Evidence map›Paper›PMID 41654792›Full record

ArticleMolecular medicine (Cambridge, Mass.)2026

Loss of XRCC1 promotes cGAS/STING mediated innate immune signaling in gastric cancer.

Aashirwad Shahi, Shengyuan Zhao, Julia A Goewey Ruiz, Dawit Kidane

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Article in Molecular medicine (Cambridge, Mass.), 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

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1citing papers in PubMed
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1 · What the graph read from it

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3 · Its place in the literature

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1 citing paper in PubMed.

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4 · The record

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5 · Who and what money

Authors and funding

4 authors.

Aashirwad Shahi *Department of Physiology & Biophysics, College of Medicine, Howard University, 520 W Street N.W., Washington, D.C., 20059, USA.
Shengyuan Zhao *Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Dell Pediatric Research Institute, Austin, TX, USA.
Julia A Goewey RuizDivision of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Dell Pediatric Research Institute, Austin, TX, USA.
Dawit KidaneDepartment of Physiology & Biophysics, College of Medicine, Howard University, 520 W Street N.W., Washington, D.C., 20059, USA. dawit.kidane-mulat@howard.edu.

Funding

Linking defects in DNA polymerase beta to mitochondrial dysfunction and cytosolic nucleic acid sensor in Helicobacter pylori associated inflammationR01AI179899 · NIAID · HOWARD UNIVERSITY · PI Dawit Kidane Mulat · 2024 to 2026
$1.3M
National Institute of Allergy and Infectious Diseases R01AI179899NIAID NIH HHS R01 AI179899
6 · The paper itself

Abstract

backgroundOne of the most defining features of gastric cancer (GC) is harboring deficiency in DNA repair that subsequently contributes to carcinogenesis. The X-ray repair cross complementing 1 (XRCC1) protein is a key molecular scaffold required for efficient repair of DNA single-strand breaks (SSBs) to maintain genomic stability. However, further investigation is needed to uncover the role of XRCC1 in innate immune signaling and inflammation in GC.

methodsWe evaluated how loss of XRCC1 leads to accumulation of cytosolic DNA using immunofluorescence localization assay and measuring DNA from cytosolic extract. We applied ON-TARGETplus™ SMARTpool siRNAs to knockdown XRCC1 in gastric cell lines and examined the innate immune siganling and inflammation with and without ATM inhibitor treatment. Further, we examined Type I interferon gene expression in various gastric cancer cell lines and assessed its role in cGAS-STING signaling using RT-qPCR, RNA-Seq, and immunoblot analysis. In addition, we generated conditional knockout XRCC1 mice and characterized the innate immune signaling from stomach tissue extract using RT-qPCR, western blot. Further, the DNA damage and histological analysis was done by immunohistochemistry.

resultsIn this work, we examined the role of XRCC1 in modulating the innate immune signaling axis via cGAS/STING pathway. We find that XRCC1 deficient gastric cancer cell lines and mouse stomach tissue shows activation of cGAS/STING signaling. Further, ATM inhibition enhances robust cGAS/STING mediate innate immune signaling and PD-L1 expression in XRCC1 deficient gastric cancer cells.

conclusionsResults from this work demonstrate that XRCC1 is essential to maintain innate immune homeostasis. Further, this work suggest that ATM inhibitors may provide a potential therapeutic strategy to enhance the PD-L1 expression that could increase the efficacy of an immune checkpoint blockade (ICB) in XRCC1 deficient or low expressing GC.

Indexed as

Immunity, InnateMembrane ProteinsNucleotidyltransferasesStomach NeoplasmsX-ray Repair Cross Complementing Protein 1AnimalsAtaxia Telangiectasia Mutated ProteinsCell Line, TumorcGAS-STING Signaling PathwayCyclic Guanosine Monophosphate-Adenosine Monophosphate SynthaseHumansMiceMice, KnockoutSignal TransductionSTING ProteinAtaxia Telangiectasia Mutated ProteinscGAS protein, humancGAS protein, mouseCyclic Guanosine Monophosphate-Adenosine Monophosphate SynthaseMembrane ProteinsNucleotidyltransferasesSTING1 protein, humanSTING ProteinX-ray Repair Cross Complementing Protein 1XRCC1 protein, humanXrcc1 protein, mouseGastric cancerInnate immunityXRCC1

Identifiers

PMID41654792
PMCPMC13040979

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.