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Data sharing statement: No additional unpublished data are available.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: http://creativecommons.org/licenses/by-nc/4.0/
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. yaodf@ahnmc.com
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
Processing time: 260 Days and 23.7 Hours
Abstract
BACKGROUND

Prevalence of nonalcoholic fatty liver disease (NAFLD) is rapidly increasing, and NAFLD has become one of the most common chronic liver diseases worldwide. With abnormal CD44 activation, the severe form of NAFLD can progress to liver cirrhosis and hepatocellular carcinoma (HCC). Thus, the molecular mechanism of CD44 in NAFLD needs to be identified.

AIM

To investigate the relationship between CD44 activation and malignant transformation of rat hepatocytes under nonalcoholic lipid accumulation.

METHODS

Sprague-Dawley rats were fed a high-fat (HF) for 12 wk to entice NAFLD and then with HF plus 2-fluorenylacetamide (0.05%) to induce HCC. Rats were sacrificed every 2 wk, and subsequently divided into the groups based on liver pathological examination (hematoxylin and eosin staining): NAFLD, denaturation, precancerosis, HCC, and control. Liver CD44 mRNA was detected by OneArray. Liver fat as assessed by Oil red O staining or CD44 by immunohistochemical assay was compared with their integral optic density. Serum CD44, alanine aminotransferase, aspartate aminotransferase, triglyceride, total cholesterol, and AFP levels were quantitatively tested.

RESULTS

Elevated CD44 was first reported in hepatocarcinogenesis, with increasing expression from NAFLD to HCC at the protein or mRNA level. The CD44 integral optic density values were significantly different between the control group and the NAFLD (t = 25.433, P < 0.001), denaturation (t = 48.822, P < 0.001), precancerosis (t = 27.751, P < 0.001), and HCC (t = 16.239, P < 0.001) groups, respectively. Hepatic CD44 can be secreted into the blood, and serum CD44 levels in HCC or precancerous rats were significantly higher (P < 0.001) than those in any of the other rats. Positive correlations were found between liver CD44 and CD44 mRNA (rs = 0.373, P = 0.043) and serum CD44 (rs = 0.541, P = 0.002) and between liver CD44 mRNA and serum CD44 (rs = 0.507, P = 0.004). Moreover, significant correlations were found between liver CD44 and liver AFP (rs = 0.572, P = 0.001), between serum CD44 and serum AFP (rs = 0.608, P < 0.001), and between CD44 mRNA and AFP mRNA (rs = 0.370, P = 0.044).

CONCLUSION

The data suggested that increasing CD44 expression is associated with the malignant transformation of hepatocytes in NAFLD.

Keywords: Hepatocarcinogenesis; CD44; Nonalcoholic fatty liver disease; Animal model; Dynamic expressions

Core tip: CD44, which belongs to a family of adhesion molecules, is a marker of cancer stem cells and is related to the transformation of nonalcoholic fatty liver disease to nonalcoholic steatohepatitis and hepatocellular carcinoma. Dynamic expression of CD44 in livers or blood at protein or mRNA level was first investigated at different stages of the progression of fat accumulating fatty liver. Increasing CD44 expression could be one of the most important progenitors and was associated with the malignant transformation of hepatocytes with lipid accumulation.