Abstract 3039: The high mobility group A1 oncogene & NF-κB cooperate in malignant transformation

Abstract

Abstract Our research is directed at elucidating key transcriptional networks and underlying cellular pathways regulated by the high mobility group A1 (HMGA1) gene in refractory malignancies. Work from our group and others has shown that blocking HMGA1 interferes with multiple oncogenic phenotypes, including proliferation, anchorage-independent cell growth, migration, invasion, xenograft tumorigenicity, and metastatic progression in murine models. HMGA1 was also identified as a key transcription factor enriched in poorly differentiated solid tumors, leukemic stem cells, and embryonic stem (ES) cells. Importantly, previous studies on diverse tumors show that patients with tumors overexpressing HMGA1 have poor clinical outcomes. Together, these findings suggest that HMGA1 is a major regulator in diverse, poorly differentiated tumors and embryonic stem cells, although the molecular mechanisms through which HMGA1 functions remain unclear. We have begun to identify a few downstream genes and cellular pathways activated by HMGA1 in transformation. In gene expression profile analysis, we found that HMGA1 induces genes involved in mediating inflammatory signals. We identified NF-κB as a major node and inflammation as a major pathway. In previously published studies, we showed that HMGA1 induces expression of STAT3, COX-2, and MMP-2, genes which function in transformation and inflammation. Moreover, we found that anti-inflammatory agents block tumorigenesis in our HMGA1 transgenic mice and in xenograft tumors from aggressive human cancer cells overexpressing HMGA1. Together, these findings are consistent with the hypothesis that HMGA1 functions together with NF-κB to drive inflammatory pathways, induce transformation, and promote a poorly differentiated, stem-like state. To test this hypothesis and dissect the role of NF-κB in transformation induced by HMGA1, we have begun genetic experiments with HMGA1 transgenic mice and mice deficient in the major components of NF-κB. The NF-κB transcriptional complex is comprised primarily of p65:p50 heterodimers in which p65 functions as an activator, and p50, which lacks a transcriptional activation domain, is thought to function as an inhibitor. The p50/p65 heterodimers are thought to activate transcription of canonical NF-κB genes, whereas p50 homodimers repress transcription. Indeed, mice deficient in p50 have been shown to have enhanced NF-κB activity and inflammatory responses. In our preliminary studies, we found that the lymphoid tumors are significantly larger in the mice that are transgenic for HMGA1 and deficient in the inhibitory p50 subunit. This suggests that the excess in the p65 “activator” could lead to enhanced tumorigenesis induced by HMGA1. These studies should not only enhance our understanding of pathways associated with HMGA1 in malignant transformation, but also uncover novel biomarkers and therapeutic targets. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3039. doi:1538-7445.AM2012-3039