Abstract
The inflammatory cytokine IL-6 is known to play a causal role in the promotion of cancer, although the underlying mechanisms remain to be completely understood. Interplay between endogenous and environmental cues determines the fate of cancer development. The Eμ-myc transgenic mouse expresses elevated levels of c-Myc in the B cell lineage and develops B cell lymphomas with associated mutations in p53 or other genes linked to apoptosis. We generated Eμ-myc mice that either lacked the IL-6 gene, or lacked the STAT3 gene specifically in B cells to determine the role of the IL-6/JAK/STAT3 pathway in tumor development. Using the Eμ-myc lymphoma mouse model, we demonstrate that IL-6 is a critical tumor promoter during early stages of B cell lymphomagenesis. IL-6 is shown to inhibit the expression of tumor suppressors, notably BIM and PTEN, and this may contribute to advancing MYC-driven B cell tumorigenesis. Several miRNAs known to target BIM and PTEN are upregulated by IL-6 and likely lead to the stable suppression of pro-apoptotic pathways early during the tumorigenic process. STAT3, a classical downstream effector of IL-6, appears dispensable for Eμ-myc driven lymphomagenesis. We conclude that the growth-promoting and anti-apoptotic mechanisms activated by IL-6 are critically involved in Eμ-myc driven tumor initiation and progression, but the B cell intrinsic expression of STAT3 is not required.
Highlights
The complex interplay between intrinsic genetic factors and externally driven signaling pathways is pivotal to cancer development
To identify signaling pathways that intersect and cooperate with MYC, we evaluated the contribution of the IL-6/STAT3 pathway to B cell development and cellular survival in the context of Eμ-myc-driven B cell lymphomagenesis
We evaluated the contribution of IL-6 in a spontaneous model of B cell lymphoma driven by the Eμ-myc transgene [26,38]
Summary
The complex interplay between intrinsic genetic factors and externally driven signaling pathways is pivotal to cancer development. Chronic inflammation within a tumor microenvironment is frequently associated with high levels of the interleukin-6 [IL-6] cytokine, and IL-6 levels have been shown to steadily increase as cancers become life threatening [1,2,3,4]. IL-6 is produced by a broad range of cell types and has pleiotropic effects that include inflammation as well as regulation of metabolic, regenerative, and neural processes. IL-6 loss inhibits B cell lymphomagenesis and analysis, decision to publish, or preparation of the manuscript
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
