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
Processing time: 93 Days and 9.7 Hours
Abstract
BACKGROUND

Liver cancer has a high mortality and morbidity rate throughout the world. In clinical practice, the prognosis of liver cancer patients is poor, and the complex reasons contribute to treatment failures, including fibrosis, hepatitis viral infection, drug resistance and metastasis. Thus, screening novel prognostic biomarkers is of great importance for guiding liver cancer therapy. Orosomucoid genes (ORMs) encode acute phase plasma proteins, including orosomucoid 1 (ORM1) and ORM2. Previous studies showed their upregulation upon inflammation, but the specific function of ORMs has not yet been determined, especially in the development of liver cancer.

AIM

To determine the expression of ORMs and their potential function in liver cancer.

METHODS

Analysis of the expression of ORMs in different human tissues was performed on data from the HPA RNA-seq normal tissues project. The expression ratio of ORMs was determined using the HCCDB database, including the ratio between liver cancer and other cancers, normal liver and other normal tissues, liver cancer and adjacent normal liver tissues. Analysis of ORM expression in different cancer types was performed using The Cancer Genome Atlas and TIMER database. The expression of ORMs in liver tumor tissues and adjacent normal tissues were further confirmed using Gene Expression Omnibus data, including GSE36376 and GSE14520. The 10-year overall survival (OS), progression-free survival (PFS) and relapse-free survival (RFS) rates between high and low ORM expression groups in liver cancer patients were determined using the Kaplan-Meier plotter tool. Gene Set Enrichment Analysis (GSEA) was employed to explore the ORM2-associated signaling network. Correlations between ORM2 expression and tumor purity or the infiltration level of macrophages in liver tumor tissues were determined using the TIMER database. The correlation between ORM2 gene levels, tumor-associated macrophage (TAM) markers (including CD68 and TGFβ1) and T cell immunosuppression (including CTLA4 and PD-1) in liver tumor tissues and liver GTEx was determined using the GEPIA database.

RESULTS

ORM1 and ORM2 were highly expressed in normal liver and liver tumor tissues. ORM1 and ORM2 expression was significantly decreased in liver tumor tissues compared with adjacent normal tissues, and similar results were also noted in cholangiocarcinoma, esophageal carcinoma, and lung squamous cell carcinoma. Further analysis of the Gene Expression Omnibus Database also confirmed the downregulation of ORM1 and ORM2 in liver tumors. Survival analysis showed that the high ORM2 group had better survival rates in OS, PFS and RFS. ORM1 only represented better performance in PFS, but not in OS or RFS. GSEA analysis of ORM2 from The Cancer Genome Atlas liver cancer data identified that ORM2 positively associated with the G2/M checkpoint, E2F target signaling, as well as Wnt/β-catenin and Hedgehog signaling. Moreover, apoptosis, IFN-α responses, IFN-γ responses and humoral immune responses were upregulated in the ORM2 high group. ORM2 expression was negatively correlated with the macrophage infiltration level, CD68, TGFβ1, CTLA4 and PD-1 levels.

CONCLUSION

The results showed that ORM1 and ORM2 were highly expressed specifically in liver tissues, whereas ORM1 and ORM2 were downregulated in liver tumor tissues. ORM2 is a better prognostic factor for liver cancer. Furthermore, ORM2 is closely associated with cancer-promoting pathways.

Keywords: Orosomucoid gene; Specific expression; Downregulation; Prognostic factor; Tumor promoter signaling; Immune suppression

Core tip: These studies revealed that ORM genes are specifically expressed in the liver and downregulated in liver tumors. Orosomucoid 2 could be a prognostic factor, and is closely associated with tumor promoter signaling and a immunosuppressive network in liver cancer.