Clinical Practice Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Mar 14, 2018; 24(10): 1152-1166
Published online Mar 14, 2018. doi: 10.3748/wjg.v24.i10.1152
Progesterone receptor membrane component 1 as a potential prognostic biomarker for hepatocellular carcinoma
Hung-Wen Tsai, Chung-Liang Ho, Shu-Wen Cheng, Yih-Jyh Lin, Chou-Cheng Chen, Pin-Nan Cheng, Chia-Jui Yen, Ting-Tsung Chang, Po-Min Chiang, Shih-Huang Chan, Cheng-Hsun Ho, Shu-Hui Chen, Yi-Wen Wang, Nan-Haw Chow, Jou-Chun Lin
Hung-Wen Tsai, Po-Min Chiang, Institute of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan
Hung-Wen Tsai, Chung-Liang Ho, Shu-Wen Cheng, Yi-Wen Wang, Nan-Haw Chow, Jou-Chun Lin, Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan
Hung-Wen Tsai, Chung-Liang Ho, Shu-Wen Cheng, Chou-Cheng Chen, Nan-Haw Chow, Jou-Chun Lin, Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan
Hung-Wen Tsai, Ting-Tsung Chang, Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan
Yih-Jyh Lin, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan
Pin-Nan Cheng, Chia-Jui Yen, Ting-Tsung Chang, Cheng-Hsun Ho, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan
Shih-Huang Chan, Department of Statistics, College of Management, National Cheng Kung University, Tainan 70403, Taiwan
Cheng-Hsun Ho, Research Center of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan
Shu-Hui Chen, Department of Chemistry, College of Sciences, National Cheng Kung University, Tainan 70403, Taiwan
Author contributions: Lin JC, Cheng SW, Wang YW and Tsai HW conducted the experiments in this study, analyzed the data, and prepared the manuscript; Tsai HW, Ho CL, Chiang PM and Chow NH performed the pathological analysis; Lin YJ, Cheng PN, Yen CJ and Chang TT provided and analyzed the clinical information; Chen CC performed the TCGA data analysis; Chan SH conducted the statistical analysis; Ho CH and Chen SH performed the mass spectrometry and data analysis; Tsai HW designed the study.
Supported by the Ministry of Science and Technology, No. NSC102-2320-B-006-011., No. MOST103-2320-B-006-021-MY2, and No. MOST105-2320-B-006-033 to Tsai HW; and National Cheng Kung University Hospital, Taiwan, No. NCKUH-10406002 and No. NCKUH-10509001 to Tsai HW.
Institutional review board statement: The study was conducted in accordance with the Declaration of Helsinki and approved by the Human Experiment and Ethics Committee of NCKUH (No. BR-100-117).
Conflict-of-interest statement: The authors declare that they have no competing interests.
Data sharing statement: Technical appendix and study data are available from the corresponding author at hungwen@mail.ncku.edu.tw with the permission of Hung-Wen Tsai. Consent was not obtained but the presented data are anonymized and the risk of identification is low. No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Hung-Wen Tsai, MD, Associate Professor, Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan 70403, Taiwan. hungwen@mail.ncku.edu.tw
Telephone: +886-6-2353535-2635 Fax: +886-6-2766195
Received: December 11, 2017
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
Processing time: 91 Days and 20.1 Hours
Abstract
AIM

To investigate the clinicopathological significance of progesterone receptor membrane component 1 (PGRMC1) and PGRMC2 in hepatocellular carcinoma (HCC).

METHODS

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.

RESULTS

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.

CONCLUSION

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.

Keywords: Progesterone receptor membrane component 1; Hormonal receptor; Proliferation; Hepatocellular carcinoma; Prognosis

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.