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Helicobacter pylori-induced RASAL2 Through Activation of Nuclear Factor-κB Promotes Gastric Tumorigenesis via β-catenin Signaling Axis.


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.

SUBMITTER: Cao L 

PROVIDER: S-EPMC9038683 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Publications

Helicobacter pylori-induced RASAL2 Through Activation of Nuclear Factor-κB Promotes Gastric Tumorigenesis via β-catenin Signaling Axis.

Cao Longlong L   Zhu Shoumin S   Lu Heng H   Soutto Mohammed M   Bhat Nadeem N   Chen Zheng Z   Peng Dunfa D   Lin Jianxian J   Lu Jun J   Li Ping P   Zheng Chaohui C   Huang Changming C   El-Rifai Wael W  

Gastroenterology 20220205 6


<h4>Background & aims</h4>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.<h4>Methods</h4>Bioinformatics analyses of local and public databases were applied to analyze RASAL2 expression, signaling pathways, and clinical significance. In vitro cell culture, spheroids, pati  ...[more]

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