The other polymorphism (rs4533622) of β-catenin gene did not markedly influence these clinical parameters, although MM was diagnosed at significantly younger age in subjects with CC genotype compared to AG/AA combined genotypes (59.1 vs. 65.7 years, p = 0.015).
Abnormal up-regulation of β-catenin expression is associated with the development and progression of multiple myeloma and is thus a potential therapeutic target.
The expression and secretion of eCyPA by BMECs was enhanced by BCL9, a Wnt-β-catenin transcriptional coactivator that is selectively expressed by these cells. eCyPA levels were higher in bone marrow serum than in peripheral blood in individuals with MM, and eCyPA-CD147 blockade suppressed MM colonization and tumor growth in the in vivo scaffold system. eCyPA also promoted the migration of chronic lymphocytic leukemia and lymphoplasmacytic lymphoma cells, two other B cell malignancies that colonize the bone marrow and express CD147.
The activation of β-catenin in MM cell lines was dependent on direct contact with BMMSCs other than separated by transwell or additional condition medium from BMMSCs and cytokines.
These findings suggest that ilimaquinone and ethylsmenoquinone exert their anti-cancer activity by blocking the Wnt/β-catenin pathway and have significant potential as therapies for multiple myeloma.
Since DKK1 itself is a target of TCF/β-catenin mediated transcription, these findings suggest that DKK1 is part of a negative feedback loop in MM and may act as a tumor suppressor.
We further delineated its mechanism of action in multiple myeloma (MM) cells and found a novel role of beta-catenin in regulating growth and survival of tumor cells.
The pleiotropic effects of beta-catenin in MM correlate with its transcriptional function, and we demonstrate regulation of a novel target gene, Aurora kinase A, implicating beta-catenin in G2/M regulation. beta-catenin and Aurora kinase A are present in most MM but not in normal plasma cells and are expressed in a pattern that parallels progression from monoclonal gammopathy of undetermined significance to MM.
Taken together, these data demonstrate the efficacy of disrupting the beta-catenin/TCF transcriptional complex to exploit tumor dependence on Wnt signaling as a therapeutic approach in the treatment of MM.
Identification of the Wnt/beta-catenin pathway is a breakthrough in the elucidation of pathophysiological mechanisms affecting bone tissue and suggests new treatment targets for patients with osteoporosis or specific malignant conditions such as myeloma and sclerotic bone metastases.