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
Abstract
AIM

To investigate the relationship between hypoxia-inducible factor-1α (HIF-1α), prolyl 4-hydroxylase beta (P4HB) expression, and clinicopathologic parameters, as well as the prognostic value of these genes for patients with gastric cancer (GC).

METHODS

Hypoxia is a critical factor that shapes the GC microenvironment. In previous reports, we have demonstrated that P4HB is a potential target of HIF-1α. In the present study, gene expression profiling interactive analysis (GEPIA) was used to analyze the relationship between P4HB and hypoxia-associated genes. To this end, 428 GC tissue samples were used to analyze the expression of HIF-1α and P4HB via immunohistochemical staining. Patient samples were classified as having weak-expression or over-expression both in terms of HIF-1α and P4HB. Correlations between biomarkers and clinicopathological factors were analyzed to predict survival.

RESULTS

P4HB demonstrated a positive correlation with hypoxia-associated genes (P < 0.05). HIF-1α and P4HB overexpression have a significant correlation with TNM staging (χ2 = 23.32, P = 0.00; χ2 = 65.64, P = 0.00) and peritoneum cavity metastasis (χ2 = 12.67, P = 0.00; χ2 = 39.29, P = 0.00). In univariate analysis, patients with a high HIF-1α expression trend had a shorter disease-free survival (DFS: 44.80 mo vs 22.06 mo) and overall survival (OS: 49.58 mo vs 39.92 mo). P4HB overexpression reflected similar results: patients with over-expression of P4HB had a shorter survival time than those with weak-expression (DFS: 48.03 mo vs 29.64 mo, OS: 52.48 mo vs 36.87 mo). Furthermore, HIF-1α is also a clinicopathological predictor of dismal prognosis according to multivariate analysis (DFS, 95%CI: 0.52-0.88, P < 0.00; OS, 95%CI: 0.50-0.85, P < 0.00). However, P4HB was meaningful in DFS (95%CI: 0.58-1.00, P < 0.05) but not in OS (95%CI: 0.72-1.23, P > 0.05).

CONCLUSION

Overexpression of HIF-1α and P4HB is associated with poor prognosis in patients with GC. Thus, these genes may be potential prognostic biomarker candidates in GC.

Keywords: Gastric cancer; Hypoxia inducible factor-1α; Prolyl 4-hydroxylase beta polypeptide; Overall survival; Clinicopathological predictors; Disease free survival

Core tip: The progression of gastric cancer is closely related to the hypoxic tumor microenvironment. In the present study, we found the expression levels of prolyl 4-hydroxylase beta (P4HB) and hypoxia-inducible factor-1α (HIF-1α) were significantly increased in gastric cancer tissue, and patients with high P4HB and HIF-1α expression had an increased risk of death and relapse compared with patients with low P4HB and HIF-1α expression after adjusting for potential confounders. Based on our research, we suggest that higher expression of P4HB and HIF-1α promotes risk of death and relapse and may act as an indicator of prognosis in patients with gastric cancer.