Protein Canopy Homolog 2 promotes hepatocarcinogenesis through regulation of tumor-associated macrophages

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Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B105
Abstract ID: 5433

Presenting Author:
Wenqing Zhang , Researcher 1 at Ohio State Univ. Comp. Cancer Ctr.

Abstract:

Hepatocellular carcinoma (HCC), the third leading cause of worldwide cancer death, is highly associated with tumor-associated macrophages (TAMs), yet the roles and mechanisms of TAMs in hepatic oncogenesis remain enigmatic. We aimed to investigate how TAMs are regulated by protein canopy homolog 2 (CNPY2) during initiation and progression of HCC and to develop therapeutic strategies targeting TAMs for cancer treatment.  We showed that CNPY2 is highly expressed in TAMs and promotes hepatocarcinogenesis. Mice lacking CNPY2 only in macrophages exhibited a significant decrease in hepatocarcinogenesis. This correlated with reduced cytokine (IL-6, TNFa) production, tumor infiltration of macrophages, and favorable anti-tumor immunity. Mechanistic studies demonstrated that CNPY2 upregulates cytokine production in macrophages by directly binding to TLR4, leading to activation of a transcription factor, NFkB. The RNA-sequencing analysis revealed macrophage-specific Cnpy2 knockout decreased the mRNA level and cell surface expression of 2 vascular endothelial growth factor receptors, Flt1 and Kdr, compared to that in wild-type counterparts, resulting in inhibition of macrophage tumor infiltration. We showed that Cnpy2 knockout inhibits NFkB2/p52-mediated transcription of Flt1 and Kdr in macrophages. These findings demonstrate that CNPY2 is a critical regulator of TAMs in hepatocarcinogenesis and provides a foundation for developing a new approach to targeting TAMs for HCC treatment.