The Role of Mcc in Mature B-cell Proliferation and Carcinogenesis

Non-Hodgkin’s lymphoma is the leading cause of hematologic cancer in adults and the 7 leading cause of death in the United States. Importantly, B-cell lymphomas account for 85% of Non-Hodgkin’s Lymphoma and 90% of lymphomas altogether. Therefore, it is necessary to further delineate the molecular mechanisms of B-cell lymphomagenesis in order to develop novel therapeutic treatments for the disease. This study sought to investigate a novel candidate oncogene, Mutated in Colorectal Cancer (MCC), identified in a new mouse B-cell lymphoma model with the tumor suppressor gene TRAF3 specifically deleted in B-cells (B-TRAF3 mice). Significantly, a striking upregulation of MCC mRNA and protein levels was observed in TRAF3 mouse B lymphomas as compared to splenic B-cells of littermate control mice (LMC). A robust increase of MCC mRNA and protein expression levels was also observed in a variety of human patient-derived multiple myeloma cell lines with TRAF3 deletions or relevant mutations. Therefore, the aberrant upregulation of MCC was verified at both the mRNA and protein levels in TRAF3 mouse B lymphomas and human multiple myeloma cells. In order to further investigate the role of MCC in B-cell lymphomagenesis, a series of lentiviral shRNA constructs were generated and used to transduce human multiple myeloma cells. Interestingly, lentiviral shRNA-mediated knockdown of MCC protein expression in multiple myeloma cells resulted in decreased cell viability, induction of apoptosis, inhibition of cell cycle progression, and reduced cell proliferation. Taken together, our results indicate that MCC plays oncogenic roles in B-cell lymphomagenesis, which is in sharp contrast to its tumor suppressive function in colorectal cancer. Our findings suggest that aberrant upregulation of MCC may serve as a diagnostic marker and therapeutic target of B lymphoma and multiple myeloma.