Identification of HO-1 as a novel biomarker for graft acute cellular rejection and prognosis prediction after liver transplantation

Junjun Jia; Yu Nie; Lei Geng; Jianhui Li; Jimin Liu; Yifan Peng; Junjie Huang; Haiyang Xie; Lin Zhou; Shu-Sen Zheng

doi:10.21037/atm.2020.01.59

Identification of HO-1 as a novel biomarker for graft acute cellular rejection and prognosis prediction after liver transplantation

Ann Transl Med. 2020 Mar;8(5):221. doi: 10.21037/atm.2020.01.59.

Authors

Junjun Jia^{1

2

3}, Yu Nie^{1

2

3}, Lei Geng^{1

2

3}, Jianhui Li^{1

2

3}, Jimin Liu⁴, Yifan Peng^{2

3}, Junjie Huang^{2

3}, Haiyang Xie^{1

2

3}, Lin Zhou^{1

2

3}, Shu-Sen Zheng^{1

2

3}

Affiliations

¹ Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, College of Medicine, Hangzhou 310003, China.
² Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Hangzhou 310003, China.
³ Collaborative Innovation Centers for Diagnosis Treatment of Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.
⁴ Department of Pathology and Molecular Medicine, Faculty of Health Sciences, McMaster University, Hamilton, Canada.

Abstract

Background: Liver transplantation (LT) is the most effective treatment for patients with end-stage liver diseases, but acute rejection is still a major concern. However, the mechanisms underlying rejection remain unclear. Biomarkers are lacking for predicting rejection and long-term survival after LT.

Methods: Isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomics was performed between acute cellular rejection (ACR) and non-rejection recipients. The molecular signature differences and potential biomarkers were identified by comprehensive bioinformatics. Heme oxygenase-1 (HO-1) expression and its association with clinical outcomes were investigated by tissue microarrays consisted of liver specimens from recipients with (n=80) and without ACR (n=57).

Results: A total of 287 differentially expressed proteins (DEPs) were identified. Pathway analysis revealed that T/B cell activation, integrin/inflammation signaling pathway, etc. were significantly correlated with ACR. Through comprehensive bioinformatics, HO-1 was identified as a candidate potential biomarker for ACR. In tissue microarray (TMA) analysis, HO-1 expression was significantly higher in ACR group than in non-rejection group (P<0.01). Preoperative Child-Pugh and Meld scores were significantly higher in recipients with high HO-1 expression (P<0.01). In a mean 5-year follow-up, recipients with high HO-1 expression were associated with a shorter overall survival (P<0.05). Further multivariate analyses indicated that HO-1 could be an independent adverse prognostic factor for post-transplant survival (P=0.005).

Conclusions: A total of 287 DEPs were identified, providing a set of targets for further research. Recipients with high preoperative HO-1 expression were associated with ACR. HO-1 may be used as a potential biomarker for predicting the development of post-transplant allograft ACR and recipient's survival.

Keywords: Acute cellular rejection (ACR); biomarker; heme oxygenase-1 (HO-1); liver transplantation (LT).