Dickkopf-related protein 1/cytoskeleton-associated protein 4 signaling activation by -induced activator protein-1 promotes gastric tumorigenesis the PI3K/AKT/mTOR pathway.

World J Gastroenterol

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.

Published: December 2022

Background: Gastric cancer (GC) is a common malignant tumor with high incidence and mortality rates globally, especially in East Asian countries. () infection is a significant and independent risk factor for GC. However, its underlying mechanism of action is not fully understood. Dickkopf-related protein (DKK) 1 is a Wnt signaling antagonist, and cytoskeleton-associated protein (CKAP) 4 is a newly identified DKK1 receptor. Recent studies found that the binding of DKK1 to CAKP4 mediated the procancer signaling of DKK1 inde-pendent of Wnt signaling. We hypothesize that -induced activation of DKK1/CKAP4 signaling contributes to the initiation and progression of GC.

Aim: To investigate the interaction of infection, DKK1 and CAKP4 in GC, as well as the underlying molecular mechanisms.

Methods: RNA sequencing was used to identify differentially expressed genes (DEGs) between -infected and uninfected primary GC cells. Gain- and loss-of-function experiments were performed to verify the -induced upregulation of activator protein-1 (AP-1) in GC cells. A dual-luciferase reporter assay and co-immunoprecipitation were used to determine the binding of AP-1 to the DKK1 promoter and DKK1 to CKAP4. Western blotting and immunohistochemistry detected the expression of DKK1, CKAP4, and phos-phatidylinositol 3-kinase (PI3K) pathway-related proteins in GC cells and tissues. Functional experiments and tumorigenicity in nude mice detected malignant behavior of GC cells and .

Results: We identified 32 DEGs between primary GC cells with and without infection, including JUN, fos-like antigen-1 (FOSL1), and DKK1, and confirmed that the three proteins and CKAP4 were highly expressed in -infected GC cells, -infected gerbil gastric tissues, and human GC tissues. JUN and FOSL1 form AP-1 to transcriptionally activate DKK1 expression by binding to the DKK1 promoter. Activated DKK1 bound to CKAP4, but not the most common Wnt coreceptor low-density lipoprotein receptor-related protein 5/6, to promote GC cell growth, colony formation, migration, invasion, and xenograft tumor growth in nude mice. All these effects were driven by activation of the PI3K/AKT/mammalian target of rapamycin (mTOR) pathway. Targeting the PI3K signaling pathway by LY294002 inhibited DKK1-mediated CKAP4/PI3K signaling activity and the malignant behavior of GC cells.

Conclusion: induces JUN and FOSL1 expression to form AP-1, which transcriptionally activates DKK1. Binding of DKK1 to KAKP4 contributes to gastric tumorigenesis the PI3K/AKT/mTOR pathway.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9813938PMC
http://dx.doi.org/10.3748/wjg.v28.i47.6769DOI Listing

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