H. pylori infection alters repair of DNA double-strand breaks via SNHG17
Taotao Han, Xiaohui Jing, Jiayu Bao, Lianmei Zhao, Aidong Zhang, Renling Miao, Hui Guo, Baoguo Zhou, Shang Zhang, Jiazeng Sun, Juan Shi
Taotao Han, Xiaohui Jing, Jiayu Bao, Lianmei Zhao, Aidong Zhang, Renling Miao, Hui Guo, Baoguo Zhou, Shang Zhang, Jiazeng Sun, Juan Shi
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Research Article Gastroenterology Oncology

H. pylori infection alters repair of DNA double-strand breaks via SNHG17

Abstract

Chronic infections can lead to carcinogenesis through inflammation-related mechanisms. Chronic infection of the human gastric mucosa with Helicobacter pylori is a well-known risk factor for gastric cancer. However, the mechanisms underlying H. pylori–induced gastric carcinogenesis are incompletely defined. We aimed to screen and clarify the functions of long noncoding RNAs (lncRNAs) that are differentially expressed in H. pylori–related gastric cancer. We found that lncRNA SNHG17 was upregulated by H. pylori infection and markedly increased the levels of double-strand breaks (DSBs). SNHG17 overexpression correlated with poor overall survival in patients with gastric cancer. The recruitment of NONO by overabundant nuclear SNHG17, along with the role of cytoplasmic SNHG17 as a decoy for miR-3909, which regulates Rad51 expression, shifted the DSB repair balance from homologous recombination toward nonhomologous end joining. Notably, during chronic H. pylori infection, SNHG17 knockdown inhibited chromosomal aberrations. Our findings suggest that spatially independent deregulation of the SNHG17/NONO and SNHG17/miR-3909/RING1/Rad51 pathways upon H. pylori infection promotes tumorigenesis in gastric cancer by altering the DNA repair system, which is critical for the maintenance of genomic stability. Upregulation of SNHG17 by H. pylori infection might be an undefined link between cancer and inflammation.

Authors

Taotao Han, Xiaohui Jing, Jiayu Bao, Lianmei Zhao, Aidong Zhang, Renling Miao, Hui Guo, Baoguo Zhou, Shang Zhang, Jiazeng Sun, Juan Shi

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Figure 3

SNHG17 expression was increased by H. pylori infection.

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SNHG17 expression was increased by H. pylori infection. (A) qRT-PCR ana...
(A) qRT-PCR analysis of SNHG17 expression in GES-1 (top) and SGC-7901 (bottom) infected with H. pylori for the indicated times with MOI 100:1 or for indicated MOIs with 6 hours. (B) qRT-PCR analysis of SNHG17 expression in GES-1 cells infected with “dead” H. pylori for 24 hours. Ctrl, control. (C) SGC-7901 cells were infected with H. pylori for 6 hours, after which bacteria were eradicated by antibiotic therapy and cells were allowed to recover for 24 hours. Then, qRT-PCR analysis of SNHG17 expression was performed. ET, eradication therapy. (D) RT-PCR analysis of SNHG17 expression in GES-1 cells infected with ΔcagA H. pylori for 24 hours. (E) CagA overexpression plasmid transfection into GES-1 cells induced increasing SNHG17 expression. (F) Fluorescence ISH of GES-1 cells performed using a Cy3-labeled SNHG17 probe (red). Nuclei were counterstained using DAPI (blue). Scale bars: 10 μm. Samples were assayed 3 times. (G) qRT-PCR analysis of SNHG17 expression in cytoplasmic (Cyto) and nuclear (Nuc) fractions of RNA in GES-1 cells infected with H. pylori. (H) Luciferase (LUC) activity in 293T cells transfected with the reporter construct as indicated. Mut, mutated. (I) ChIP-PCR analysis of p65-binding activity on the predicted sites in GES-1 cells infected with H. pylori. Data are represented as mean ± SEM. *P < 0.05; **P < 0.01, ANOVA (A–E and I); 2-tailed Student’s t test (H).