Basic Study
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Feb 28, 2024; 30(8): 901-918
Published online Feb 28, 2024. doi: 10.3748/wjg.v30.i8.901
Metadherin promotes stem cell phenotypes and correlated with immune infiltration in hepatocellular carcinoma
Yi-Ying Wang, Mei-Mei Shen, Jian Gao
Yi-Ying Wang, Mei-Mei Shen, Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
Jian Gao, Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
Author contributions: Wang YY and Shen MM performed the experiments and wrote the manuscript; Gao J revised the manuscript; all the authors have approved the final manuscript.
Supported by National Natural Science Foundation of China, No. 82173359; Basic Research and Frontier Exploration Project of Chongqing and Technology Commission, No. cstc2018jcyjAX0181; and Kuanren Talents Program of The Second Affiliated Hospital of Chongqing Medical University.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by The Ethics Committee of the Second Hospital of Chongqing Medical University [Protocol No. 2023(4)].
Conflict-of-interest statement: No conflict of interest has been declared by any of the authors.
Data sharing statement: No additional 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 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:
Corresponding author: Jian Gao, PhD, Doctor, Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Chongqing Medical University, No. 76 Linjiang Road, Yuzhong District, Chongqing 400010, China.
Received: October 8, 2023
Peer-review started: October 8, 2023
First decision: December 6, 2023
Revised: December 18, 2023
Accepted: January 24, 2024
Article in press: January 24, 2024
Published online: February 28, 2024

Metadherin (MTDH) is a key oncogene in most cancer types, including hepatocellular carcinoma (HCC). Notably, MTDH does not affect the stemness pheno-type or immune infiltration of HCC.


To explore the role of MTDH on stemness and immune infiltration in HCC.


MTDH expression in HCC tissues was detected using TCGA and GEO databases. Immunohistochemistry was used to analyze the tissue samples. MTDH was stably knocked down or overexpressed by lentiviral transfection in the two HCC cell lines. The invasion and migration abilities of HCC cells were evaluated using Matrigel invasion and wound healing assays. Next, we obtained liver cancer stem cells from the spheroids by culturing them in a serum-free medium. Gene expression was determined by western blotting and quantitative reverse transcri-ption PCR. Flow cytometry, immunofluorescence, and tumor sphere formation assays were used to characterize stem-like cells. The effects of MTDH inhibition on tumor growth were evaluated in vivo. The correlation of MTDH with immune cells, immunomodulators, and chemokines was analyzed using ssGSEA and TISIDB databases.


HCC tissues expressed higher levels of MTDH than normal liver tissues. High MTDH expression was associated with a poor prognosis. HCC cells overexpressing MTDH exhibited stronger invasion and migration abilities, exhibited a stem cell-like phenotype, and formed spheres; however, MTDH inhibition attenuated these effects. MTDH inhibition suppressed HCC progression and CD133 expression in vivo. MTDH was positively correlated with immature dendritic, T helper 2 cells, central memory CD8+ T, memory B, activated dendritic, natural killer (NK) T, NK, activated CD4+ T, and central memory CD4+ T cells. MTDH was negatively correlated with activated CD8+ T cells, eosinophils, activated B cells, monocytes, macrophages, and mast cells. A positive correlation was observed between the MTDH level and CXCL2 expression, whereas a negative correlation was observed between the MTDH level and CX3CL1 and CXCL12 expression.


High levels of MTDH expression in patients with HCC are associated with poor prognosis, promoting tumor stemness, immune infiltration, and HCC progression.

Keywords: Metadherin, Hepatocellular carcinoma, Cancer stem cells, Immune infiltration

Core Tip: This study demonstrated that high metadherin (MTDH) expression is associated with poor prognosis in hepatocellular carcinoma (HCC). High MTDH expression increased the invasion and migration abilities of HCC cells and promoted stemness and self-renewal. Moreover, MTDH influenced immune cell infiltration and chemokine levels. These results provide additional evidence for the potential role of MTDH as a molecular marker for HCC.