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Single-cell RNA sequencing shows the heterogeneity of cancer-associated fibroblast in HBV-related hepatocellular carcinoma

ABSTRACT: Single-cell RNA sequencing shows the heterogeneity of cancer-associated fibroblast in HBV-related hepatocellular carcinoma

PROVIDER: PRJNA836868 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR19159054.fastq.gz	Fastqsanger.gz
	SRR19159055.fastq.gz	Fastqsanger.gz
	SRR19159056.fastq.gz	Fastqsanger.gz
	SRR19159057.fastq.gz	Fastqsanger.gz
	SRR19159058.fastq.gz	Fastqsanger.gz

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Single-cell RNA sequencing shows the heterogeneity of cancer-associated fibroblast in HBV-related hepatocellular carcinoma

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Project description:Hepatitis B virus (HBV) infection promotes liver cancer initiation by inducing inflammation and cellular stress, but its impact in established tumors is not well understood. We used affinity purification mass spectrometry to comprehensively map a network of 145 physical interactions between HBV and human proteins in hepatocellular carcinoma (HCC). A subset of the host factors targeted by HBV proteins are preferentially mutated in non-HB¬V-associated HCC suggesting that their interaction with HBV influences HCC biology. These include proteins involved in mRNA splicing, mitogenic signaling and DNA repair, with the latter set interacting with the HBV oncoprotein X (HBx). We show that HBx remodels the PP2A phosphatase complex by excluding striatin regulatory subunits from the PP2A holoenzyme. We find that HBx effects on PP2A cause Hippo kinase activation, particularly in cells with high striatin levels. In parallel, HBx activates mTOR complex 2 (mTORC2) to prevent YAP degradation. mTORC2 effects on YAP can be observed in human HCC specimens and mouse HCC models and can be targeted with mTOR kinase inhibitors. Thus, HBV interaction with host proteins rewires HCC signaling rather than directly activating mitogenic pathways. These findings provide a new paradigm for the cellular effects of a tumor promoting virus and support a model where HBV may have therapeutic actionable effects on HCC biology.

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