Basic Study
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jun 21, 2023; 29(23): 3606-3621
Published online Jun 21, 2023. doi: 10.3748/wjg.v29.i23.3606
BMI-1 activates hepatic stellate cells to promote the epithelial-mesenchymal transition of colorectal cancer cells
Zhong-Yang Jiang, Xi-Mei Ma, Xiao-Hui Luan, Zhen-Yu Liuyang, Yi-Yang Hong, Yuan Dai, Qing-Hua Dong, Guan-Yu Wang
Zhong-Yang Jiang, Xiao-Hui Luan, Zhen-Yu Liuyang, Guan-Yu Wang, Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang Province, China
Xi-Mei Ma, Department of Emergency, The Second Affiliated Hospital of Zhejing University, Hangzhou 310016, Zhejiang Province, China
Yi-Yang Hong, Yuan Dai, Qing-Hua Dong, Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang Province, China
Qing-Hua Dong, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Hangzhou 310009, Zhejiang Province, China
Author contributions: Jiang ZY, Dong QH, and Wang GY conceived and designed the study; Jiang ZY, Ma XM, Luan XH, Liuyang ZY, Hong YY, and Dai Y performed the research, and collected and analyzed the data; Jiang ZY, Dong QH, and Wang GY wrote the manuscript; All authors read and approved the final manuscript.
Supported by National Natural Science Foundation of China, No. 81472213; the Health Commission of Zhejiang Province, No. 2019ZD010 and No. 2019ZD029; the Science Technology Department of Zhejiang Province, No. LGF20H220001; and the Zhejiang Provincial Administration of Traditional Chinese Medicine, No. 2021ZA088.
Institutional review board statement: This study was reviewed and approved by the Ethics Committee of Sir Run Run Shaw Hospital affiliated with the Zhejiang University School of Medicine, No. 2023-404-01.
Institutional animal care and use committee statement: All animal experiments were performed in accordance with the guidelines of the Committee on the Ethics of Animal Experiments of Zhejiang University, No. ZJU20220447.
Informed consent statement: All study participants or their legal guardian provided informed written consent about personal and medical data collection prior to study enrolment.
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: Guan-Yu Wang, MD, PhD, Surgeon, Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, No. 3 East Qingchun Road, Hangzhou 310016, Zhejiang Province, China. wangguanyu@zju.edu.cn
Received: February 1, 2023
Peer-review started: February 1, 2023
First decision: February 12, 2023
Revised: February 25, 2023
Accepted: May 4, 2023
Article in press: May 4, 2023
Published online: June 21, 2023
ARTICLE HIGHLIGHTS
Research background

Hepatic stellate cells (HSCs) are an important component of liver tissue and are a major source of cancer-associated fibroblasts. Cancer cells can activate HSCs, and in turn activated HSCs (aHSCs) promote tumor growth and metastasis. However, the mechanisms by which HSCs interact with colorectal cancer (CRC) cells to promote liver metastases (LM) are largely unknown.

Research motivation

We previously discovered that the expression of BMI-1 was abnormally high in LM of CRC. We speculated that BMI-1 plays an important role in the interaction between HSCs and CRC cells.

Research objectives

To examine the role of BMI-1 in HSC activation, and investigate the potential mechanisms of BMI-1 in the interaction between HSCs and CRC cells.

Research methods

The expression of BMI-1 in liver tissue of patients with CRC liver metastasis (CRLM) was determined by immunohistochemistry analysis. We established a mouse LM model to assess the expression of BMI-1 during CRLM. We used lentiviral vectors to overexpress BMI-1 in LX2 HSCs (LX2 BMI-1) and evaluated the molecular markers of aHSCs. The proliferation and mobility of CRC cells in LX2 BMI-1 conditioned medium (CM) was detected. The epithelial-mesenchymal transition (EMT) and transforming growth factor beta (TGF-β)/SMAD pathway in CRC cells treated with LX2 BMI-1 CM were investigated by Western blot analysis and quantitative polymerase chain reaction. A mouse xenograft model was established to investigate the effects of co-implantation of LX2 BMI-1 and CRC cells on tumor growth, and the EMT phenotype of CRC.

Research results

BMI-1 expression was upregulated in liver cells during CRLM. Overexpression of BMI-1 induced the activation of LX2 HSCs. CRC cells cultured in LX2 BMI-1 CM showed higher proliferation, migration, and EMT ability compared with cells cultured in NC CM. LX2 BMI-1 CM induced activation of the TGF-β/SMAD pathway in CRC cells, and the TGF-βR inhibitor SB-505124 diminished the effect of BMI-1 CM. In addition, LX2 BMI-1 HSCs promoted CRC tumor growth and EMT in the mouse model.

Research conclusions

BMI-1 aHSCs promoted the proliferation and migration of CRC partly via the TGF-β/SMAD pathway.

Research perspectives

Targeting BMI-1 in liver tissues may have potential therapeutic implications for the treatment of CRLM.