Colon tumorigenesis occurs in a step-wise progression from adenoma to invasive carcinoma in a process that includes accumulation of genetic hits. Inflammation is an essential component of the colon cancer microenvironment and promotes activation of key oncogenic signaling pathways, including STAT3 signaling. STAT3 signaling is an inflammation-induced pathway, which leads to activation of the STAT3 transcription factor and expression of target genes involved in cancer cell proliferation and evasion of apoptosis. STAT3 is activated by extracellular cytokines, which promote STAT3 phosphorylation through JAKs. Under normal conditions, STAT3 activation is transient and subject to negative feedback. In colon tumors, however, STAT3 is persistently activated. Therefore, understanding factors promoting maintenance of this pathway may provide novel insights into disease pathogenesis and uncover novel drug targets. Our recent studies show that the inflammation responsive myc-associated zinc finger (MAZ) protein is highly upregulated in colon cancer and is essential for growth of colon cancer cell lines. Moreover, we show that MAZ directly interacts with JAK1 and is an essential modifier of oncogenic STAT3 signaling. However, the precise function of MAZ upregulation and MAZ regulation of STAT3 signaling in colon cancer have not been characterized. Therefore, this research proposal will test the hypothesis that MAZ is a central molecular mechanism regulating the pro- inflammatory response in tumors through maintenance of STAT3 signaling. To test this hypothesis, we have generated novel whole-body Maz knockout and intestine-specific Maz overexpressing genetic mouse models, which we will use in conjunction with mouse models of colon cancer to understand the functional significance of MAZ. We will use two complementary in vivo colon cancer models (sporadic colon cancer and colitis-associated cancer) and couple these with in vitro assays to characterize the functional roles of MAZ in colon cancer. This research proposal will test two interconnected specific aims: (1) Characterize the mechanism of MAZ regulation of STAT3 signaling (2) Determine the dependence of MAZ-induced STAT3 signaling in colon cancer. The proposed studies will understand the cellular and molecular mechanisms by which MAZ promotes inflammatory responses in colon cancer through STAT3. This has important implications in the pathogenesis of colon cancer and development of novel therapeutic targets.
Colon cancer is a devastating disease that affects more than 90,000 Americans annually and will lead to the deaths of nearly 50,000 patients this year. We show that Myc-associated zinc finger (MAZ) is highly upregulated in human colon cancer and regulates the activation of the oncogenic STAT3 signaling pathway; however, the functional significance of this signaling node in colon cancer is unknown. This project aims to understand mechanistically the importance of MAZ-induced STAT3 signaling in colon cancer, which will provide novel insights into this disease as well as uncover potential therapeutic targets.
