The microRNA miR-155 is essential for normal immune function;however, persistent up-regulation of miR-155 in B-lymphocytes is associated with cancer development. The broad objectives of this work are to understand how miR-155 over-expression induces tumorigenesis and to assess whether suppressing miR-155 activity can inhibit progression of relevant cancers. The hypotheses of this proposal are: 1) miR-155 promotes cell cycle progression and cell proliferation in B-lymphocytes;2) persistent over-expression of miR-155 in B-lymphocytes thus leads to uncontrolled cell cycle/cell proliferation and ultimately promotes tumorigenesis;and 3) inhibition of miR-155 in tumor cells should restore cell cycle regulation and reverse cancer progression. The following aims shall be addressed to examine these hypotheses.
Aim #1 : Examine whether miR-155 promotes cell cycle progression and cell proliferation in normal B- lymphocytes. MiR-155 will be over-expressed in normal B-lymphocytes. The proliferation rate and the population of these cells in S, M, G1, and G2 cell cycle phases will be compared to control B-lymphocytes. These experiments will address whether over-expression of miR-155 in normal B-lymphocytes is sufficient to disrupt cell cycle and cell proliferation processes.
Aim #2 : Assess the role of cell cycle regulators in mediating miR-155 associated tumorigenesis. A panel of miR-155 targets that regulate cell cycle has been identified;some of these contain putative miR-155 binding sites and have been associated with cancer development. Thus, this aim shall examine whether these genes are directly regulated by miR-155 and whether rescued expression of these genes will inhibit the tumorigenic property of miR-155 in vitro.
Aim #3 : Address whether miR-155 inhibition can restore cell cycle regulation in B-lymphoma cells and reverse tumorigenesis.
This aim shall assess whether suppressing miR-155 activity in cultured B-lymphoma cells will restore normal cell cycle regulation and induce cytotoxicity of these tumor cells. Furthermore, antagomirs that inhibit miR-155 will be injected into mice that have existing lymphomas to examine whether targeting miR-155 could reverse tumor progression.
MiR-155 is associated with various tumors, including leukemias and carcinomas. This study will provide insights of miR-155 function in normal immune responses and how its over-expression induces cancer development. Furthermore, by examining whether inhibiting miR-155 can reverse tumor progression, it may provide a new therapeutic target against relevant cancers.
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