Abstract
BackgroundLutheran/basal cell adhesion molecule (Lu/BCAM) is a membrane bound glycoprotein. This study was performed to investigate the role and downstream signaling pathway of Lu/BCAM in human bladder tumorigenesis.MethodsFive human bladder cancer (E6, RT4, TSGH8301, TCCSUP and J82), one stable mouse fibroblast cell line (NIH-Lu) expressing Lu/BCAM transgene and sixty human uroepithelial carcinoma specimens were analyzed by real-time PCR, immunohistochemistry (IHC), immunofluorescence (IFA) staining, Western blotting and promoter luciferase assay for Lu/BCAM, respectively. The tumorigenicity of Lu/BCAM was demonstrated by focus formation, colony-forming ability, tumour formation, cell adhesion and migration.ResultsH-rasV12 was revealed to up-regulate Lu/BCAM at both transcriptional and translation levels. Lu/BCAM expression was detected on the membrane of primary human bladder cancer cells. Over-expression of Lu/BCAM in NIH-Lu stable cells increased focus number, colony formation and cell adhesion accompanied with F-actin rearrangement and decreased cell migration compared with parental NIH3T3 fibroblasts. In the presence of laminin ligand, Lu/BCAM overexpression further suppressed cell migration accompanied with increased cell adhesion. We further revealed that laminin-Lu/BCAM-induced cell adhesion and F-actin rearrangement were through increased Erk phosphorylation with an increase of RhoA and a decrease of Rac1 activity. Similarly, high Lu/BCAM expression was detected in the tumors of human renal pelvis, ureter and bladder, and was significantly associated with advanced tumor stage (p = 0.02). Patients with high Lu/BCAM expression showed a trend toward larger tumor size (p = 0.07) and lower disease-specific survival (p = 0.08), although not reaching statistical significance.ConclusionThis is the first report showing that Lu/BCAM, in the presence of its ligand laminin, is oncogenic in human urothelial cancers and may have potential as a novel therapeutic target.
Highlights
Lutheran/basal cell adhesion molecule (Lu/Basal cell adhesion molecule (BCAM)) is a membrane bound glycoprotein
The Western blotting showed that Lutheran/basal cell adhesion molecule (Lu/BCAM) expression was upregulated when H-rasVl2 transgene expression was increased (Fig. 1A), which is consistent with the result of the microarray
We showed that lower level of expression of Lu/BCAM was detected in E6 and RT4 cells, and higher level of Lu/ BCAM was demonstrated in TSGH8301, TCCSUP and J82 cells (Fig. 1B)
Summary
Lutheran/basal cell adhesion molecule (Lu/BCAM) is a membrane bound glycoprotein. This study was performed to investigate the role and downstream signaling pathway of Lu/BCAM in human bladder tumorigenesis. Accumulating evidence indicates that alteration of cell adhesion plays a pivotal role in cancer metastasis. Lu/BCAM (Lutheran/basal cell-adhesion molecule, a glycoprotein) belongs to the immunoglobulin superfamily which contains both Lu blood group and BCAM tumor-associated antigens. BCAM protein consists of two isoforms: Lu (628 amino acid) and Lu (v13) (588 amino acid), which differ in the size of cytosolic domain. Lu/BCAM contains the binding sites for SH3 domain and phosphorylation for signal transduction. It is known that Lu/BCAM functions as the receptor for specific ligand laminin-α5 chain, a major component of the extracellular matrix proteins, such as laminin-10 (α5β1γ1), −11 (α5β2γ1) and −15 (α5β2γ3) [7,8,9]
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