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JOURNAL ARTICLE

PRMT1-dependent macrophage IL6 production is required for alcohol-induced HCC progression

Jie Zhao, Maura O'Neil, Anusha Vittal, Steven A Weinman, Irina Tikhanovich
Gene Expression 2018 September 18
30236171
Alcohol is a well-established risk factor for hepatocellular carcinoma, but the mechanisms are not well understood. Several studies suggested that alcohol promotes tumor growth by altering immune cell phenotypesin the liver.Arginine methylation is a common posttranslational modification generated mostly by a single protein,PRMT1. In myeloid cells PRMT1 is a key regulator of immune response. Myeloid specific PRMT1 knockout mice are hyper-responsive to LPS and deficient in PPARγ-dependent macrophage M2 polarization. We aimed to define the role of myeloid PRMT1 in alcohol-associated liver tumor progressionusing a mouse model of DEN injection followed by Lieber-DeCarli alcohol liquid diet feeding. We found that PRMT1 knockout mice showed significantly lower expression of IL10 and IL6 cytokines in the liverand downstream STAT3 activation, which correlated with reduced number of surface tumors, reduced proliferation and reduced number of M2 macrophages in the liver as well as within proliferating nodules. We found that blocking IL6 signaling in alcohol fed mice reducedthe number of tumorsand liver proliferation in wild type mice but not in knockout mice suggesting that reduced IL6 in PRMT1 knockout mice contributes to the protection from alcohol. Additionally, PRMT1 knockout did not show any protection in tumor formation in the absence of alcohol. Finally, we confirmed that this mechanism is relevant in humans. We found that PRMT1 expression in tumor associated macrophages correlated with STAT3 activation in human HCC specimens. Taken together these data suggest that the PRMT1-IL6-STAT3 axis is an important mechanism of alcohol-associated tumor progression.

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