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
Research background

Metadherin (MTDH) is a key oncogene in most cancer types, including hepatocellular carcinoma (HCC). Tumor stem cells are associated with tumorigenesis, metastasis, cell proliferation, and postoperative recurrence. The type and number of immune cells in the HCC microenvironment have prognostic value and can influence the response to immunotherapy. The impacts of MTDH expression on stem cell characteristics and immune cell infiltration in HCC remain unclear.

Research motivation

MTDH is a key oncogene in most cancers. It is important to explore the impact of MTDH on the prognosis of HCC patients and determine whether it affects tumor progression by influencing stem cell phenotype and immune infiltration.

Research objectives

This study aimed to investigate the effects of MTDH on tumor stemness and immunity in HCC.

Research methods

Differential expression of MTDH in tissues was detected using TCGA and GEO databases, and immunohistochemistry was performed on HCC and para-cancerous tissue samples. MTDH was stably downregulated or overexpressed by lentiviral transfection in both HCC cell types. Invasiveness and migration were assessed using stromal infiltration and wound healing assays. HCC stem cells were obtained by culturing spheroids in a serum-free medium. Flow cytometry, immunofluorescence, and sphere formation assays were used to identify stem-like cells. Relevant gene expression was detected through western blotting and real-time quantitative reverse transcription-PCR. The effect of MTDH inhibition on tumor growth was investigated using in vivo tumor formation assays. Correlations between MTDH and immune cells, immunomodulators, and chemokines were analyzed using ssGSEA and the TISIDB database.

Research results

This study confirmed that the expression of MTDH in HCC tissues was higher than that in normal liver tissues and that the high expression of MTDH resulted in poor prognosis of patients with HCC. HCC cells overexpressing MTDH exhibited stronger invasion and migration abilities, exhibited a stem cell-like phenotype, and formed spheres, whereas MTDH inhibition attenuated these effects. MTDH inhibition suppressed tumor growth and CD133 expression in vivo. Correlation analysis showed that MTDH exhibited positive correlation with immature dendritic cells (DCs), T helper (Th)2 cells, central memory CD8+ T cells, memory B cells, activated DCs, natural killer (NK) T cells, NK cells, activated CD4+ T cells, and central memory CD4+ T cells. The results also showed that MTDH exhibited negative correlation with activated CD8+ T cells, eosinophils, activated B cells, monocytes, macrophages, and mast cells. Correlation analysis of MTDH expression with immunomodulators and chemokines showed that MTDH levels positively correlated with CXCL2 expression and negatively correlated with CX3CL1 and CXCL12 expression.

Research conclusions

In HCC, MTDH expression is increased, leading to poor prognosis. MTDH promotes the acquisition of tumor cell stemness and tumor growth in HCC, influencing immune infiltration and immunotherapy.

Research perspectives

Through database analysis, as well as in vivo and in vitro experiments, we confirmed that MTDH leads to poor prognosis in patients with HCC, promotes the acquisition of the tumor stem cell phenotype, and influences immune infiltration. The exact mechanism through which MTDH influences HCC stem cell and immune cell infiltration requires further exploration. This may provide a scientific basis for further understanding of the prognosis and treatment of patients with HCC.