Progesterone receptor membrane component 1 as a potential prognostic biomarker for hepatocellular carcinoma

doi:10.3748/wjg.v24.i10.1152

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World Journal of Gastroenterology

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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.

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

ARTICLE HIGHLIGHTS

Research background

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.

Research motivation

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.

Research objectives

The aim of this study was to clarify the potential significance of PGRMCs as prognostic biomarkers in HCC and their biological effects in vitro.

Research methods

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.

Research results

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.

Research conclusions

PGRMC1 is a prognostic marker for HCC. PGRMC1 may play a protective role in hepatocarcinogenesis by inhibiting cell proliferation and tumor dedifferentiation.

Research perspectives

PGRMC1 could be a novel therapeutic target for human HCC, especially as a biotarget of chemoprevention.