Basic Study
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Jan 15, 2020; 12(1): 66-76
Published online Jan 15, 2020. doi: 10.4251/wjgo.v12.i1.66
Abnormal CD44 activation of hepatocytes with nonalcoholic fatty accumulation in rat hepatocarcinogenesis
Miao Fang, Min Yao, Jie Yang, Wen-Jie Zheng, Li Wang, Deng-Fu Yao
Miao Fang, Min Yao, Jie Yang, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
Wen-Jie Zheng, Deng-Fu Yao, Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
Li Wang, Department of Medical Informatics, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
Author contributions: Fang M, Yao M, and Yang J contributed equally to this work and wrote the first draft; Fang M and Yang J conducted the animal model study; Zheng WJ and Wang L analyzed the data; Yao M and Yao DF revised the manuscript; All authors approved the final version of the manuscript.
Supported by the Projects of the Ministry of S. and T. National Key Research and Development Program, No. 2018YFC0116902; the National Natural Science Foundation of China, No. 31872738; the National Natural Science Foundation of China, No. 81673241; the National Natural Science Foundation of China, No. 81702419; the National Natural Science Foundation of China, No. 81873915; and the Jiangsu Medical Science of China, No. BE2016698.
Institutional animal care and use committee statement: The study protocol was approved by the Animal Medical Ethics Committee of Nantong University.
Conflict-of-interest statement: The authors declare no conflicts of interest.
Data sharing statement: No additional unpublished data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (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:
Corresponding author: Deng-Fu Yao, MD, PhD, Professor, Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, 20 West Temple Road, Nantong 226001, Jiangsu Province, China.
Received: April 15, 2019
Peer-review started: April 15, 2019
First decision: May 16, 2019
Revised: July 26, 2019
Accepted: October 1, 2019
Article in press: October 1, 2019
Published online: January 15, 2020
Research background

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, and its prevalence is rapidly increasing worldwide. The severe form of NAFLD can progress to liver cirrhosis and hepatocellular carcinoma (HCC). Recently, several related papers expounded that CD44 played an important role in NAFLD and that there was rather little known knowledge about CD44 expression in different stages of hepatocyte malignant transformation correlated with fatty accumulation.

Research motivation

Although CD44 is initially regarded as an adhesion molecule, which has a close relationship with tumor growth, invasion, and metastasis of HCC, the abnormal activation of CD44 in NAFLD has yet to be discovered, and the fact that CD44 is overexpressed in hepatocytes with fatty accumulation needs to be investigated.

Research objectives

CD44 is a non-kinase transmembrane glycoprotein, and its expression is high in malignant tumors and low in benign and low-metastatic tumors. This new mechanism of CD44 expression with fatty metabolism was worthy to be explored. The objective of this study was to initiate the investigation of the relationship between CD44 activation and hepatocyte malignant transformation under nonalcoholic lipid accumulation

Research methods

In order to clarify the mechanism of CD44 high expression and NAFLD, the models with lipid accumulation were constructed and then the malignant transformation of rat hepatocytes was induced with 2-fluorenylacetamide. Histopathological alterations were identified from normal liver cells to denaturation at the early-, to precancerosis at the middle-, and to HCC formation at last-stage by hematoxylin and eosin examination, with increasing CD44 activation from NAFLD involving inflammation with abnormal metabolism to HCC progression.

Research results

CD44 in hepatocarcinogenesis of rat liver cells was increased from NAFLD to HCC at the protein or mRNA level. Significant difference of CD44 was found between the control group and the NAFLD, denaturation, precancerosis, or HCC group, respectively. Serum CD44 levels in HCC or precancerous rats were significantly higher than those in any of the other rats. Positive correlations were found between liver CD44 mRNA and circulating CD44 or alpha-fetoprotein.

Research conclusions

To the best of our knowledge, this is the first report to investigate the relationship between increasing CD44 activation and malignant transformation of hepatocytes. Hepatic CD44 mRNA and circulating CD44 expression are early molecules contributing to the progression from NAFLD to HCC. The new findings are promising, and the initial evidence confirmed that hepatic CD44 is one of the early molecules leading to the progression from NAFLD to HCC.

Research perspectives

CD44 represents a continuous increasing expression during the entire process of hepatocyte malignant transformation associated with fatty accumulation. Targeting CD44 might prevent NAFLD from turning into HCC and might become a potential therapeutic strategy for HCC. Moreover, further experiments should be conducted to collect the data of CD44 in normal people and of NAFLD, hepatitis, cirrhosis, and HCC and to clarify the molecule mechanism of high expression and carcinogenesis of CD44.