenal hyperplasia regresses in male knockouts. This male-specific phenotype is associated with androgen-dependent induction of senescence, recruitment and differentiation of highly phagocytic macrophages that clear-out senescent cells. In contrast, in females, macrophage recruitment is delayed and dampened, which allows for aggressive tumour progression. Consistently, analysis of TCGA-ACC data shows that phagocytic macrophages are more prominent in men and associated with better prognosis. Altogether, these data show that phagocytic macrophages are key players in the sexual dimorphism of ACC and establish them as novel therapeutic targets for this devastating cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE202940 | GEO | 2022/10/15

REPOSITORIES: GEO

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Project description:Neuropathic pain is a chronic debilitating condition with a high comorbidity with depression. Clinical reports and animal studies have suggested that both the medial prefrontal cortex (mPFC) and the anterior cingulate cortex (ACC) are critically implicated in regulating the affective symptoms of neuropathic pain. Neuropathic pain induces long-term structural, functional and biochemical changes in both regions, which are thought to be regulated by multiple waves of gene transcription. However, the similarity and differences in the transcriptomic profiles changed by neuropathic pain between these regions are largely unknown. Furthermore, women are more susceptible to pain and depression than men. The molecular mechanisms underlying this sexual dimorphism remain to be explored. Here, we performed RNA sequencing and analyzed the transcriptomic profiles of the mPFC and ACC of female and male mice at 2 weeks after spared nerve injury (SNI), an early time point when the mice began to show mild depressive symptoms. Our results show that the SNI-induced transcriptomic changes in female and male mice are largely distinct. Interestingly, the female mice exhibit more robust transcriptomic changes in the ACC than male, whereas the opposite pattern occurs in the mPFC. Cell type enrichment analyses reveal that the differentially expressed genes involve genes enriched in both neurons and various types of glia. We further performed Gene Set Enrichment Analysis (GSEA), which reveal significant de-enrichment of myelin sheath development in both female and male mPFC after SNI. In the female ACC, gene sets for synaptic organization and mitochondria function are enriched, and gene sets for extracellular matrix are de-enriched after SNI, while such signatures are absent in male ACC. Collectively, these findings reveal sexual dimorphism at the transcriptional level induced by neuropathic pain, and provide novel therapeutic targets for chronic pain and its associated affective disorders.

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Kinetic comparative analysis of gene expression in whole adrenal glands from Znrf3 cKO and control mice

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