Abstract
Abstract Neuroblastoma is the most common extracranial pediatric solid tumor with an undifferentiated status and is characterized by heterogeneous clinical courses. The RUNX gene family comprises RUNX1, RUNX2, and RUNX3 transcription factors and is closely involved in a variety of cellular processes including development, differentiation, and tumorigenesis. Since RUNX genes play crucial roles in neuronal differentiation, we studied the expression of RUNX mRNAs in human neuroblastoma NB1691 cells. An increased RUNX2 mRNA expression was found in NB1691 cells compared with RUNX1 and RUNX3 mRNAs. Hypoxia is known to be a significant physiological stress in the tumor microenvironment and is associated with tumor malignant phenotype. NB1691 cells exhibited an increased expression of RUNX2 mRNA upon exposure to hypoxia compared with normoxic cells. Knockdown of HIF-2α, but not HIF-1α, decreased hypoxia-induced up regulation of RUNX2 mRNA in NB1691 cells. BothHIF-1α and HIF-2α mRNAs as well as proteins were downregulated in hypoxic NB1691 cells treated with RUNX2 siRNA compared with non-targeted control siRNA. GLUT1, a HIF-1α downstream target gene and Oct4, a HIF-2α downstream target gene were also found to be decreased in RUNX2 siRNA-treated NB1691 cells exposed to hypoxia. Runx2 knockdown using RNA interference in NB1691 cells resulted in decreased cell proliferation under normoxic as well as hypoxic conditions. An increased percentage of apoptotic cells was found in NB1691 cells treated with RUNX2 siRNA, and this percentage further increased in hypoxic NB1691 cells treated with RUNX2 siRNA. Further, these observations were validated by TUNEL assay. Real-time PCR analysis revealed elevated levels of Bax, Puma, Noxa and Nix in NB1691 cells treated with RUNX2 siRNA compared with cells treated with non-targeted control siRNA-treated cells under hypoxic conditions. In conclusion, our study suggests that hypoxia up regulates RUNX2 in NB1691 cells in a HIF2α- dependent manner and RUNX2 protects neuroblastoma cells against apoptosis. Citation Format: Manu Gnanamony, Indra Mohanam, Sanjeeva Mohanam. RUNX2 protects human neuroblastoma cells against apoptosis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 499. doi:10.1158/1538-7445.AM2014-499
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