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

SIMPLE SUMMARY: Epithelial tissues are the most common sites for the development of cancer. Loss of epithelial cell characteristics and dedifferentiation are hallmarks of cancer. A specialized and complex function in epithelial cells is receptor-mediated endocytosis. LRP2 (megalin) is the largest known endocytic membrane receptor of absorptive epithelia and mediates uptake of numerous ligands. However, its role and regulation in cancer has not been delineated. Therefore, we examined LRP2 expression across 33 cancer types in The Cancer Genome Atlas. As expected, we found the highest LRP2 expression in cancers arising from LRP2-expressing epithelia. However, in a subset of these tumors, we observed epigenetic silencing of LRP2. Interestingly, low LRP2 expression was associated with tumor cell dedifferentiation and poorer patient outcome, suggesting LRP2 is a potential cancer biomarker. Based on this, we warrant further studies on the functional role of LRP2 in tumors of epithelial origin and the implications of LRP2 downregulation. ABSTRACT: More than 80% of human cancers originate in epithelial tissues. Loss of epithelial cell characteristics are hallmarks of tumor development. Receptor-mediated endocytosis is a key function of absorptive epithelial cells with importance for cellular and organismal homeostasis. LRP2 (megalin) is the largest known endocytic membrane receptor and is essential for endocytosis of various ligands in specialized epithelia, including the proximal tubules of the kidney, the thyroid gland, and breast glandular epithelium. However, the role and regulation of LRP2 in cancers that arise from these tissues has not been delineated. Here, we examined the expression of LRP2 across 33 cancer types in The Cancer Genome Atlas. As expected, the highest levels of LRP2 were found in cancer types that arise from LRP2-expressing absorptive epithelial cells. However, in a subset of tumors from these cancer types, we observed epigenetic silencing of LRP2. LRP2 expression showed a strong inverse correlation to methylation of a specific CpG site (cg02361027) in the first intron of the LRP2 gene. Interestingly, low expression of LRP2 was associated with poor patient outcome in clear cell renal cell carcinoma, papillary renal cell carcinoma, mesothelioma, papillary thyroid carcinoma, and invasive breast carcinoma. Furthermore, loss of LRP2 expression was associated with dedifferentiated histological and molecular subtypes of these cancers. These observations now motivate further studies on the functional role of LRP2 in tumors of epithelial origin and the potential use of LRP2 as a cancer biomarker.