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COMPLEMENT C3aR ACTS AS AN ONCOSUPPRESSOR IN COLORECTAL CANCER BY MODULATING GUT MICROBIOTA

ABSTRACT: COMPLEMENT C3aR ACTS AS AN ONCOSUPPRESSOR IN COLORECTAL CANCER BY MODULATING GUT MICROBIOTA

PROVIDER: PRJEB35288 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	ERR3650300_1.fastq.gz	Fastqsanger.gz
	ERR3650300_2.fastq.gz	Fastqsanger.gz
	ERR3650310_1.fastq.gz	Fastqsanger.gz
	ERR3650310_2.fastq.gz	Fastqsanger.gz
	ERR3650320_1.fastq.gz	Fastqsanger.gz

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COMPLEMENT C3aR ACTS AS AN ONCOSUPPRESSOR IN COLORECTAL CANCER BY MODULATING GUT MICROBIOTA

Project description:Several lines of evidence suggest that inflammation plays a pivotal role in the development and progression of CRC and can be unleashed by the loss of innate immunosurveillance. The complement system is a well characterized first line of defense against pathogens and a central component of the immune responses. As such, the complement system is an important determinant in the maintenance of intestinal homeostasis and emerging evidences suggest that complement dysregulation is involved in the development and progression of CRC. Here we show that in CRC patients CpG island methylation occurs in the gene encoding for the complement anaphylatoxin C3a receptor (c3aR) and strong C3aR down-regulation resulted in decreased overall survival and events-free survival in CRC patients. Ablation of c3ar in mouse models of CRC resulted in the establishment of a pro-inflammatory microbial flora, which fostered strong Th1/Th17 immune responses and a striking increase in tumor incidence and growth that were both dependent on the microbiota. Our findings highlight a previously unrecognized tumor oncosuppressive role for C3aR in CRC that could be exploited as a biomarker for more effective therapeutic intervention.

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Intracellular activation of complement C3 leads to PD-L1 antibody treatment resistance via modulating tumor-associated macrophages

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Complement C3aR depletion reverses HIF-1α induced metabolic impairment and improves microglial phagocytic and barrier function in response to Aβ pathology.

Project description:Complement C3aR is primarily expressed in microglial cells in the brain. Our study found elevated expression of C3aR in microglia in Alzheimer's disease. To understand the underlying molecular mechanism, we sorted microglia based on their C3aR expression from 9-month-old wild-type and APP-KI mice. Through RNA-seq analysis, we identified metabolic perturbations in C3aR-positive microglia from 9-month-old APP-KI mice. Furthermore, we performed RNA-seq on sorted microglial cells from wild-type, C3aR knockout, APP-KI, and APP-KI;C3aR knockout mice. This analysis revealed a dampening of metabolic dysfunction in the absence of C3aR.

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