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UBE2C expression is elevated in hepatoblastoma and correlates with inferior patient survival

ABSTRACT: UBE2C expression is elevated in hepatoblastoma and correlates with inferior patient survival

PROVIDER: PRJNA833957 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR19026746_1.fastq.gz	Fastqsanger.gz
	SRR19026746_2.fastq.gz	Fastqsanger.gz
	SRR19026747_1.fastq.gz	Fastqsanger.gz
	SRR19026747_2.fastq.gz	Fastqsanger.gz
	SRR19026748_1.fastq.gz	Fastqsanger.gz

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UBE2C expression is elevated in hepatoblastoma and correlates with inferior patient survival

Project description:To gain insight into the pathobiology of hepatoblastoma (HB), RNA sequence analysis and protein-protein interaction analysis of previously established and sequenced HB samples were conducted. Ubiquitination was identified as a key pathway dysregulated in HB and UBE2C, encoding an E2 ubiquitin ligase often overexpressed in cancer cells, was markedly upregulated in 5 of the 6 HB cell lines. The silencing of UBE2C in HUH6 HB cell model resulted in decreased cell viability and migration. RNA sequencing analysis showed alterations in cell cycle regulation after UBE2C knockdown.

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<i>UBE2C</i> expression is elevated in hepatoblastoma and correlates with inferior patient survival.

Project description:Hepatoblastoma (HB) is the most common malignant liver tumor among children. To gain insight into the pathobiology of HB, we performed RNA sequence analysis on 5 patient-derived xenograft lines (HB-243, HB-279, HB-282, HB-284, HB-295) and 1 immortalized cell line (HUH6). Using cultured hepatocytes as a control, we found 2,868 genes that were differentially expressed in all of the HB lines on mRNA level. The most upregulated genes were ODAM, TRIM71, and IGDCC3, and the most downregulated were SAA1, SAA2, and NNMT. Protein-protein interaction analysis identified ubiquitination as a key pathway dysregulated in HB. UBE2C, encoding an E2 ubiquitin ligase often overexpressed in cancer cells, was markedly upregulated in 5 of the 6 HB cell lines. Validation studies confirmed UBE2C immunostaining in 20 of 25 HB tumor specimens versus 1 of 6 normal liver samples. The silencing of UBE2C in two HB cell models resulted in decreased cell viability. RNA sequencing analysis showed alterations in cell cycle regulation after UBE2C knockdown. UBE2C expression in HB correlated with inferior patient survival. We conclude that UBE2C may hold prognostic utility in HB and that the ubiquitin pathway is a potential therapeutic target in this tumor.

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Project description:Notwithstanding advances in the prognostication of chronic lymphocytic leukemia (CLL), it remains challenging to distinguish between patients with favorable and unfavorable treatment-free survival (TFS). Additionally, the downstream protein correlates of well-known molecular features of CLL are not always clear. To address this, we performed large-scale, unbiased characterization of global intracellular protein expression in a cohort of 40 CLL cases (patients with time to first treatment [TTFT] ≤24 months of sampling) and 40 age- and sex-matched CLL controls (patients with TTFT >24 months since sampling). Expression of 3268 proteins was quantified in the cohort. IGHV mutational status and trisomy 12 were most impactful on the CLL proteome. Intriguingly, comparing our results to three recently performed CLL mass-spectrometry screens, we identified four proteins that are strongly and consistently associated with IGHV mutational status: ZAP70, LMNA, FTL and FTH1. Additionally, we found that high intracellular protein levels of THEMIS2, a signaling protein acting downstream of the B-cell receptor, was significantly associated with short TTFT, independently of IGHV and TP53 mutational status (HR 2.47 [95%CI 1.54-3.95], P<0.01). This association was validated on the mRNA and protein level by qPCR and ELISA, respectivelly. Lastly, analysis of an independently generated CLL mass-spectrometry dataset verified the association between THEMIS2 expression and TFS (high THEMIS2, median TFS 4 months, versus low THEMIS2, median TFS not reached, P<0.0001)3. In conclusion, we present a comprehensive characterization of the proteome of untreated CLL. Of note, we identify elevated gene and protein expression of THEMIS2 as putative biomarker of inferior TTFT.

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