Related Experiment Video

Updated: Sep 20, 2025

In Vitro Cultivation Techniques for Modeling Liver Organogenesis, Building Assembloids, and Designing Synthetic Tissues using Human Cell Lines
08:50

In Vitro Cultivation Techniques for Modeling Liver Organogenesis, Building Assembloids, and Designing Synthetic Tissues using Human Cell Lines

Published on: April 18, 2025

574

Genetic and Epigenetic Mechanisms Deregulate the CRL2pVHL Complex in Hepatocellular Carcinoma

Brenda C Minatel1, David E Cohn1, Michelle E Pewarchuk1

  • 1Department of Integrative Oncology, British Columbia Cancer Research Institute, Vancouver, BC, Canada.

Frontiers in Genetics
|June 6, 2022
PubMed

Insights

Dysregulation of ubiquitin-proteasome pathway genes, including CRL2pVHL components, is linked to hepatocellular carcinoma (HCC) progression. Multiple alterations correlate with poorer survival, suggesting novel therapeutic targets.

Area of Science:

  • Molecular Biology
  • Oncology
  • Genetics

Background:

  • Ubiquitin-proteasome pathway gene dysregulation (copy number alteration, hypomethylation, miRNA deregulation) contributes to cancer.
  • Hepatocellular carcinoma (HCC) presents challenges for identifying druggable targets.
  • The CRL2pVHL E3 ubiquitin ligase complex is a key component of this pathway.

Purpose of the Study:

  • To investigate alterations in CRL2pVHL component genes in HCC.
  • To explore the role of miRNA deregulation in CRL2pVHL overexpression.
  • To assess the correlation between gene alterations and patient survival.

Main Methods:

  • Analysis of 377 HCC and 59 non-malignant liver tissues.
  • Examination of mRNA expression, DNA methylation, and copy number alterations.
  • Identification and correlation analysis of downregulated miRNAs targeting CRL2pVHL components.
  • Multidimensional survival analysis integrating various molecular data.

Main Results:

  • Upregulation of CRL2pVHL component genes was common in HCC, linked to hypomethylation and copy number increase.
  • Overexpression not explained by DNA alterations suggests other regulatory mechanisms.
  • 66 miRNAs, including 39 novel ones, were downregulated and predicted to target CRL2pVHL components.
  • Downregulated miRNAs (e.g., hsa-miR-101-3p, hsa-miR-139-5p) correlated with component gene overexpression.
  • Increased numbers of molecular alterations in CRL2pVHL genes significantly associated with poorer overall survival.

Conclusions:

  • Multiple mechanisms, including non-traditional ones like miRNA deregulation, contribute to CRL2pVHL gene dysregulation in HCC.
  • miRNA downregulation is a potential driver of CRL2pVHL overexpression in HCC.
  • Combined molecular alterations in CRL2pVHL genes serve as a prognostic indicator for HCC survival.
  • Further research into CRL2pVHL complex regulation may reveal novel therapeutic strategies for HCC.
Keywords:
DNA copy numberDNA hypomethylationliver cancernovel microRNAsubiquitin-proteasome

More Related Videos

Isolation of CD133+ Liver Stem Cells for Clonal Expansion12:06

Isolation of CD133+ Liver Stem Cells for Clonal Expansion

Published on: October 10, 2011

22.5K
CRISPR-Mediated Reorganization of Chromatin Loop Structure09:20

CRISPR-Mediated Reorganization of Chromatin Loop Structure

Published on: September 14, 2018

12.7K

Related Concept Videos

Epigenetic Regulation01:37

Epigenetic Regulation

Epigenetic changes alter the physical structure of the DNA without changing the genetic sequence and often regulate whether genes are turned on or off. This regulation ensures that each cell produces only proteins necessary for its function. For example, proteins that promote bone growth are not produced in muscle cells. Epigenetic mechanisms play an essential role in healthy development. Conversely, precisely regulated epigenetic mechanisms are disrupted in diseases like cancer.
X-chromosome...
3.1K
Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
4.6K
Cell Specific Gene Expression01:58

Cell Specific Gene Expression

Multicellular organisms contain a variety of structurally and functionally distinct cell types, but the DNA in all the cells originated from the same parent cells. The differences in the cells can be attributed to the differential gene expression. Liver cells, whose functions include detoxification of blood, production of bile to metabolize fats, and synthesis of proteins essential for metabolism, must express a specific set of genes to perform their functions. Gene expression also varies with...
14.0K
Mechanisms of Retrovirus-induced Cancers01:51

Mechanisms of Retrovirus-induced Cancers

Retroviruses are RNA viruses that have been shown to cause cancers in diverse species, including chickens, mice, cats, and monkeys. The RNA genomes of these viruses are first reverse-transcribed into single and then double-stranded DNA (dsDNA) copies. This dsDNA called proviral DNA then integrates into the host genome. Subsequently, the host cell transcribes the proviral DNA in concert with the chromosomal DNA. This leads to the production of viral RNA and proteins that assemble at the host...
5.3K
Negative Regulator Molecules01:23

Negative Regulator Molecules

Positive regulators allow a cell to advance through cell cycle checkpoints. Negative regulators have an equally important role as they terminate a cell’s progression through the cell cycle—or pause it—until the cell meets specific criteria.
36.2K
Covalently Linked Protein Regulators02:04

Covalently Linked Protein Regulators

Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
These groups modify specific amino acids in a protein....
7.5K