Alteration of the LRP1B Gene Region Is Associated with High Grade of Urothelial Cancer

Abstract

SUMMARY:We have delineated regions of interest at chromosome 2q21.2, 2q36.3, and 2q37.1 by deletion mapping of 114 urothelial cancers (UC). Altogether, 17%, 18%, and 63% of the G1, G2, and G3 tumors displayed loss of heterozygosity at chromosome 2q, respectively, The region at 2q21.2 was narrowed down to the LRP1B gene (NT_005129.6). Hemi-and homozygous deletion at the LRP1B gene region was seen in 31 of 114 UCs. Only 8% of the UCs with G1 and none with G2 tumors showed loss of heterozygosity at the LRP1B gene, whereas 49% of the G3 UCs had allelic loss at this region. RT-PCR analysis of the LRP1B gene showed the lack of expression of several exons in 2 of 9 cases analyzed. Our analysis suggests that the LRP1B gene is a candidate tumor suppressor gene in UCs. (Lab Invest 2002, 82:639 -643).C ancer of the urinary bladder is one of the most common tumors in the Western world. The majority of urothelial cancers (UC) are diagnosed as noninvasive tumors (Ta), whereas 20% to 25% of the cases show an invasive growth (T1-4) at the time of first presentation. From the clinical point of view, the question arises whether these two major groups of tumors are distinct entities or correspond to different stages of progression of a single tumor entity. Pioneering cytogenetic analyses before the chromosome banding era have suggested that the number of gross karyotype alterations predicts the clinical course of UCs, for example, recurrency and progression (Falor and Ward, 1978;Lamb, 1967). Later, several studies showed that allelic changes at specific chromosomal regions and alterations of tumor suppressor genes, such as PTEN, RB, and TP53, correlate with stage and grade of bladder cancers (for review see Knowles, 1999). Comparative genomic hybridization (CGH) studies also suggested quantitative differences of genetic changes, including DNA losses at chromosome 2q22-33, 2q32-qter, and 2q34-qter regions, between the noninvasive and invasive bladder cancers (Richter et al, 1997Simon et al, 1998Simon et al, , 2000. Loss of heterozygosity (LOH) at chromosome 2q is also associated with aggressive growth of head and neck and non-small cell lung carcinomas (Ransom et al, 1998;Shiseki et al, 1994). Recently, Liu et al (2000) identified a putative tumor suppressor gene LRP1B from the chromosome 2q21.2 region that was found to be homozygously deleted in several cancer cell lines, including the bladder cancer cell line VM-CUB-2. To delineate putative tumor suppressor gene regions, we analyzed 114 UCs for 20 microsatellite loci at the chromosome 2q including those from the LRP1B region. We identified three distinct regions of LOH in 40% of tumors and found a correlation between LOH at chromosome 2q and tumor grade. Results Three Target Regions of Allelic Loss at Chromosome 2qCGH analysis of 18 Grade 3 (G3) UCs of this series revealed a gain at chromosome 2p in 7 cases and loss of DNA at chromosome 2q in 11 cases (one example is shown in Fig. 2). Therefore, we evaluated score 2 at chromosome 2p as a duplication of one allele, but at chromoso...

Low Density Lipoprotein (LDL) Receptor-related Protein 1B Impairs Urokinase Receptor Regeneration on the Cell Surface and Inhibits Cell Migration

“…Although the role of LRP in tumor progression remains unclear at present, several studies show a correlation between LRP expression and human cancer cell invasion and metastasis (9, 30 -36). LRP1B was originally discovered as a putative tumor suppressor gene and is frequently inactivated in non-small cell lung cancer cell lines (11) and in high grade of urothelial cancer (37). Therefore, our present results warrant further studies on the potential role of LRP1B as a tumor suppressor and in inhibition of tumor metastasis.…”

Genetic or epigenetic silencing of low density lipoprotein receptor‐related protein 1B expression in oral squamous cell carcinoma

“…(30,31) LRP1B is also a very large gene, containing 92 exons and spanning 1.9 Mb of genomic sequence within FRA2F (2q22.1, http://www.ncbi.nlm.nih.gov/). (17) Inactivation of this gene due to homozygous deletions or epigenetic events has been reported in various cancers (19)(20)(21)(22) and by us in ESCC. (16) Thus, LRP1B is another very large CFS gene that is inactivated in multiple tumors.…”

“…In view of previous reports of homozygous deletions of LRP1B in various types of tumors, (17,(19)(20)(21)(22) we screened a panel of OSCC cell lines for homozygous losses by genomic PCR using primers flanking exons 1, 5, 7 and 10 of LRP1B (GenBank accession number NM_018557 for cDNA sequence and NT_005058 for genomic sequence). All primer sequences used in this study are available on request.…”

γ-Secretase-mediated Release of the Low Density Lipoprotein Receptor-related Protein 1B Intracellular Domain Suppresses Anchorage-independent Growth of Neuroglioma Cells

“…In human esophagus cancer cell lines and primary tumors the LRP1B gene was shown to be inactivated by transcriptional silencing through hypermethylation of its promoter CpG island (3). Homozygous deletions of LRP1B have also been reported in human liver cancers (4) and urothelial cancers (5). By conventional and array-based comparative genomic hybridization analysis, loss of the LRP1B allele was noted in endocervical adenocarcinomas of uterus (6).…”

“…mLRP1B4 Suppresses Tumor Cell Anchorage-independent Growth-LRP1B is known to be frequently inactivated by genetic or epigenetic alterations in tumor cells (3)(4)(5)(6). We employed PCR to examined LRP1B transcripts in neuroglioma H4 cells and detected aberrant transcripts with deletions in exon 2 to exon 7 leading to a loss of protein (data not shown), revealing that these LRP1B-deficient cells represent a good model system to explore the potential of LRP1B to alter cellular function.…”