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): 1564-1577
Published online Apr 15, 2024. doi: 10.4251/wjgo.v16.i4.1564
Upregulated lncRNA PRNT promotes progression and oxaliplatin resistance of colorectal cancer cells by regulating HIPK2 transcription
Sai-Nan Li, Shan Yang, Hao-Qi Wang, Tian-Li Hui, Meng Cheng, Xi Zhang, Bao-Kun Li, Gui-Ying Wang
Sai-Nan Li, Shan Yang, Hao-Qi Wang, Tian-Li Hui, Meng Cheng, Xi Zhang, The First Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei Province, China
Sai-Nan Li, Bao-Kun Li, Gui-Ying Wang, The Second Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei Province, China
Gui-Ying Wang, Department of General Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
Author contributions: Li SN and Wang GY contributed to conception, design and writing of the manuscript; Li SN, Hui TL, Yang S, Zhang X and Wang HQ performed the research; Cheng M, Li BK and Li SN contributed to analysis and interpretation of data; and all authors read and approved the final manuscript.
Supported by Hebei Provincial Health Commission Youth Science and Technology Project, No. 20210027.
Institutional review board statement: The study was reviewed and approved by the Fourth Yuan Medical Ethics Committee of Hebei Medical University, No. 2023KS025.
Institutional animal care and use committee statement: All experiments with designed animals were reviewed and approved by the Ethics Committee for Laboratory Animal Welfare of the Fourth Hospital of Hebei Medical University, No. IACUC-4th Hos Hebmu-.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: All data are available from the corresponding author.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines and have prepared and revised the manuscript 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: Gui-Ying Wang, PhD, Surgeon, Department of General Surgery, The Second Hospital of Hebei Medical University, No. 215 Heping West Road, Shijiazhuang 050000, Hebei Province, China. hebeiwangguiying@163.com
Received: December 22, 2023
Peer-review started: December 22, 2023
First decision: January 9, 2024
Revised: January 26, 2024
Accepted: February 18, 2024
Article in press: February 18, 2024
Published online: April 15, 2024
Processing time: 111 Days and 0.8 Hours
Abstract
BACKGROUND

Colorectal cancer (CRC) is the third most common cancer and a significant cause of cancer-related mortality globally. Resistance to chemotherapy, especially during CRC treatment, leads to reduced effectiveness of drugs and poor patient outcomes. Long noncoding RNAs (lncRNAs) have been implicated in various pathophysiological processes of tumor cells, including chemotherapy resistance, yet the roles of many lncRNAs in CRC remain unclear.

AIM

To identify and analyze the lncRNAs involved in oxaliplatin resistance in CRC and to understand the underlying molecular mechanisms influencing this resistance.

METHODS

Gene Expression Omnibus datasets GSE42387 and GSE30011 were reanalyzed to identify lncRNAs and mRNAs associated with oxaliplatin resistance. Various bioinformatics tools were employed to elucidate molecular mechanisms. The expression levels of lncRNAs and mRNAs were assessed via quantitative reverse transcription-polymerase chain reaction. Functional assays, including MTT, wound healing, and Transwell, were conducted to investigate the functional implications of lncRNA alterations. Interactions between lncRNAs and transcription factors were examined using RIP and luciferase reporter assays, while Western blotting was used to confirm downstream pathways. Additionally, a xenograft mouse model was utilized to study the in vivo effects of lncRNAs on chemotherapy resistance.

RESULTS

LncRNA prion protein testis specific (PRNT) was found to be upregulated in oxaliplatin-resistant CRC cell lines and negatively correlated with homeodomain interacting protein kinase 2 (HIPK2) expression. PRNT was demonstrated to sponge transcription factor zinc finger protein 184 (ZNF184), which in turn could regulate HIPK2 expression. Altered expression of PRNT influenced CRC cell sensitivity to oxaliplatin, with overexpression leading to decreased sensitivity and decreased expression reducing resistance. Both RIP and luciferase reporter assays indicated that ZNF184 and HIPK2 are targets of PRNT. The PRNT/ZNF184/HIPK2 axis was implicated in promoting CRC progression and oxaliplatin resistance both in vitro and in vivo.

CONCLUSION

The study concludes that PRNT is upregulated in oxaliplatin-resistant CRC cells and modulates the expression of HIPK2 by sponging ZNF184. This regulatory mechanism enhances CRC progression and resistance to oxaliplatin, positioning PRNT as a promising therapeutic target for CRC patients undergoing oxaliplatin-based chemotherapy.

Keywords: Colorectal cancer; Oxaliplatin resistance; Prion protein testis specific; Zinc finger protein 184; Homeodomain interacting protein kinase 2

Core Tip: The revelation that long noncoding RNA prion protein testis specific, which is overexpressed in oxaliplatin-resistant colorectal cancer (CRC) cells, regulates the expression of homeodomain interacting protein kinase 2 by sponging transcription factor zinc finger protein 184 unveils a promising target for enhancing the efficacy of chemotherapy. This mechanistic insight could lead to the development of novel therapeutic strategies to combat resistance in CRC treatments.