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Helicobacter pylori CagA Protein Regulating the Biological Characteristics of Gastric Cancer through the miR-155-5p/SMAD2/SP1 axis.

ABSTRACT: Helicobacter pylori (Hp) is a grade Ι carcinogen of gastric cancer (GC), and its high infection rate seriously affects human health. Cytotoxin-associated gene A (CagA) plays a key role in the carcinogenesis of Hp as one of its main virulence factors. miR-155-5p is abnormally expressed in patients with GC, associated with the occurrence and development of cancer. However, little is known about the association between CagA and miR-155-5p. (1) Background: This study explored the association and mechanism of CagA and miR-155-5p in GC. (2) Methods: The CagA sequence was obtained from the NCBI. After sequence optimization, it was connected to the pcDNA3.1 vector to construct a CagA eukaryotic expression plasmid (pcDNA-CagA). Quantitative real-time polymerase chain reaction (qRT-PCR) was used to investigate the expression of miR-155-5p and CagA in GC cells. The function of CagA on GC cells was detected by CCK8, wound healing, and Transwell assays. Similarly, the function of miR-155-5p was also studied through the above functional experiments after the miR-155-5p overexpression and knockdown models had successfully been constructed. The associations among CagA, miR-155-5p, and SMAD2/SP1 were evaluated using RNA immunoprecipitation (RIP) and rescue experiments. (3) Results: The expression of miR-155-5p was significantly reduced in GC cells, and the expression of miR-155-5p was further reduced after CagA induction. Both overexpressed CagA and knockdown miR-155-5p cell models enhanced malignant transformation, whereas overexpressed miR-155-5p inhibited malignant transformation in vitro. The function of miR-155-5p on GC cells could be influenced by CagA. We also found that the influence of miR-155-5p on SMAD2 and SP1 could be regulated by CagA. (4) Conclusions: CagA potentially regulates the biological function of GC cells through the miR-155-5p/SMAD2/SP1 axis. miR-155-5p could be a therapeutic target for GC related to CagA.

SUBMITTER: Wu L

PROVIDER: S-EPMC9414533 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Helicobacter pylori CagA Protein Regulating the Biological Characteristics of Gastric Cancer through the miR-155-5p/SMAD2/SP1 axis.

Wu Leilei L Jiang Fei F Shen Xiaobing X

Pathogens (Basel, Switzerland) 20220728 8

Helicobacter pylori (Hp) is a grade Ι carcinogen of gastric cancer (GC), and its high infection rate seriously affects human health. Cytotoxin-associated gene A (CagA) plays a key role in the carcinogenesis of Hp as one of its main virulence factors. miR-155-5p is abnormally expressed in patients with GC, associated with the occurrence and development of cancer. However, little is known about the association between CagA and miR-155-5p. (1) Background: This stu ...[more]

PMID: 36014967

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Project description:BackgroundAs a marker of Helicobacter pylori, Cytotoxin-associated gene A (cagA) has been revealed to be the major virulence factor causing gastroduodenal diseases. However, the molecular mechanisms that underlie the development of different gastroduodenal diseases caused by cagA-positive H. pylori infection remain unknown. Current studies are limited to the evaluation of the correlation between diseases and the number of Glu-Pro-Ile-Tyr-Ala (EPIYA) motifs in the CagA strain. To further understand the relationship between CagA sequence and its virulence to gastric cancer, we proposed a systematic entropy-based approach to identify the cancer-related residues in the intervening regions of CagA and employed a supervised machine learning method for cancer and non-cancer cases classification.MethodologyAn entropy-based calculation was used to detect key residues of CagA intervening sequences as the gastric cancer biomarker. For each residue, both combinatorial entropy and background entropy were calculated, and the entropy difference was used as the criterion for feature residue selection. The feature values were then fed into Support Vector Machines (SVM) with the Radial Basis Function (RBF) kernel, and two parameters were tuned to obtain the optimal F value by using grid search. Two other popular sequence classification methods, the BLAST and HMMER, were also applied to the same data for comparison.ConclusionOur method achieved 76% and 71% classification accuracy for Western and East Asian subtypes, respectively, which performed significantly better than BLAST and HMMER. This research indicates that small variations of amino acids in those important residues might lead to the virulence variance of CagA strains resulting in different gastroduodenal diseases. This study provides not only a useful tool to predict the correlation between the novel CagA strain and diseases, but also a general new framework for detecting biological sequence biomarkers in population studies.

Dataset Information

Helicobacter pylori CagA Protein Regulating the Biological Characteristics of Gastric Cancer through the miR-155-5p/SMAD2/SP1 axis.

Publications

<i>Helicobacter pylori</i> CagA Protein Regulating the Biological Characteristics of Gastric Cancer through the <i>miR-155-5p</i>/SMAD2/SP1 axis.

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