CCAAT/Enhancer-Binding Protein Homologous (CHOP) Protein Promotes Carcinogenesis in the DEN-Induced Hepatocellular Carcinoma Model

Background and Aims: C/EBP homologous protein (CHOP) plays pro-apoptotic roles in the integrated stress response. Recently, a tumor suppressive role for CHOP was demonstrated in lung cancer via regulation of tumor metabolism. To explore the role of CHOP in hepatocarcinogenesis, we induced hepatocellular carcinoma (HCC) in wild type (wt) and CHOP knockout (KO) mice using the carcinogen N-diethylnitrosamine (DEN). Results: Analysis of tumor development showed reduced tumor load, with markedly smaller tumor nodules in the CHOP KO animals, suggesting oncogenic roles of CHOP in carcinogen-induced HCC. In wt tumors, CHOP was exclusively expressed in tumor tissue, with minimal expression in normal parenchyma. Analysis of human adenocarcinomas of various origins demonstrated scattered expression of CHOP in the tumors, pointing to relevance in human pathology. Characterization of pathways that may contribute to preferential expression of CHOP in the tumor identified ATF6 as a potential candidate. ATF6, a key member of the endoplasmic reticulum stress signaling machinery, exhibited a similar pattern of expression as CHOP and strong activation in wt but not CHOP KO tumors. Because HCC is induced by chronic inflammation, we assessed whether CHOP deficiency affects tumor-immune system crosstalk. We found that the number of macrophages and levels of IFN gamma and CCL4 mRNA were markedly reduced in tumors from CHOP KO relative to wt mice, suggesting a role for CHOP in modulating tumor microenvironment and macrophage recruitment to the tumor. Conclusion: Our data highlights a role for CHOP as a positive regulator of carcinogen-induced HCC progression through a complex mechanism that involves the immune system and modulation of stress signaling pathways.