Basic Study
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Jun 15, 2023; 15(6): 988-1004
Published online Jun 15, 2023. doi: 10.4251/wjgo.v15.i6.988
Transcription factor glucocorticoid modulatory element-binding protein 1 promotes hepatocellular carcinoma progression by activating Yes-associate protein 1
Cheng Chen, Hai-Guan Lin, Zheng Yao, Yi-Ling Jiang, Hong-Jin Yu, Jing Fang, Wei-Na Li
Cheng Chen, Yi-Ling Jiang, Hong-Jin Yu, Jing Fang, Wei-Na Li, Department of Medical Oncology, Zhejiang Xiaoshan Hospital, Hangzhou 311202, Zhejiang Province, China
Hai-Guan Lin, Department of General Surgery, People’s Liberation Army Strategic Support Force Characteristic Medical Center, Beijing 100101, China
Zheng Yao, Department of Radiation Oncology, Cancer Hospital of The University of Chinese Academy of Sciences, Hangzhou 310022, Zhejiang Province, China
Author contributions: Chen C and Lin HG contributed equally to this work; Chen C, Lin HG and Yao Z designed the research; Lin HG, Yao Z, Jiang YL and Yu HJ contributed to methodological establishment and completion of experiments; Lin HG, Yao Z, Jiang YL, Yu HJ, Fang J and Li WN analyzed and interpreted the data; Chen C and Lin HG drafted the manuscript; Chen C and Fang J and Li WN critically revised the manuscript for important intellectual content.
Institutional review board statement: The study was reviewed and approved by Ethics Committee of Zhejiang Xiaoshan Hopital.
Institutional animal care and use committee statement: The experimental protocol was approved by the Animal Care and Use Committee of Zhejiang Xiaoshan Hopital.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
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: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Cheng Chen, MM, Attending Doctor, Department of Medical Oncology, Zhejiang Xiaoshan Hospital, No. 728 Yucai North Road, Xiaoshan District, Hangzhou 311202, Zhejiang Province, China. chencheng858@126.com
Received: January 17, 2023
Peer-review started: January 17, 2023
First decision: February 28, 2023
Revised: March 18, 2023
Accepted: April 12, 2023
Article in press: April 12, 2023
Published online: June 15, 2023
Processing time: 148 Days and 18.2 Hours
ARTICLE HIGHLIGHTS
Research background

Most hepatocellular carcinoma (HCC) cases have already been in an intermediate to advanced stage at diagnosis, missing the optimal time for surgical treatment. Besides, the high cost and huge shortage of donors greatly limit the clinical application of liver transplantation. Therefore, the lack of reliable diagnostic markers and interventions makes the overall survival rate of HCC patients hardly improved, and the prognosis of patients is generally poor.

Research motivation

Mechanistic understanding of proliferation promotion, increased metastatic potential and cellular defense against apoptosis can inform novel therapeutic strategies in HCC treatment. We would like to clarify the biological functions and clinical significance of glucocorticoid modulatory element-binding protein 1 (GMEB1) in HCC to provide more reliable biomarkers and target candidates for HCC diagnosis and treatment.

Research objectives

Due to the lack of reliable early diagnosis biomarkers and clinical intervention targets, patients with HCC are often diagnosed in the middle and late stages with poor prognosis. This study aims to find new molecular biomarkers with high reference value and effective candidate targets for the treatment of HCC.

Research methods

GMEB1 expression level was detected through bioinformatics analysis first and further validation was conducted in HCC clinical tissue samples by using immunohistochemistry and qPCR; immunoblotting and qPCR were used to detect the expression of GMEB1 in HCC cell lines. Cell counting kit-8 assay, Transwell and flow cytometry were performed to assess the alteration on proliferation and metastasis potential of HCC cells after changes on GMEB1 expression level in HCC cell lines. The binding site of GMEB1 to Yes-associate protein 1 (YAP1) promoter was predicted by bioinformatics analysis and verified by dual luciferase reporter gene assay and ChIP-qPCR.

Research results

GMEB1 was abnormally highly expressed in HCC, whose expression correlates with some clinicopathological features of HCC patients, such as tumor size and TNM stage. According to in vitro results, overexpression of GEMB1 promotes the malignant proliferation and metastasis of HCC cell lines, while knockdown of GMEB1 suppresses the degree of malignancy. In mechanism, GEMB1 positively regulates the expression of YAP1 in transcription level, which finally promote the progression of HCC.

Research conclusions

GMEB1 is a new oncogenic factor of HCC, which promotes the malignant proliferation and metastasis of HCC by promoting YAP1 transcriptional activation.

Research perspectives

This study reveals that GMEB1, a member of KDWK gene family to modulate the transactivation of the glucocorticoid receptor, has a previously unrecognized role in HCC progression, suggesting that it may be a promising biomarker for early-stage HCC diagnosis and it is possible to intervene in anti-tumor therapy against HCC by inhibiting GMEB1-mediated tumor proliferation, metastasis and anti-apoptosis effect.