Basic Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jun 14, 2018; 24(22): 2381-2391
Published online Jun 14, 2018. doi: 10.3748/wjg.v24.i22.2381
Prognostic value of hypoxia-inducible factor-1 alpha and prolyl 4-hydroxylase beta polypeptide overexpression in gastric cancer
Jun Zhang, Yue Wu, Yu-Hang Lin, Shuai Guo, Pei-Fang Ning, Zhi-Chao Zheng, Yue Wang, Yan Zhao
Jun Zhang, Shuai Guo, Zhi-Chao Zheng, Yue Wang, Yan Zhao, Department of Gastric Cancer, Liaoning Cancer Hospital and Institute (Cancer Hospital of China Medical University), Shenyang 110042, Liaoning Province, China
Yue Wu, Department of Emergency, ShengJing Hospital of China Medical University, Shenyang 110042, Liaoning Province, China
Yu-Hang Lin, Department of Pancreatic and Thyroid Surgery, ShengJing Hospital of China Medical University, Shenyang 110042, Liaoning Province, China
Pei-Fang Ning, Department of Pathology, Liaoning Cancer Hospital and Institute (Cancer Hospital of China Medical University), Shenyang 110042, Liaoning Province, China
Author contributions: Zhang J performed the majority of experiments and drafted the manuscript; Zheng ZZ and Zhao Y designed the research; Wu Y and Lin YH conducted the IHC assays and assisted in writing the manuscript; Guo S and Wang Y collected and analyzed the data; Ning PF provided critical revision of the manuscript for important intellectual content.
Supported by Liaoning S and T Project, No. 2015020269 and Doctor fund of Liaoning Province Cancer Hospital and Institute, No. Z1410.
Institutional review board statement: The study was reviewed and approved by the Faculty of Science Ethics Committee at Liaoning Cancer Hospital & Institute (Cancer Hospital of China Medical University)(20150308-2).
Informed consent statement: All study participants provided informed written consent prior to their treatments and study enrollment.
Conflict-of-interest statement: The authors declare that there are no conflicts of interest related to this study.
Data sharing statement: 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: Yan Zhao, PhD, Professor, Surgeon, Department of Gastric Cancer, Liaoning Cancer Hospital and Institute (Cancer Hospital of China Medical University), No. 44 Xiaoheyan Road, Dadong District, Shenyang 110042, Liaoning Province, China. zhaoyan@CancerHosp-LN-CMU.com
Telephone: +86-24-31916823 Fax: +86-24-2431-5679
Received: February 11, 2018
Peer-review started: February 12, 2018
First decision: February 24, 2018
Revised: March 8, 2018
Accepted: April 16, 2018
Article in press: April 15, 2018
Published online: June 14, 2018
Processing time: 119 Days and 19.4 Hours
ARTICLE HIGHLIGHTS
Research background

The poor prognosis of patients diagnosed with gastric cancer (GC) reflects the limitation of our arsenal of anticancer therapeutic strategies. Hypoxia is a critical factor that shapes the GC microenvironment. However, the involvement of GC cells under such conditions remains poorly explained. Although the core transcription factor of the hypoxia signal pathway hypoxia-inducible factor-1α (HIF-1α) has been studied for decades, its prognostic value in GC is still unclear and controversial.

Research motivation

In a previous report, we demonstrated that prolyl 4-hydroxylase beta (P4HB) is a potential target of HIF-1α, but the exact mechanism was not determined.

Research objectives

The aim of the present study is to evaluate the prognostic value of HIF-1α and P4HB in GC.

Research methods

This study included 428 patients with confirmed GC who underwent gastrectomy in a single Chinese Cancer Center between 2009 and 2011. Clinicopathologic features as well as immunohistochemical analysis of HIF- 1a and P4HB were determined. Long-term survival of these patients was analyzed using univariate and multivariate analyses.

Research results

P4HB was positively correlated with hypoxia-associated genes. HIF-1α and P4HB overexpression were significantly correlation with TNM staging and peritoneum cavity metastasis. In univariate analysis, patients with high HIF-1α expression trend had a shorter disease-free survival and overall survival. P4HB overexpression exhibited similar results. Furthermore, HIF-1α is a clinicopathological predictor of dismal prognosis by multivariate analysis.

Research conclusions

The prognostic value of P4HB in GC was first reported. We confirmed that HIF-1α overexpression could be considered a useful independent prognostic biomarker in GC after gastrectomy and is correlated to both poor overall survival and disease-free survival. Taken together with our previous research, we are more determined that P4HB is a hypoxia-associated gene and regulated by HIF-1α.

Research perspectives

Our research team will explore the mutual regulatory mechanism of HIF-1 and P4HB in future studies through mass spectrometry analysis and co-immunoprecipitation. In addition, we will explore the relationship between the two biomarkers by establishing animal models.