Published online Mar 14, 2018. doi: 10.3748/wjg.v24.i10.1152
Peer-review started: December 12, 2017
First decision: December 27, 2017
Revised: January 16, 2018
Accepted: January 24, 2018
Article in press: January 24, 2018
Published online: March 14, 2018
To investigate the clinicopathological significance of progesterone receptor membrane component 1 (PGRMC1) and PGRMC2 in hepatocellular carcinoma (HCC).
We performed immunohistochemical staining to evaluate the estrogen receptor (ER), progesterone receptor (PR), PGRMC1, and PGRMC2 in a clinical cohort consisting of 89 paired HCC and non-tumor liver samples. We also analyzed HCC data (n = 373) from The Cancer Genome Atlas (TCGA). We correlated the expression status of PGRMC1 and PGRMC2 with clinicopathological indicators and the clinical outcomes of the HCC patients. We knocked down or overexpressed PGRMC1 in HCC cell lines to evaluate its biological significance in HCC cell proliferation, differentiation, migration, and invasion.
We found that few HCC cases expressed ER (5.6%) and PR (4.5%). In contrast, most HCC cases expressed PGRMC1 (89.9%) and PGRMC2 (100%). PGRMC1 and PGRMC2 exhibited significantly lower expression in tumor tissue than in non-tumor tissue (P < 0.001). Lower PGRMC1 expression in HCC was significantly associated with higher serum alpha-fetoprotein expression (P = 0.004), poorer tumor differentiation (P = 0.045) and liver capsule penetration (P = 0.038). Low PGRMC1 expression was an independent predictor for worse disease-free survival (P = 0.002, HR = 2.384, CI: 1.377-4.128) in our cases, as well as in the TCGA cohort (P < 0.001, HR = 2.857, CI: 1.781-4.584). The expression of PGRMC2 did not relate to patient outcome. PGRMC1 knockdown promoted a poorly differentiated phenotype and proliferation of HCC cells in vitro, while PGRMC1 overexpression caused the opposite effects.
PGRMC1 is a non-classical hormonal receptor that negatively regulates hepatocarcinogenesis. PGRMC1 down-regulation is associated with progression of HCC and is a poor prognostic indicator.
Core tip: Neither estrogen receptor or progesterone receptor are commonly expressed in hepatocellular carcinoma (HCC), implying the existence of other hormone-related events in the pathogenesis of HCC. Most primary HCC cases expressed progesterone receptor membrane component 1 (PGRMC1) (89.9%) in our clinical cohort (n = 89). Down-regulation of PGRMC1 was associated with poor tumor differentiation and worse patient survival. The potential prognostic significance was independently validated by The Cancer Genome Atlas (TCGA) database (n = 373). Knockdown of PGRMC1 promoted proliferation and a poorly differentiated phenotype in vitro. Overexpression of PGRMC1 resulted in suppressed proliferation in response to progesterone treatment. PGRMC1 is a prognostic marker and a potential auxiliary therapeutic target for human HCC.