Basic Study
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Apr 15, 2024; 16(4): 1547-1563
Published online Apr 15, 2024. doi: 10.4251/wjgo.v16.i4.1547
Long noncoding RNAs HAND2-AS1 ultrasound microbubbles suppress hepatocellular carcinoma progression by regulating the miR-873-5p/tissue inhibitor of matrix metalloproteinase-2 axis
Qiang Zou, Hao-Wen Wang, Xi-Liang Di, Yuan Li, Hui Gao
Qiang Zou, Department of Interventional Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China
Qiang Zou, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, China
Hao-Wen Wang, College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, Heilongjiang Province, China
Xi-Liang Di, Yuan Li, Department of Hematology and Oncology, Linyi People’s Hospital, Linyi 251500, Shandong Province, China
Hui Gao, Department of Comprehensive Oncology, Baotou Cancer Hospital, Baotou 014030, Inner Mongolia Autonomous Region, China
Co-first authors: Qiang Zou and Hao-Wen Wang.
Author contributions: Di XL, Li Y were responsible for conducting the experiments; Di XL, Li Y, Gao H were responsible for data analysis; Gao H were responsible for writing and revising the manuscript. All authors read and approved the final manuscript. The reasons for designating Zou Q and Wang HW as the co-first authors are that they made crucial and indispensable contributions towards the completion of the project, played important and indispensable roles in the experimental design, data interpretation and ensuring effective communication post submission. Zou Q proposed, designed, and conducted analysis, performed data analysis, and prepared the first draft of the manuscript. Wang HW was responsible for patient screening, enrollment, collection of clinical data and revision of the manuscript. Further, the overall research team all plays important contributions to complete the study and the resultant paper. Zou Q and Wang HW as co-first authors of is fitting for our manuscript as it accurately reflects our team's collaborative spirit, contributions, and diversity.
Institutional review board statement: The study was reviewed and approved by the Tianjin Medical University Cancer Institute and Hospital ethics committee approved this investigation.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the Tianjin Medical University Cancer Institute and Hospital.
Conflict-of-interest statement: All other authors have nothing to disclose.
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: Hui Gao, Department of Comprehensive Oncology, Baotou Cancer Hospital, No. 18 Tuanjie Street, Baotou 014030, Inner Mongolia Autonomous Region, China. gaohui145@163.com
Received: December 8, 2023
Peer-review started: December 8, 2023
First decision: December 22, 2023
Revised: January 8, 2024
Accepted: February 7, 2024
Article in press: February 7, 2024
Published online: April 15, 2024
Processing time: 124 Days and 19.9 Hours
Abstract
BACKGROUND

Increasing data indicated that long noncoding RNAs (lncRNAs) were directly or indirectly involved in the occurrence and development of tumors, including hepatocellular carcinoma (HCC). Recent studies had found that the expression of lncRNA HAND2-AS1 was downregulated in HCC tissues, but its role in HCC progression is unclear. Ultrasound targeted microbubble destruction mediated gene transfection is a new method to overexpress genes.

AIM

To study the role of ultrasound microbubbles (UTMBs) mediated HAND2-AS1 in the progression of HCC, in order to provide a new reference for the treatment of HCC.

METHODS

In vitro, we transfected HAND2-AS1 siRNA into HepG2 cells by UTMBs, and detected cell proliferation, apoptosis, invasion and epithelial-mesenchymal transition (EMT) by cell counting kit-8 assay, flow cytometry, Transwell invasion assay and Western blotting, respectively. In addition, we transfected miR-837-5p mimic into UTMBs treated cells and observed the changes of cell behavior. Next, the UTMBs treated HepG2 cells were transfected together with miR-837-5p mimic and tissue inhibitor of matrix metalloproteinase-2 (TIMP2) overexpression vector, and we detected cell proliferation, apoptosis, invasion and EMT. In vivo, we established a mouse model of subcutaneous transplantation of HepG2 cells and observed the effect of HAND2-AS1 silencing on tumor formation ability.

RESULTS

We found that UTMBs carrying HAND2-AS1 restricted cell proliferation, invasion, and EMT, encouraged apoptosis, and HAND2-AS1 silencing eliminated the effect of UTMBs. Additionally, miR-873-5p targets the gene HAND2-AS1, which also targets the 3’UTR of TIMP2. And miR-873-5p mimic counteracted the impact of HAND2-AS1. Further, miR-873-5p mimic solely or in combination with pcDNA-TIMP2 had been transformed into HepG2 cells exposed to UTMBs. We discovered that TIMP2 reversed the effect of miR-873-5p mimic caused by the blocked signalling cascade for matrix metalloproteinase (MMP) 2/MMP9. In vivo results showed that HAND2-AS1 silencing significantly inhibited tumor formation in mice.

CONCLUSION

LncRNA HAND2-AS1 promotes TIMP2 expression by targeting miR-873-5p to inhibit HepG2 cell growth and delay HCC progression.

Keywords: Hepatocellular carcinoma; Ultrasound microbubbles; Long noncoding RNA HAND2-AS1; miR-873-5p; Tissue inhibitor of matrix metalloproteinase-2

Core Tip: In this study, we found that ultrasound microbubbles loaded with long noncoding RNA HAND2-AS1 inhibited the growth of hepatocellular carcinoma cells and tumor formation in mice in vivo and in vitro by downregulating miR-873-5p to promote tissue inhibitor of matrix metalloproteinase-2 expression.