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
Hepatocellular carcinoma (HCC) is a sexually dimorphic disease with a significantly higher incidence in males than females. The androgen receptor appears to function as a tumor promoter, whereas the estrogen receptor appears to act as a tumor suppressor for HCC. Whether additional hormone-related events are implicated in the pathogenesis of HCC remain to be clarified.
The membrane-associated progesterone receptors, i.e. PGRMC1 and PGRMC2, have been investigated in female cancers of the breast, endometrium and ovary. PGRMC1 is thought to coordinate non-classical progesterone signaling. PGRMC1 was demonstrated to mediate the anti-mitotic actions of progesterone in endometrial and ovarian cancer cells. This study was performed to examine the significance of PGRMC1 and/or PGRMC2 in the progression of HCC.
The aim of this study was to clarify the potential significance of PGRMCs as prognostic biomarkers in HCC and their biological effects in vitro.
Immunohistochemical staining of the estrogen receptor (ER), progesterone receptor (PR), PGRMC1 and PGRMC2 was performed in a clinical cohort consisting of 89 cases of paired HCC and non-tumor liver. The clinical implications of PGRMCs in HCC (n = 373) from The Cancer Genome Atlas (TCGA) database were also analyzed. The expression of PGRMC1 and PGRMC2 was correlated with clinicopathological indicators and the clinical outcome of HCC patients. The impact of PGRMC1 on the biological effects of HCC was investigated by knocking down its expression in HepG2 and Hep3B cell lines, and overexpressing in PLC/PRF-5 and Huh7 cell lines. The analyzed cellular functions included proliferation, differentiation, migration, and invasion.
Primary HCC demonstrated a high incidence of PGRMC1 (89.9%) and PGRMC2 (100%) expression, respectively. Down-regulated PGRMC1 was significantly associated with higher serum alpha-fetoprotein levels, poor tumor differentiation, liver capsule penetration, and the risk of recurrence. Low PGRMC1 expression was an independent indicator of worse disease-free survival. Knock-down of PGRMC1 promoted a poorly differentiated phenotype and proliferation of HCC in vitro, while over-expression of PGRMC1 suppressed cell proliferation.
PGRMC1 is a prognostic marker for HCC. PGRMC1 may play a protective role in hepatocarcinogenesis by inhibiting cell proliferation and tumor dedifferentiation.
PGRMC1 could be a novel therapeutic target for human HCC, especially as a biotarget of chemoprevention.