Basic Study
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World J Gastroenterol. Dec 21, 2022; 28(47): 6769-6787
Published online Dec 21, 2022. doi: 10.3748/wjg.v28.i47.6769
Dickkopf-related protein 1/cytoskeleton-associated protein 4 signaling activation by Helicobacter pylori-induced activator protein-1 promotes gastric tumorigenesis via the PI3K/AKT/mTOR pathway
Mei Luo, Yuan-Jia Chen, Yuan Xie, Qin-Rong Wang, Yi-Ning Xiang, Ni-Ya Long, Wen-Xiu Yang, Yan Zhao, Jian-Jiang Zhou
Mei Luo, Yuan-Jia Chen, Yuan Xie, Qin-Rong Wang, Yan Zhao, Jian-Jiang Zhou, Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education & Key Laboratory of Medical Molecular Biology of Guizhou Province, Guizhou Medical University, Guiyang 550004, Guizhou Province, China
Yi-Ning Xiang, Wen-Xiu Yang, Department of Pathology of Affiliated Hospital, Guizhou Medical University, Guiyang 550004, Guizhou Province, China
Ni-Ya Long, Department of Neurology of Affiliated Hospital, Guizhou Medical University, Guiyang 550004, Guizhou Province, China
Author contributions: Luo M and Chen YJ contributed equally to this work; Zhou JJ and Xie Y designed the research study; Luo M, Chen YJ, Zhao Y, and Long NY performed the research; Wang QR, Xiang YN, and Yang WX collected samples and analysis data; Zhou JJ and Zhao Y wrote the manuscript; all authors have read and approve the final manuscript.
Supported by the National Natural Science Foundation of China, No. 32160166, No. 31760328, and No. 31960028; Natural Science Foundation of Guizhou Province, No. ZC[2020]4Y026, No. JC[2020]1Z010, No. JC[2020]1Y333, and No. ZK[2022]041; and Scientific Research Project of Guizhou Medical University, No. 20NSP068.
Institutional review board statement: The study was reviewed and approved by the Guizhou Medical University Ethics Committee [Approval No. 2017(43)].
Institutional animal care and use committee statement: All procedures involving animal subjects were reviewed and approved by the Animal Care Welfare Committee of Guizhou Medical University (No: 1702155).
Informed consent statement: All study participants provided informed written consent.
Conflict-of-interest statement: All authors declare no competing interests for this article.
Data sharing statement: All the data presented in the study are included in the article/supplementary materials. The datasets analyzed in the study can be found online, and the names of the datasets can be found in the article. Other data are available from the corresponding author on reasonable request.
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:
Corresponding author: Jian-Jiang Zhou, Doctor, Professor, Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education & Key Laboratory of Medical Molecular Biology of Guizhou Province, Guizhou Medical University, No. 9 Beijing Road, Guiyang 550004, Guizhou Province, China.
Received: October 12, 2022
Peer-review started: October 12, 2022
First decision: October 20, 2022
Revised: November 5, 2022
Accepted: November 30, 2022
Article in press: November 30, 2022
Published online: December 21, 2022
Research background

Gastric cancer (GC) is one of the most common malignant tumors with a high morbidity and mortality rate globally, especially in East Asian countries. Helicobacter pylori (H. pylori) infection is the most significant risk factor for GC. Studying their interaction can reveal the potential pathogenesis and therapeutic targets of GC.

Research motivation

Although substantial efforts have been done to link H. pylori infection and GC over the past decades, the molecular mechanisms of H. pylori-induced GC are not fully understood, which results in reduced treatment benefits.

Research objectives

The present study aimed to study the interaction of H. pylori infection, dickkopf-related protein (DKK) 1, and cytoskeleton-associated protein (CAKP) 4 in GC and the underlying molecular mechanisms.

Research methods

RNA sequencing identified differentially expressed genes (DEGs) between H. pylori-infected and uninfected primary GC cells. Dual-luciferase reporter assay and co-immunoprecipitation determined the interaction of activator protein (AP)-1, DKK1 and CKAP4. Western blotting and immunohistochemistry detected the expression of DKK1, CKAP4 and phosphatidylinositol 3-kinase (PI3K) pathway-related proteins in GC cells and tissues. Functional experiments and tumorigenicity in nude mice detected the malignant behavior of GC cells in vitro and in vivo.

Research results

H. pylori infection upregulated JUN, FOSL1, DKK1 and CKAP4 expression in GC cells, H. pylori-infected gerbil gastric tissues, and human GC samples. JUN and FOSL1 formed activator protein-1 (AP-1) to transcriptionally activate DKK1. DKK1 bound to CKAP4, but not Wnt coreceptor, to promote GC cell growth, migration, invasion, and xenograft tumor growth in nude mice via activating the PI-3K/AKT/mammalian target of rapamycin (mTOR) pathway. Targeting PI3K inhibited DKK1-mediated CKAP4/PI3K signaling activity and the malignant behavior of GC cells.

Research conclusions

H. pylori-induced AP-1 promotes the binding of DKK1 to CAKP4, which contributes to gastric tumorigenesis via the PI3K/AKT/mTOR pathway.

Research perspectives

The findings suggest that the DKK1/CKAP4 interaction may be a therapeutic target for H. pylori-induced GC. The identification of small compounds and drugs targeting the DKK1/CKAP4 axis will be a crucial aspect of future studies. We will also investigate this possibility further.