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

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.

Dietary Intake of 17α-Ethinylestradiol Promotes HCC Progression in Humanized Male Mice Expressing Sex Hormone-Binding Globulin

“…Although HCC progression was phenotypically suppressed in SHBG mice compared with that in WT mice, which is similar to our published data [28], EE2 could expose SHBG mice to HCC risk by triggering markedly pronounced hepatitis, fibrosis, and compensatory proliferation with AR activation. Although survival data are not included in the present study, it is expected that a substantially high number and burden of tumors might lead to a short survival period of HCC-bearing mice, similar to the previous study [29]. Our study highlights the clinical risk for men taking EE2, particularly those expressing high SHBG levels, and women ingesting EE2, particularly those with high androgen levels.…”

“…We analyzed whether HCC progression in SHBG EE2 mice is related to proliferation or inflammation-triggered proliferation. Results showed that SHBG EE2 substantially increased the growth factor response mediated by EGFR, which is known to be highly activated during hepatocarcinogenesis and is an inflammatory target for HCC therapy [29]. As a cell proliferation marker [43], PCNA levels were induced by SHBG EE2.…”

Unde venisti PGRMC? Grand-Scale Biology from Early Eukaryotes and Eumetazoan Animal Origins

“…Lee et al [161] show that PGRMC1 is involved in a pro-inflammatory response involving EGFR in hepatocellular carcinoma. It will be interesting to see whether TSPO is involved in that system.…”

Quo vadis PGRMC? Grand-Scale Biology in Human Health and Disease

“…PGRMC1 activates the epidermal growth factor receptor (EGFR)-dependent PI3K/Akt pathway in breast cancer to promote inflammatory responses and tumor progression [378,386], and interacts with ESRα [148][149][150][151][152]371]. Lee et al [408] show that PGRMC1 is involved in an EGFRdependent inflammatory response in hepatocellular carcinoma, and Peluso and Pru [393] have reviewed the contribution of PGRMCs to ovarian and endometrial cancer.…”