RRC ID 74474
Author Cao L, Zhu S, Lu H, Soutto M, Bhat N, Chen Z, Peng D, Lin J, Lu J, Li P, Zheng C, Huang C, El-Rifai W.
Title Helicobacter pylori-induced RASAL2 Through Activation of Nuclear Factor-κB Promotes Gastric Tumorigenesis via β-catenin Signaling Axis.
Journal Gastroenterology
Abstract BACKGROUND & AIMS:Helicobacter pylori infection is the predominant risk factor for gastric cancer. RAS protein activator like 2 (RASAL2) is considered a double-edged sword in carcinogenesis. Herein, we investigated the role of RASAL2 in response to H pylori infection and gastric tumorigenesis.
METHODS:Bioinformatics analyses of local and public databases were applied to analyze RASAL2 expression, signaling pathways, and clinical significance. In vitro cell culture, spheroids, patient-derived organoids, and in vivo mouse models were used. Molecular assays included chromatin immunoprecipitation, co-immunoprecipitation, Western blotting, quantitative polymerase chain reaction, and immunocyto/histochemistry.
RESULTS:H pylori infection induced RASAL2 expression via a nuclear factor-κB (NF-κB)-dependent mechanism whereby NF-κB was directly bound to the RASAL2 promoter activating its transcription. By gene silencing and ectopic overexpression, we found that RASAL2 upregulated β-catenin transcriptional activity. RASAL2 inhibited protein phosphatase 2A activity through direct binding with subsequent activation of the AKT/β-catenin signaling axis. Functionally, RASAL2 silencing decreased nuclear β-catenin levels and impaired tumor spheroids and organoids formation. Furthermore, the depletion of RASAL2 impaired tumor growth in gastric tumor xenograft mouse models. Clinicopathological analysis indicated that abnormal overexpression of RASAL2 correlated with poor prognosis and chemoresistance in human gastric tumors.
CONCLUSIONS:These studies uncovered a novel signaling axis of NF-κB/RASAL2/β-catenin, providing a novel link between infection, inflammation and gastric tumorigenesis.
Volume 162(6)
Pages 1716-1731.e17
Published 2022-5-1
DOI 10.1053/j.gastro.2022.01.046
PII S0016-5085(22)00101-9
PMID 35134322
PMC PMC9038683
MeSH Animals Carcinogenesis / pathology Cell Line, Tumor Cell Transformation, Neoplastic / pathology GTPase-Activating Proteins / metabolism Gastric Mucosa / pathology Helicobacter Infections* / genetics Helicobacter pylori* / metabolism Humans Mice NF-kappa B / metabolism Stomach Neoplasms* / genetics Stomach Neoplasms* / metabolism beta Catenin / metabolism
IF 17.373
Human and Animal Cells MKN28(RCB1000) MKN45(RCB1001)