Dataset Information

Defects in mTORC1 Network and mTORC1-STAT3 Pathway Crosstalk Contributes to Noninflammatory Hepatocellular Carcinoma

ABSTRACT: mTORC1-driven noninflammatory HCC and provide insight into further development of a protective strategy against noninflammatory HCC. Background & Aims: Mammalian target of rapamycin complex 1 (mTORC1) is frequently hyperactivated in hepatocellular carcinoma (HCC). Cases of HCC without inflammation and cirrhosis are not rarely seen in clinics. However, the molecular basis of noninflammatory HCC remains unclear. Methods: Spontaneous noninflammatory HCC in mice was triggered by constitutive elevation of mTORC1 by liver-specific Tsc1 knockout (LTsc1KO). A multi-omics approach was utilized on tumor tissues to better understand the molecular basis for the development of HCC in the LTsc1KO model. Results: We showed that LTsc1KO in mice triggered spontaneous noninflammatory HCC, with molecular characteristics similar to those of diethylnitrosamine-mediated noncirrhotic HCC. Mitochondrial and autophagy defects, as well as hepatic metabolic disorder were manifested in HCC development by LTsc1KO. mTORC1 activation on its own regulated an oncogenic network (DNA-damage-inducible transcript 4, nuclear protein 1 and fibroblast growth factor 21), and mTORC1–signal transducer and activator of transcription pathway crosstalk that altered specific metabolic pathways contributed to the development of noninflammatory HCC. Conclusion: Our findings reveal the mechanisms of mTORC1-driven noninflammatory HCC and provide insight into further development of a protective strategy against noninflammatory HCC.

ORGANISM(S): Mus musculus

PROVIDER: GSE147354 | GEO | 2020/04/13

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:The mechanistic target of rapamycin (mTOR) pathway integrates diverse environmental inputs, including immune signals and metabolic cues, to direct T cell fate decisions1. Activation of mTOR, comprised of mTORC1 and mTORC2 complexes, delivers an obligatory signal for proper activation and differentiation of effector CD4+ T cells2,3, whereas in the regulatory T cell (Treg) compartment, the Akt-mTOR axis is widely acknowledged as a crucial negative regulator of Treg de novo differentiation4-8 and population expansion9. However, whether mTOR signaling affects the homeostasis and function of Tregs remains largely unexplored. Here we show that mTORC1 signaling is a pivotal positive determinant of Treg function. Tregs have elevated steady-state mTORC1 activity compared to naïve T cells. Signals via T cell receptor (TCR) and IL-2 provide major inputs for mTORC1 activation, which in turn programs suppressive function of Tregs. Disruption of mTORC1 through Treg-specific deletion of the essential component Raptor leads to a profound loss of Treg suppressive activity in vivo and development of a fatal early-onset inflammatory disorder. Mechanistically, Raptor/mTORC1 signaling in Tregs promotes cholesterol/lipid metabolism, with the mevalonate pathway particularly important for coordinating Treg proliferation and upregulation of suppressive molecules CTLA-4 and ICOS to establish Treg functional competency. In contrast, mTORC1 does not directly impact the expression of Foxp3 or anti- and pro-inflammatory cytokines in Tregs, suggesting a non-conventional mechanism for Treg functional regulation. Lastly, we provide evidence that mTORC1 maintains Treg function partly through inhibiting the mTORC2 pathway. Our results demonstrate that mTORC1 acts as a fundamental ‘rheostat’ in Tregs to link immunological signals from TCR and IL-2 to lipogenic pathways and functional fitness, and highlight a central role of metabolic programming of Treg suppressive activity in immune homeostasis and tolerance. We used microarrays to explore the gene expression profiles differentially expressed in regulatory T-cells from wild-type and CD4(cre) x Raptor(fl/fl) mice

Dataset Information

Defects in mTORC1 Network and mTORC1-STAT3 Pathway Crosstalk Contributes to Noninflammatory Hepatocellular Carcinoma

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets