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

• Type: Article in International Scientific Journal
• Date: 2011

Authors

Prazeres H (Author) Other; Torres J (Author) Other; Rodrigues F (Author) Other; Pinto M (Author) Other; Pastoriza MC (Author) Other; Gomes D (Author) Other; Cameselle-Teijeiro J (Author) Other; Vidal A (Author) Other; Martins TC (Author) Other; Sobrinho-Simões M (Author) FMUP; Soares P (Author) FMUP

Journal

Title: Oncogene

Vol. 30

Pages: 1302-1317

ISSN: 0950-9232

Publisher: Springer Nature

Indexing

ISI Proceedings

ISI Web of Knowledge - 66 Citations

ISI Web of Science

Scopus - 65 Citations

Pubmed / Medline

Scientific classification

FOS: Medical and Health sciences > Clinical medicine

CORDIS: Health sciences ; Health sciences > Medical sciences > Medicine > Oncology

Other information

Authenticus ID: P-002-TMH

DOI: 10.1038/onc.2010.512

Abstract (EN): 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. Oncogene (2011) 30, 1302-1317; doi:10.1038/onc.2010.512; published online 8 November 2010

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 16