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

Martin Q. Rasmussen, Gitte Tindbæk, Morten Muhlig Nielsen, Camilla Merrild, Torben Steiniche, Jakob Skou Pedersen, Søren K. Moestrup, Søren E. Degn, Mette Madsen*

*Kontaktforfatter

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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.

OriginalsprogEngelsk
Artikelnummer1830
TidsskriftCancers
Vol/bind15
Udgave nummer6
Antal sider21
ISSN2072-6694
DOI
StatusUdgivet - 17. mar. 2023

Bibliografisk note

Funding Information:
This project was supported by grants from The Max Wørzner and wife Inger Wørzner’s Memorial Grant (Aarhus University reference number: 30109), The Foundation of Holger Hjortenberg and wife Dagmar Hjortenberg (Aarhus University reference number: 29877), The Eva and Henry Fraenkel’s Memorial Fund (Aarhus University reference number: 32535), The Dagmar Marshall Foundation (Aarhus University reference numbers: 33449 and 37155), The AP Moeller Foundation (19-L-0255), The Einar Willumsen’s Memorial Grant (Aarhus University reference number: 34604), the Novo Nordisk Foundation; grants NNF20OC0065103 and NNF18OC0053222, the Independent Research Fund Denmark; Medical Sciences; grant number: 8021-00419B, and Aarhus University; 4-year PhD fellowship for Martin Qvist Rasmussen.

Publisher Copyright:
© 2023 by the authors.

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