Abstract 2366: YB-1 an oncogenic transcription factor regulates macrophage polarization and tumor microenvironment
Authors: Khan Mohammad Imran , Hamid Abid , Adhami Vaqar M. , Mukhtar Hasan 
Published: August 2015

Abstract
Prostate cancer (PCa) is the most common cancer and one of the leading causes of cancer related deaths in men in North America and many western countries. Solid tumors including PCa have been known to be strongly infiltrated by inflammatory leukocytes. Also, significant correlation between increased numbers and/or density of macrophages and poor prognosis has been found in PCa. Based on this, understanding both the recruitment and activation of tumor associated macrophages (TAMs) are considered important targets for therapeutic intervention. We observed that IL-4 (M2 type stimuli) treatment significantly induces YB-1 expression in murine macrophages when compared to LPS (M1 type stimuli). YB-1 is a well-established oncogenic transcription factor known to be expressed by major immune cells like monocytes, T cells and macrophages. However, its expression is found to be relatively lower in differentiated monocytes (i.e. macrophages). Studies have shown an involvement of YB-1 in orchestration of immune responses. In response to proper stimuli like LPS or TGFβ that are associated with inflammatory diseases YB-1 is post-transnationally modified which allows its secretion. This extracellular YB-1 binds to specific unknown receptors on the cell surface of monocytes and promotes activation of different kinases which phosphorylate YB-1 and help in its nuclear translocation. In the nucleus, YB-1 binds to specific gene promoters and activates transcription of target genes like CCL5/RANTES. We over expressed YB-1 in murine macrophages and observed activation of gene network which is representative of M2 phenotype. Macrophages are a fundamental part of the innate defense mechanisms, which can promote specific immunity by inducing T cell recruitment and activation. Despite this, their presence within the tumor microenvironment has been associated with enhanced tumor progression and shown to promote cancer cell growth, angiogenesis and immunosuppression. Further, gain and loss of function studies of YB-1 in murine (RAW264.7) and human (THP-1) macrophages suggested that stable YB-1 knockout in both types of macrophages fails to activate M2 marker genes such as Arg-1, Mrc1, Ass-1, ASL and Pparg. Overexpression of YB-1 in RAW 264.7 macrophages after 16 hours of stimulation with IL-4 (5 ng/ml) significantly decreased the expression of iNOS, an M1 type marker with tumoricidal activity. Our studies provide a novel role of YB-1 in macrophage polarization and provide mechanistic insights as to how YB-1 plays an important role in regulation of tumor microenvironment.
Citation Format: Mohammad Imran Khan, Abid Hamid, Vaqar M. Adhami, Hasan Mukhtar. YB-1 an oncogenic transcription factor regulates macrophage polarization and tumor microenvironment. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2366. doi:10.1158/1538-7445.AM2015-2366