Interleukin-1β mediates metalloproteinase-dependent renal cell carcinoma tumor cell invasion through the activation of CCAAT enhancer binding protein β

Effective treatment of metastatic renal cell carcinoma (RCC) remains a major medical concern, as these tumors are refractory to standard therapies and prognosis is poor. Although molecularly targeted therapies have shown some promise in the treatment of this disease, advanced RCC tumors often develop resistance to these drugs. Dissecting the molecular mechanisms underlying the progression to advanced disease is necessary to design alternative and improved treatment strategies. Tumor-associated macrophages (TAMs) found in aggressive RCC tumors produce a variety of inflammatory cytokines, including interleukin-1 beta (IL-1 beta). Moreover, the presence of TAMs and high serum levels of IL-1 beta in RCC patients correlate with advanced disease. We hypothesized that IL-1 beta in the tumor microenvironment promotes the development of aggressive RCC tumors by directing affecting tumor epithelial cells. To address this, we investigated the role of IL-1 beta in mediating RCC tumor cell invasion as a measure of tumor progression. We report that IL-1 beta induced tumor cell invasion of RCC cells through a process that was dependent on the activity of matrix metalloproteinases (MMPs) and was independent of migration rate. Specifically, IL-1 beta induced the expression of MMP-1, MMP-3, MMP-10, and MT1-MMP in a mechanism dependent on IL-1 beta activation of the transcription factor CCAAT enhancer binding protein beta (CEBP beta). Consistent with its role in MMP gene expression, CEBP beta knockdown significantly reduced invasion, but not migration, of RCC tumor cells. These results identify the IL-1 beta /CEBP beta/MMP pathway as a putative target in the design of anti-metastatic therapies for the treatment of advanced RCC.