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Epigenetic Silencing of LRP2 Is Associated with Dedifferentiation and Poor Survival in Multiple Solid Tumor Types

Martin Q Rasmussen1, Gitte Tindbæk1,2, Morten Muhlig Nielsen3,4

  • 1Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark.

Cancers
|March 29, 2023
PubMed

Insights

The study found that the LRP2 (megalin) receptor, crucial for epithelial cell function, is epigenetically silenced in many cancers. Loss of LRP2 expression correlates with poorer patient outcomes and dedifferentiation in several epithelial cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Epithelial cancers, representing over 80% of human malignancies, often involve the loss of normal epithelial cell characteristics.
  • Receptor-mediated endocytosis, a vital function of absorptive epithelial cells mediated by receptors like LRP2 (megalin), is critical for homeostasis.
  • The role and regulation of LRP2, the largest known endocytic membrane receptor, in cancers of epithelial origin remain largely unexplored.

Purpose of the Study:

  • To investigate the expression patterns and regulatory mechanisms of LRP2 in various human cancers.
  • To determine the correlation between LRP2 expression, epigenetic modifications, and patient prognosis in epithelial cancers.
  • To explore the association of LRP2 loss with cancer subtypes and histological differentiation.

Main Methods:

  • Analysis of LRP2 expression across 33 cancer types using The Cancer Genome Atlas (TCGA) database.
  • Examination of the correlation between LRP2 gene methylation (specifically at CpG site cg02361027) and LRP2 expression levels.
  • Statistical analysis to associate LRP2 expression with patient survival data and histological/molecular subtypes in specific cancer types.

Main Results:

  • LRP2 expression was highest in cancers originating from LRP2-expressing absorptive epithelial cells.
  • Epigenetic silencing of LRP2 was observed in a subset of these tumors, inversely correlated with methylation at a specific CpG site.
  • Low LRP2 expression was linked to poor patient outcomes in clear cell renal cell carcinoma, papillary renal cell carcinoma, mesothelioma, papillary thyroid carcinoma, and invasive breast carcinoma.
  • Loss of LRP2 expression correlated with dedifferentiated histological and molecular subtypes.

Conclusions:

  • LRP2 expression is dysregulated in various epithelial cancers, often through epigenetic silencing.
  • Reduced LRP2 expression is associated with aggressive tumor phenotypes and poor prognosis in several key epithelial cancers.
  • Further research into LRP2's functional role in tumorigenesis and its potential as a cancer biomarker is warranted.
Keywords:
LRP2cancer biomarkerepigeneticsmegalinmethylationtumor dedifferentiation

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