Genetic and Epigenetic Mechanisms Deregulate the CRL2pVHL Complex in Hepatocellular Carcinoma

Dysregulation of ubiquitin-proteasome pathway genes through copy number alteration, promoter hypomethylation, and miRNA deregulation is involved in cancer development and progression. Further characterizing alterations in these genes may uncover novel drug targets across a range of diseases in which...

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Published in:Frontiers in genetics 2022-05, Vol.13, p.910221-910221
Main Authors: Minatel, Brenda C., Cohn, David E., Pewarchuk, Michelle E., Barros-Filho, Mateus C., Sage, Adam P., Stewart, Greg L., Marshall, Erin A., Telkar, Nikita, Martinez, Victor D., Reis, Patricia P., Robinson, Wendy P., Lam, Wan L.
Format: Article
Language:English
Subjects:
DNA copy number
DNA hypomethylation
Genetics
liver cancer
novel microRNAs
ubiquitin-proteasome
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Summary:Dysregulation of ubiquitin-proteasome pathway genes through copy number alteration, promoter hypomethylation, and miRNA deregulation is involved in cancer development and progression. Further characterizing alterations in these genes may uncover novel drug targets across a range of diseases in which druggable alterations are uncommon, including hepatocellular carcinoma (HCC). We analyzed 377 HCC and 59 adjacent non-malignant liver tissue samples, focusing on alterations to component genes of the widely studied CRL2 pVHL E3 ubiquitin ligase complex. mRNA upregulation of the component genes was common, and was correlated with DNA hypomethylation and copy number increase, but many tumours displayed overexpression that was not explained by either mechanism. Interestingly, we found 66 miRNAs, including 39 previously unannotated miRNAs, that were downregulated in HCC and predicted to target one or more CRL2 pVHL components. Several miRNAs, including hsa-miR-101-3p and hsa-miR-139-5p, were negatively correlated with multiple component genes, suggesting that miRNA deregulation may contribute to CRL2 pVHL overexpression. Combining miRNA and mRNA expression, DNA copy number, and methylation status into one multidimensional survival analysis, we found a significant association between greater numbers of alterations and poorer overall survival for multiple component genes. While the intricacies of CRL2 pVHL complex gene regulation require additional research, it is evident that multiple causes for the deregulation of these genes must be considered in HCC, including non-traditional mechanisms.
ISSN:1664-8021
1664-8021
DOI:10.3389/fgene.2022.910221