Chromosomal, epigenetic and microRNA-mediated inactivation of LRP1B, a modulator of the extracellular environment of thyroid cancer cells

Abstract

The low-density lipoprotein receptor-related protein (LRP1B), encoding an endocytic LDL-family receptor, is among the 10 most significantly deleted genes across 3312 human cancer specimens. However, currently the apparently crucial role of this lipoprotein receptor in carcinogenesis is not clear. Here we show that LRP1B inactivation (by chromosomal, epigenetic and microRNA (miR)-mediated mechanisms) results in changes to the tumor environment that confer cancer cells an increased growth and invasive capacity. LRP1B displays frequent DNA copy number loss and CpG island methylation, resulting in mRNA underexpression. By using CpG island reporters methylated in vitro, we found that DNA methylation disrupts a functional binding site for the histone-acetyltransferase p300 located at intron 1. We identified and validated an miR targeting LRP1B (miR-548a-5p), which is overexpressed in cancer cell lines as a result of 8q22 DNA gains. Restoration of LRP1B impaired in vitro and in vivo tumor growth, inhibited cell invasion and led to a reduction of matrix metalloproteinase 2 in the extracellular medium. We emphasized the role of an endocytic receptor acting as a tumor suppressor by modulating the extracellular environment composition in a way that constrains the invasive behavior of the cancer cells.

LRP1B Deletion in High-Grade Serous Ovarian Cancers Is Associated with Acquired Chemotherapy Resistance to Liposomal Doxorubicin

“…LRP1B is a member of the LDL receptor family and is among the top 10 genes mutated in human cancer (41). Its large size and location near the FRA2F fragile site (53) may contribute to a high mutation rate as a passenger event; however, several observations favor LRP1B being a bona fide driver mutation in human cancer, including a very high frequency of homozygous deletions (54), frequent point mutation in lung cancer (55,56) and melanoma (57), and promoter methylation in esophageal (58), oral (59), thyroid (60), and gastric cancer (45). Although located adjacent to a fragile site, FRA2F is the least sensitive fragile site in the aphidicolin fragility assay and scored highest in a computational measure for homozygous deletion selection pressure (54).…”

Frequency of TERT promoter mutations in human cancers

“…qPCR for human TERT was performed in 28 thyroid samples, 24 tumours and 3 normal tissue specimens. We also included a normal reference that was produced by pooling RNAs from nine samples of normal thyroid tissue 19 .…”

Molecular Markers Involved in Tumorigenesis of Thyroid Carcinoma: Focus on Aggressive Histotypes

“…Our group reported that the LRP1B expression level in UTC was significantly lower than in WDTC, and that such reduced expression was due to mutation and genomic loss of the LRP1B gene [Prazeres et al, 2011]. UTC showed frequent methylation of the promoter region of the gene, leading to loss of LRP1B expression in more than 80% of UTC [Beroukhim et al, 2010;Prazeres et al, 2011;Eloy et al, 2015].…”