Retrospective Study
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Jul 15, 2021; 13(7): 716-731
Published online Jul 15, 2021. doi: 10.4251/wjgo.v13.i7.716
High expression of protein phosphatase 2 regulatory subunit B'' alpha predicts poor outcome in hepatocellular carcinoma patients after liver transplantation
Jia-Jia He, Lei Shang, Qun-Wei Yu, Ning Jiao, Shuang Qiu, Wei-Xiong Zhu, Dong-Feng Wu, Yun-Er Tian, Qing Zhang
Jia-Jia He, Qing Zhang, Clinical College of General Hospital of Chinese People's Armed Police Force, Anhui Medical University, Hefei 230032, Anhui, China
Jia-Jia He, Ning Jiao, Shuang Qiu, Wei-Xiong Zhu, Dong-Feng Wu, Yun-Er Tian, Qing Zhang, Department of Organ Transplantation, The Third Medical Center of Chinese PLA General Hospital, Beijing 100039, China
Lei Shang, Department of Health Statistics, Fourth Military Medical University, Xi'an 710032, Shanxi Province, China
Qun-Wei Yu, Department of Ophthalmology, The Third Medical Center of Chinese PLA General Hospital, Beijing 100039, China
Author contributions: He JJ, Shang L and Yu WQ contributed equally to this study; He JJ contributed to the design of the research plan, the implementation of the experiment, and the writing of the manuscript; Shang L performed the data analyses; Yu WQ performed the data collection; Jiao N and Qiu S performed the data collection and sorting; Zhu XW, Wu FD, and Tian EY reviewed the intellectual content of the article; and Zhang Q proposed research ideas and revised the final version.
Supported by National Natural Science Foundation of China, No. 81372595.
Institutional review board statement: This study was performed in compliance with the principles of the Declaration of Helsinki. The protocol was approved by the Ethics Committee of the Third Medical Center of Chinese PLA General Hospital.
Conflict-of-interest statement: The authors have no any conflicts 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: Qing Zhang, PhD, Department of Organ Transplantation, Third Medical Center of Chinese PLA General Hospital, Anhui Medical University, No. 69 Yongding Road, Haidian District, Beijing 100039, China. zqy6920@sina.com
Received: March 21, 2021
Peer-review started: March 21, 2021
First decision: April 30, 2021
Revised: June 6, 2021
Accepted: June 23, 2021
Article in press: June 23, 2021
Published online: July 15, 2021
Processing time: 111 Days and 1 Hours
Abstract
BACKGROUND

Protein phosphatase 2 regulatory subunit B'' alpha (PPP2R3A) gene has been reported in other tumors, but the influence of PPP2R3A gene expression on the occurrence, development, and prognosis of hepatocellular carcinoma (HCC) remains unclear.

AIM

To investigate whether the PPP2R3A gene could be used to predict tumor recurrence and survival of HCC patients after liver transplantation (LT).

METHODS

Diseased liver tissues of HCC patients after LT were collected as well as their clinical data and follow-up information. The immunohistochemical method was used to detect the expression of PPP2R3A protein in the tissues of 108 patients with primary liver cancer. The χ2 test was used to analyze the relationship between PPP2R3A protein expression levels and the clinicopathological features of tumors. The Kaplan-Meier method was used to analyze overall postoperative survival. The COX proportional hazard model was used to analyze adverse prognostic factors.

RESULTS

Immunohistochemistry showed that the PPP2R3A protein was mainly expressed in the cytoplasm of HCC cells. Compared to corresponding peritumoral tissues, expression was higher in HCC tissues (P ≤ 0.001). Correlation analysis showed that high PPP2R3A expression was correlated with preoperative serum alpha-fetoprotein (AFP) levels (P = 0.003), tumor-node-metastasis-t stage (P ≤ 0.001), and envelope invasion (P = 0.001). Univariate analysis showed that overall survival (P ≤ 0.001) and recurrence-free survival (P = 0.025) of patients with high PPP2R3A expression (≥ 4 points) were poor compared to those with low expression (< 4 points). The overall survival rates or recurrence-free survival rates at 1, 2, and 3 years with high PPP2R3A expression were 73%, 38%, and 23% or 31%, 23%, and 23%, respectively. Multivariate analysis showed that high PPP2R3A expression (hazard ratio = 2.900, 95% confidence interval: 1.411–5.960, P = 0.004) was an independent survival risk factor of HCC patients after LT, and it was also an independent predictor of postoperative tumor recurrence. This study also showed in patients with AFP ≥ 400 ng/mL, the overall survival (P ≤ 0.001) and recurrence-free survival (P = 0.023) of those with high PPP2R3A expression were significantly worse compared to those with low PPP2R3A expression. When PPP2R3A expression was low, the overall survival rate (P = 0.461) or recurrence-free survival rate (P = 0.072) after LT in patients with AFP < 400 ng/mL and ≥ 400 ng/mL was not significantly difference. The 1, 2, and 3 year survival rate of patients with low PPP2R3A expression and AFP < 400 ng/mL were 98%, 80%, and 69%, respectively, while patients who met Hangzhou criteria had a post-transplant 1, 2, and 3 years overall survival rate of 89%, 66%, and 55%, respectively.

CONCLUSION

High expression of PPP2R3A might be a potential marker for predicting poor prognosis of HCC after LT. Combined with serum AFP levels, PPP2R3A might enhance the accuracy of predicting HCC outcome in patients after LT and supplement the efficacy of the Hangzhou criteria.

Keywords: Protein phosphatase 2 regulatory subunit B'' α; Hepatocellular carcinoma; Liver transplantation; Prognosis; Alpha-fetoprotein

Core Tip: Protein phosphatase 2 regulatory subunit B''α (PPP2R3A) is an independent risk factor impacting the prognosis of liver transplantation (LT) in patients with hepatocellular carcinoma, with PPP2R3A being related to serum alpha-fetoprotein. PPP2R3A combined with alpha-fetoprotein can predict the prognosis of LT more accurately, supplementing the Hangzhou criteria, to a certain extent.