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Illegitimate WNT signaling promotes proliferation of multiple myeloma cells.

ABSTRACT: The unrestrained growth of tumor cells is generally attributed to mutations in essential growth control genes, but tumor cells are also influenced by signals from the environment. In multiple myeloma (MM), the factors and signals coming from the bone marrow microenvironment are possibly even essential for the growth of the tumor cells. As targets for intervention, these signals may be equally important as mutated oncogenes. Given their oncogenic potential, WNT signals form a class of paracrine growth factors that could act to influence MM cell growth. In this paper, we report that MM cells have hallmarks of active WNT signaling, whereas the cells have not undergone detectable mutations in WNT signaling genes such as adenomatous polyposis coli and beta-catenin (CTNNB1). We show that the malignant MM plasma cells overexpress beta-catenin, including its N-terminally unphosphorylated form, suggesting active beta-catenin/T cell factor-mediated transcription. Further accumulation and nuclear localization of beta-catenin, and/or increased cell proliferation, was achieved by stimulation of WNT signaling with either Wnt3a, LiCl, or the constitutively active S33Y mutant of beta-catenin. In contrast, by blocking WNT signaling by dominant-negative T cell factor, we can interfere with the growth of MM cells. We therefore suggest that MM cells are dependent on an active WNT signal, which may have important implications for the management of this incurable form of cancer.

SUBMITTER: Derksen PW

PROVIDER: S-EPMC395933 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Purpose:Evidence describing TMED3 in the context of breast cancer is scarce, and the effect of TMED3 on Wnt/?-catenin signaling in breast cancer has not been reported. The objective of this study was to determine the potential physiological functions and molecular mechanisms of TMED3 in breast cancer. Materials and Methods:Quantitative real-time PCR and Western blot analysis were used to analyze the expression of TMED3 mRNA and protein in 182 paraffin-embedded primary breast cancer tissues and 60 paired noncancerous tissues and 25 fresh primary breast cancer tissues and surrounding adjacent noncancerous tissues. Associations between TMED3 expression and clinicopathologic factors or overall survival were determined. The effects of overexpression or knockdown of TMED3 on proliferation, migration, invasion, and cell cycle progression in breast cancer cell lines were investigated with the Cell Counting Kit-8, clone formation assay, transwell assay, wound healing assay, and flow cytometry, respectively. Immunofluorescence and Western blot analysis were used to detect the expression of cell cycle, migration-related, and Wnt/?-catenin signaling proteins. Results:The expression of TMED3 mRNA and protein were significantly increased in breast cancer tissues and cell lines compared to normal controls. TMED3 upregulation was significantly correlated with clinicopathologic characteristics and predicted poor prognosis in patients with breast cancer. TMED3 overexpression promoted proliferation, migration, invasion, and cell cycle progression compared to controls in breast cancer cell lines. TMED3 knockdown suppressed proliferation, migration, invasion, and cell cycle progression compared to controls in breast cancer cell lines. TMED3 promoted proliferation and migration of breast cancer cells by a mechanism that involved Wnt/?-catenin signaling. Conclusion:TMED3 behaves as an oncogene that promotes the proliferation and migration of breast cancer cells by a mechanism that involved Wnt/?-catenin signaling. Strategies targeting TMED3 have potential therapeutic implications for patients with breast cancer.

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Illegitimate WNT signaling promotes proliferation of multiple myeloma cells.

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