Basic Study
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Feb 28, 2020; 26(8): 804-817
Published online Feb 28, 2020. doi: 10.3748/wjg.v26.i8.804
Downregulation of orosomucoid 2 acts as a prognostic factor associated with cancer-promoting pathways in liver cancer
Han-Zhang Zhu, Wei-Jiang Zhou, Ya-Feng Wan, Ke Ge, Jun Lu, Chang-Ku Jia
Han-Zhang Zhu, Wei-Jiang Zhou, Ya-Feng Wan, Ke Ge, Jun Lu, Chang-Ku Jia, Department of Hepatopancreatobiliary Surgery, Hangzhou First People’s Hospital, The Affiliated Hospital of Medical School of Zhejiang University. Hangzhou 310006, Zhejiang Province, China
Author contributions: Zhu HZ and Zhou WJ conceived and wrote the manuscript, the two authors contributed equally to the study; Wan YF conducted the data collection; Ge K and Lu J provided the statistical analysis; Jia CK directed the study and revised the manuscript.
Supported by Medicine and Health Science and Technology Plan Projects of Zhejiang Province, No. 2018KY569; and Zhejiang Provincial Natural Science Foundation of China, No. LY17H030002.
Institutional review board statement: The study was reviewed and approved by the Ethics Committee of Hangzhou First People’s Hospital.
Conflict-of-interest statement: The authors declare no conflict of interest.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (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/
Corresponding author: Chang-Ku Jia, PhD, Chief Doctor, Department of Hepatopancreatobiliary Surgery, Hangzhou First People’s Hospital, The Affiliated Hospital of Medical School of Zhejiang University, Hangzhou 310006, Zhejiang Province, China. jiachk@126.com
Received: November 26, 2019
Peer-review started: November 26, 2019
First decision: December 30, 2019
Revised: January 4, 2020
Accepted: January 11, 2020
Article in press: January 11, 2020
Published online: February 28, 2020
ARTICLE HIGHLIGHTS
Research background

Liver cancer is an important factor in cancer-related death, where the rate of mortality is significantly higher than the rate of morbidity. Many factors contribute to the poor prognosis of liver cancer, and the deficiency of drugs is worthy of attention. Furthermore, drug resistance could shorten the survival time of liver cancer patients. Thus, to screen a novel and efficient biomarker is important for optimizing treatment therapies for liver cancer patients.

Research motivation

To confirm the expression and significance of orosomucoid genes (ORMs) in liver cancer, especially for assessing the prognostic value of ORM2 in liver cancer.

Research objectives

This study aimed to evaluate the expression of ORM genes in liver cancer, and to reveal its significance for patient prognosis. Besides, this study also aimed to screen the potential mechanism of ORM2’s involvement in the development of liver cancer.

Research methods

Different human tissues were included to evaluate the expression of ORM1 and ORM2 as part of the HPA RNA-seq project. Analysis of ORM1 and ORM2 expression in different tumor types was achieved using the HCCDB database and TIMER portal. ORM1 and ORM2 expression in liver tumor tissues and surrounding normal tissues were tested using the TCGA database and GEO series, including GSE36376 and GSE14520. Survival rate analysis between ORM1 and ORM2 high or low expression groups, respectively, was assessed by a Kaplan-Meier plotter portal, including the overall survival (OS), progression-free survival (PFS) and relapse-free survival (RFS). The potential mechanism associated with ORM2 was evaluated by Gene Set Enrichment Analysis (GSEA). The correlation between ORM2 expression and the infiltration of tumor and macrophage cells was analyzed using the TIMER portal. The expression of ORM2, CD68, TGFβ1, CTLA4, and PD-1 were assessed using the GEPIA database, and correlation analysis was performed on normal and tumor liver GTEx samples.

Research results

We determined that ORM1 and ORM2 are highly expressed in liver tissues, and, more interestingly, that ORM1 and ORM2 expression are downregulated in liver tumor tissues, which was also confirmed in cholangiocarcinomas, esophageal carcinomas and lung squamous cell carcinomas. The high ORM2 expression group showed better survival rates in liver cancer patients upon OS, PFS and RFS analysis. The GSEA analysis associated with ORM2 in liver cancer showed that ORM2 was closely associated with the G2/M, E2F, Wnt/β-catenin and Hedgehog signaling pathways. Besides, the ORM2 high-expression patients group showed a close association with apoptosis, an IFN-α response, IFN-γ response and humoral immune response in liver cancer. Correlation analysis also revealed a negative correlation between ORM2 and the macrophage infiltration level, CD68, TGFβ1, CTLA4 and PD-1 expression.

Research conclusions

Our findings revealed that ORM1 and ORM2 are highly expressed in liver tissues, but downregulated in liver tumor tissues, suggesting that this is an important factor in the development of liver cancer. ORM2 could act as a good biomarker for predicting the prognosis of liver cancer patients, and it is closely associated with some cancer-promoting pathways.

Research perspectives

In this project, we identified the downregulation of ORM1 and ORM2 in liver cancer, and revealed that ORM2 could perform as a novel biomarker to predict the prognosis of liver cancer patients. In the following work, multivariate analysis of ORM2 and its clinical applications could be further evaluated.