PBRM1 regulates proliferation and the cell cycle in renal cell carcinoma through a chemokine/chemokine receptor interaction pathway.

Abstract

PBRM1 is a novel tumor suppressor gene that can inhibit cancer cell proliferation and predict the outcome of renal cell carcinoma (RCC), but its biological role needs further elucidation. We examined expression of the PBRM1 gene in RCC cell lines and the effect of PBRM1 on cell proliferation and cell cycle in RCC ACHN cells. Microarray processing and analysis was used to explore novel pathways involved in tumorigenesis related to PBRM1 knockdown. PBRM1 was expressed at high levels in RCC ACHN cells and lentivirus-mediated PBRM1 knockdown in these cells caused an increase in the proportion of cells in S phase of the cell cycle and promoted in vitro proliferation and migration. In vivo experiments showed that downregulation of PBRM1 promoted tumorigenesis in nude mice. In pathway gene chip analysis, the chemokine/chemokine receptor interaction pathway showed the greatest difference in gene expression upon PBRM1 knockdown. Protein levels of IL6ST and CCL2 were increased, whereas levels of interleukin (IL)-8, IL-6, and CXCL2 were decreased, in knockdown cells. Re-expression of IL-8 in PBRM1 knockdown ACHN cells could significantly decrease cell proliferation/migration and induced cell arrest in the G2/M phase. These findings indicate that PBRM1 alters cell cycle progression and inhibits proliferation and migration of ACHN cells through the chemokine/chemokine receptor pathway.