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Frequent Silencing of Low Density Lipoprotein Receptor-Related Protein 1B (LRP1B) Expression by Genetic and Epigenetic Mechanisms in Esophageal Squamous Cell Carcinoma

¹ Department of Molecular Cytogenetics, Medical Research Institute, and ² Maxillofacial Surgery, Graduate School, and ³ Center of Excellence Program for Frontier Research on Molecular Destruction and Reconstitution of Tooth and Bone, Tokyo Medical and Dental University, Tokyo, Japan; ⁴ Core Research for Evolutional Science and Technology of Japan Science and Technology Corporation, Saitama, Japan; ⁵ Pathology Division, National Cancer Center Research Institute, Tokyo, Japan; ⁶ Department of Surgery, Surgically Basic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan; and ⁷ University of California San Francisco Comprehensive Cancer Center, University of California, San Francisco, California

Low-density lipoprotein receptor-related protein 1B (LRP1B) is frequently deleted in tumors of various types, but its status and expression in esophageal squamous cell carcinomas (ESCs) have never been reported. In the course of a program to screen ESC cell lines for copy-number aberrations using array-based comparative genomic hybridization, we identified a homozygous deletion of LRP1B. Genomic PCR experiments revealed homozygous deletions of LRP1B in additional ESC cell lines (total, 6 of 43; 14.0%) and in primary esophageal tumors (30 of 70; 42.9%). Moreover, expression of LRP1B mRNA was frequently silenced in ESC lines without homozygous deletions (14 of 37; 37.8%). Using bisulfite-PCR analysis and sequencing, we found that LRP1B-nonexpressing cells without homozygous deletions were highly methylated at a CpG island of LRP1B, a sequence possessing promoter activity. Treatment with 5-aza-2'-deoxycytidine restored expression of LRP1B in those ESC lines. Histone acetylation status correlated directly with expression of LRP1B and inversely with the methylation status of the CpG island. Methylation of LRP1B was also detected in primary esophageal tumors. Restoration of LRP1B expression in ESC cells reduced colony formation. These results suggest that loss of LRP1B function in esophageal carcinogenesis most often occurs either by homozygous deletion or by transcriptional silencing through hypermethylation of its CpG island.

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