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

• Published in: Oncogene Vol. 30; no. 11; pp. 1302 - 1317
• Main Authors: PRAZERES, H, TORRES, J, SOARES, P, RODRIGUES, F, PINTO, M, PASTORIZA, M. C, GOMES, D, CAMESELLE-TEIJEIRO, J, VIDAL, A, MARTINS, T. C, SOBRINHO-SIMOES, M
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 17.03.2011
• Subjects: Acetyltransferase; Binding sites; Biological and medical sciences; Cancer; Carcinogenesis; Cell Line, Tumor; Cell physiology; Cell receptors; Cell structures and functions; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cellular biology; Copy number; CpG Islands; Development and progression; DNA Methylation; Endocrinopathies; Epigenesis, Genetic; Epigenetics; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Silencing; Gene Targeting; Genes, Tumor Suppressor; Genetic aspects; Histones; Humans; Invasiveness; Low density lipoprotein; LRP1B protein; Malignant tumors; Matrix metalloproteinase; Matrix Metalloproteinase 2 - genetics; Matrix Metalloproteinase 2 - metabolism; Medical sciences; Messenger RNA; Metalloproteinase; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; MicroRNAs - physiology; miRNA; Miscellaneous; Molecular and cellular biology; mRNA; Neoplasm Invasiveness; Oncology; Properties; Proteins; Receptor density; Receptors, LDL - chemistry; Receptors, LDL - genetics; Receptors, LDL - metabolism; Reproducibility of Results; Ribonucleic acid; RNA; RNA, Messenger - genetics; RNA, Messenger - metabolism; Thyroid cancer; Thyroid Neoplasms - genetics; Thyroid. Thyroid axis (diseases); Tumor cell lines; Tumor suppressor genes; Tumors; United States; Endocrinopathy; endocytosis and tumor microenvironment; RNA interference; low-density lipoprotein receptor family; EP300 histone-acetyltransferase; Metalloendopeptidases; Inactivation; Carcinogenesis; Lipoprotein LDL; Endocytosis; Tumor suppressor gene; Biological receptor; Acyltransferases; Enzyme; Transferases; Thyroid diseases; Micro RNA; Malignant tumor; Extracellular; Histone acetyltransferase; Gelatinase A; matrix metalloproteinase 2; Peptidases; Gene silencing; Thyroid cancer; Epigenetics; Hydrolases; Environment; microRNA; Cancer
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2010.512

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.