Loss of PGRMC1 Delays the Progression of Hepatocellular Carcinoma via Suppression of Pro-Inflammatory Immune Responses

SIMPLE SUMMARY: Progesterone receptor membrane component 1 (PGRMC1) and epidermal growth factor receptor (EGFR) are highly expressed in various cancers. Here, we first analyzed two sets of clinical data and found that the levels of PGRMC1 and EGFR in hepatocellular carcinomas (HCCs) were both inversely correlated with the survival of HCC patients. Accordingly, by using a carcinogen-induced mouse model of HCC, we found that Pgrmc1 knockout suppressed HCC development and extended the lifespan of HCC-bearing mice. In the acute setting of high-dose carcinogen administration, Pgrmc1 knockout was associated with increases in hepatic necrosis and decreases in the production of the pro-inflammatory cytokine IL-6. Indeed, silencing of Pgrmc1 in murine macrophages suppressed IL-6 production and NF-κB activity, and this process was significantly mediated by EGFR. Our study shows that Pgrmc1 affects the development of HCCs by regulating the EGFR-mediated inflammatory responses. Pgrmc1 may serve as a biomarker and a therapeutic target of HCC. ABSTRACT: Pgrmc1 is a non-canonical progesterone receptor related to the lethality of various types of cancer. PGRMC1 has been reported to exist in co-precipitated protein complexes with epidermal growth factor receptor (EGFR), which is considered a useful therapeutic target in hepatocellular carcinoma (HCC). Here, we investigated whether Pgrmc1 is involved in HCC progression. In clinical datasets, PGRMC1 transcription level was positively correlated with EGFR levels; importantly, PGRMC1 level was inversely correlated with the survival duration of HCC patients. In a diethylnitrosamine (DEN)-induced murine model of HCC, the global ablation of Pgrmc1 suppressed the development of HCC and prolonged the survival of HCC-bearing mice. We further found that increases in hepatocyte death and suppression of compensatory proliferation in the livers of DEN-injured Pgrmc1-null mice were concomitant with decreases in nuclear factor κB (NF-κB)-dependent production of interleukin-6 (IL-6). Indeed, silencing of Pgrmc1 in murine macrophages led to reductions in NF-κB activity and IL-6 production. We found that the anti-proinflammatory effect of Pgrmc1 loss was mediated by reductions in EGFR level and its effect was not observed after exposure of the EGFR inhibitor erlotinib. This study reveals a novel cooperative role of Pgrmc1 in supporting the EGFR-mediated development of hepatocellular carcinoma, implying that pharmacological suppression of Pgrmc1 may be a useful strategy in HCC treatment.