Plasma MicroRNA, a Potential Biomarker for Acute Rejection... : Transplantation (original) (raw)

Basic and Experimental Research

Hu, Jie1; Wang, Zheng1; Tan, Chang-Jun1; Liao, Bo-Yi1; Zhang, Xin1; Xu, Min1; Dai, Zhi1; Qiu, Shuang-Jian1; Huang, Xiao-Wu1; Sun, Jian1; Sun, Qi-Man1; He, Yi-Feng1; Song, Kang1; Pan, Qi1; Wu, Ying2; Fan, Jia1,3,4; Zhou, Jian1,3,4

1 Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), the Chinese Ministry of Education, and Shanghai Key Laboratory for Organ Transplantation, Shanghai, P.R. China.

2Department of Pathology, Shanghai Medical College, Fudan University, Shanghai, P.R. China.

3Institute of Biomedical Sciences, Fudan University, Shanghai, P.R. China.

4Address correspondence to: Jian Zhou, M.D., or Jia Fan, Ph.D., 180 Feng Lin Road, Shanghai 200032, P.R. China.

This work was supported by the National Natural Science Foundation of China (Grant Nos. 30972949 and 81172277), the Shanghai Key-Tech Research & Development Program (Grant No. 09411951700), the National Science Foundation for Distinguished Young Scholars of China (Grant No. 81225019), and the Program of Shanghai Excellent Subject Leaders (Grant No. 10XD1401200).

The authors declare no conflicts of interest.

E-mail: [email protected] or [email protected]

J.H., Z.W., C.-J.T., and B.-Y.L. contributed equally to this work. J.Z. and J.F. designed the research. J.H., Z.W., C.-J.T., B.-Y.L., X.Z., M.X., and Z.D. performed the research. S.-J.Q., X.-W.H., J.S., Q.-M.S., Y.-F.H., K.S., and Q.P. contributed the new reagents and analytic tools. J.H., Z.W., B.-Y.L., and Y.W. analyzed the data. J.H., Z.W., B.-Y.L., J.Z., and J.F. wrote the article.

Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantjournal.com).

Received 9 July 2012. Revision requested 30 July 2012.

Accepted 3 January 2013.

Background

Acute rejection (AR) of an organ transplant is a life-threatening complication. Currently, there are few diagnostic biomarkers suitable for clinical application. We aim to determine the potential of plasma microRNAs as biomarkers for AR.

Methods

Using rat orthotopic liver transplantation model and microarrays, we compared the difference in the spectrum and levels of microRNAs in both plasma and grafts between AR rats and control. AR-related plasma microRNAs were selected and validated using real-time quantification polymerase chain reaction. Plasma from AR rats with or without tacrolimus treatment was used for microRNA dynamic monitoring. To clarify the origin of AR-related plasma microRNAs, drug-induced liver damage rat model were performed and in situ hybridization was used to detect and localize the specific microRNA in allografts.

Results

We found that plasma miR-122, miR-192, and miR-146a was significantly up-regulated when AR occur (fold change>2; P<0.05) and the elevation could be repressed by immunosuppression. In liver injury rat model, up-regulated plasma miR-122 (fold change=22.126; _P_=0.002) and miR-192 (fold change=8.833; P<0.001) rather than miR-146a (fold change=1.181; _P_=0.594) were observed. Further study demonstrated that miR-146a was up-regulated by sixfold in microvesicles isolated from AR plasma, whereas miR-122 and miR-192 showed no distinct change. In situ hybridization revealed that the portal areas of the AR graft were brimming with lymphocytes, which showed highly intense staining for miR-146a.

Conclusions

Our study provides the global fingerprint of plasma microRNAs in AR rats and suggests that plasma miR-122 and miR-192 reflect liver injury, whereas miR-146a may associate with cellular rejection.