Basic Study
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Nov 28, 2023; 29(44): 5919-5934
Published online Nov 28, 2023. doi: 10.3748/wjg.v29.i44.5919
Tousled-like kinase 1 promotes gastric cancer progression by regulating the tumor growth factor-beta signaling pathway
Ruo-Chuan Sun, Jing Li, Ya-Xian Li, Hui-Zhen Wang, Emre Dal, Ming-Liang Wang, Yong-Xiang Li
Ruo-Chuan Sun, Jing Li, Ya-Xian Li, Hui-Zhen Wang, Ming-Liang Wang, Yong-Xiang Li, Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui Province, China
Emre Dal, Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112, United States
Co-first authors: Ruo-Chuan Sun and Jing Li.
Co-corresponding authors: Ming-Liang Wang and Yong-Xiang Li.
Author contributions: Li YX and Wang ML conceived the study design; Wang HZ and Dal E wrote the manuscript. Sun RC and Li J performed the experiments; Li YX participated in the cell culture and in vitro experiments; All authors contributed to the article and approved the final submitted version. Li YX and Wang ML contributed equally to this work as co-corresponding authors. The reasons for designating Li YX and Wang ML as co-corresponding authors are twofold. First, the main design of this project is completed by Li YX and Wang ML, which makes our project more rigorous. Second, the choice of these researchers as co-corresponding authors acknowledges and respects this equal contribution, while recognizing the spirit of teamwork and collaboration of this study. Sun RC and Li J contributed equally to this work as co-first authors. The reasons for designating Sun RC and Li J as co-first authors are also twofold. Sun RC and Li J completed all in vitro and in vivo experiments of this study, and made great contributions to this study. They contributed efforts of equal substance throughout the research process. Second, the research was performed as a collaborative effort, and the designation of co-first authorship accurately reflects the distribution of responsibilities and burdens associated with the time and effort required to complete the study and the resultant paper. This also ensures effective communication and management of post-submission matters, ultimately enhancing the paper's quality and reliability. summary, we believe that designating Li YX and Wang ML as co-corresponding authors and Sun RC and Li J as co-first authors of is fitting for our manuscript as it accurately reflects our team's collaborative spirit, equal contributions, and diversity.
Supported by the Key Programs of the Educational Commission of Anhui Province, No. 2023AH053313; and the Research Project of Higher Education in Anhui Province in 2022, No. 2022AH051192.
Institutional review board statement: Institutional review board statement: The study was reviewed and approved by the the Ethics Committee of Anhui Medical University (Approval No. 20180323).
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of Anhui Medical University (No. 20180345).
Conflict-of-interest statement: The authors have no conflict of interest to declare.
Data sharing statement: Technical appendix, statistical code, and dataset available from the corresponding author at liyongxiang@ahmu.edu.cn.
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: Yong-Xiang Li, Doctor, Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Road, Shushan District, Hefei 230022, Anhui Province, China. liyongxiang@ahmu.edu.cn
Received: July 20, 2023
Peer-review started: July 20, 2023
First decision: October 9, 2023
Revised: October 23, 2023
Accepted: November 14, 2023
Article in press: November 14, 2023
Published online: November 28, 2023
Processing time: 130 Days and 2.8 Hours
ARTICLE HIGHLIGHTS
Research background

Gastric cancer (GC) is the fifth most prevalent cancer and the third leading cause of cancer-related mortality worldwide. Endoscopy is the mainstay of early-stage GC treatment whereas advanced GC must be managed through surgery and other interventions including chemotherapy and targeted therapy. Despite significant progress in GC control, however, its overall survival remains unsatisfactory.

Research motivation

Potential therapeutic targets against GC are urgently required.

Research objectives

The present study aimed to elucidate the functional significance of Tousled-like kinase 1 (TLK1) in GC cells and potentially identify a novel therapeutic target against this disease.

Research methods

We measured TLK1 protein expression levels and localized TLK1 in GC cells and tissues by western blot and immunofluorescence, respectively. We transfected various GC cells with lentiviruses to create TLK1 overexpression and knockdown lines and established the functional roles of TLK1 through in vitro colony formation, 5-ethynyl-2`-deoxyuridine, and Transwell assays as well as flow cytometry. We applied bioinformatics to elucidate the signaling pathways associated with TLK1. We performed in vivo validation of TLK1 functions by inducing subcutaneous xenograft tumors in nude mice.

Research results

TLK1 was significantly upregulated in GC cells and tissues compared to their normal counterparts and was localized mainly to the nucleus. TLK1 knockdown significantly decreased colony formation, proliferation, invasion, and migration but increased apoptosis in GC cells. TLK1 overexpression had the opposite effects. Bioinformatics revealed, and subsequent experiments verified, that the tumor growth factor-beta (TGF-β) signaling pathway was implicated in TLK1-mediated GC progression. The in vivo assays confirmed that TLK1 promotes tumorigenesis in GC.

Research conclusions

We demonstrated that TLK1 is highly expressed in GC, localized mainly to the nucleus, significantly promotes GC cell proliferation, invasion, and migration, and inhibits apoptosis. TLK1 may facilitate GC progression by modulating TGF-β expression. We believe that TLK1 could be a crucial therapeutic target for GC.

Research perspectives

Future investigations evaluate the feasibility and practicality of targeting TLK1 in GC treatment.