Downregulation of tumor suppressor RACK1 by Helicobacter pylori infection promotes gastric carcinogenesis through the integrin β-1/NF-κB signaling pathway

Hu, Yi; Liu, Jianping; Li, Xue-Yang; Cai, Yan; He, Cong; Li, Nianshuang; Xie, Chuan; Xiong, Zhijuan; Ge, Zhongming; Lü, Nonghua; Zhu, Yin

doi:10.1016/j.canlet.2019.02.039

Cited by 29 publications

(26 citation statements)

References 35 publications

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“…1B) of the 179 overlapping proteins showed that integrin signaling pathway (including ITGB3 and its related factors such as ILK, ACTN1, PIK3C2A, MAPK3 and FYN) is one of the most enriched pathways. As strong evidence has demonstrated that RACK1 could interact with a number of integrins during various physiological processes and pathogenesis (19, 24, 31, 38), ITGB3 was therefore chosen for the following studies. The mRNA and amino acids sequences of ITGB3 from eighteen species were downloaded for phylogenetic analysis using online tool Clustal Omega (https://www.ebi.ac.uk/Tools/msa/clustalo/) with the default parameters (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

“…RACK1, a 36-kDa protein comprising of seven WD-40 repeats, is well known as a scaffolder protein (21) and plays its unique functions in various cancers (22–24) and infections (24–28). RACK1 serves as an adaptor molecule for the binding of key signaling molecules (19, 22–24, 29–31),with elaborate involvement in the regulation of multiple signal pathways (24, 30, 32). RACK1 is reported to interact with β integrins to stabilize the focal adhesion through cell-ECM interaction with the entanglement of integrin-induced FAK autophosphoryation (19, 31, 33).…”

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confidence: 99%

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Integrin β3, a RACK1 interacting protein, is required for porcine reproductive and respiratory syndrome virus infection and NF-κB activation in Marc-145 cells

Yang

Lan

Wang

et al. 2020

Preprint

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22Word count for the Abstract: 219 words. 23Word count for the Importance: 149 words. 24Word count for the main text: 3461 words 25 ABSTRACT Porcine reproductive and respiratory syndrome virus (PRRSV) is the pathogen 26 of porcine reproductive and respiratory syndrome (PRRS), which is one of the most 27 economically harmful diseases in modern pig production worldwide. Receptor of activated 28 protein C kinase 1 (RACK1) was previously shown to be indispensable for the PRRSV 29 replication and NF-κB activation in Marc-145 cells. Here we identified a membrane protein, 30 integrin β3 (ITGB3) , as a RACK1-interacting protein. PRRSV infection in Marc-145 cells 31 upregulated the ITGB3 expression. Abrogation of ITGB3 by siRNA knockdown or antibody 32 blocking inhibited PRRSV infection and NF-κB activation, while on the other hand, 33 overexpression of ITGB3 enhanced PRRSV infection and NF-κB activation. Furthermore, 34inhibition of ITGB3 alleviated the cytopathic effects and reduced the TCID 50 titer in Marc-35 145 cells. We also showed that RACK1 and ITGB3 were NF-κB target genes during PRRSV 36 infection, and that they regulate each other. Our data indicate that ITGB3, presumably as a co-37 receptor, plays an imperative role for PRRSV infection and NF-κB activation in Marc-145 38 cells. PRRSV infection activates a positive feedback loop involving the activation of NF-κB 39 and upregulation of ITGB3 and RACK1 in Marc-145 cells. The findings would advance our 40 elaborated understanding of the molecular host-pathogen interaction mechanisms underlying 41 PRRSV infection in swine and suggest ITGB3 and NF-κB signaling pathway as potential 42 therapeutic targets for PRRS control. 43 44 IMPORTANCE Porcine reproductive and respiratory syndrome virus (PRRSV) is one of 45 the pathogens in pig production worldwide. Several cell surface receptors, such as heparan 46sulphate, sialoadhesin, vimentin and CD163, were identified to be involved in PRRSV 47 infection and NF-κB activation in Marc-145 cells, presumably as a co-receptor of CD136 or 51 vimentin. Both ITGB3 and RACK1 were NF-κB target genes, and they regulate each other. 52The activation of NF-κB and the transcription of its downstream genes are beneficial for 53 PRRSV infection/replication. The novel findings would advance our elaborated understanding 54 of the molecular host-pathogen interaction mechanisms underlying PRRSV infection in swine 55 and suggest ITGB3-RACK1-NF-κB axis as a potential therapeutic target for PRRS control. 56 57 KEYWORDS Integrin β3; RACK1; porcine reproductive and respiratory syndrome virus; 58 infection; NF-κB; Marc-145 cells 59 60

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Integrin β3, a RACK1 interacting protein, is required for porcine reproductive and respiratory syndrome virus infection and NF-κB activation in Marc-145 cells

Yang

Lan

Wang

et al. 2020

Preprint

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“…The authors demonstrated that H pylori upregulates TRIP12 E3 ubiquitin ligase in vitro, an effect that is mediated by the bacterial virulence factor CagA, and that TRIP12 is also upregulated in the gastric mucosa of H pylori ‐infected patients. Hu et al showed that H pylori downregulates tumor suppressor activities of RACK1. They proposed that RACK1 suppression by H pylori leads to upregulation of integrin β‐1, and to activation of the canonical NF‐κB signaling pathway, with a release of proinflammatory cytokines which can be promoters of carcinogenesis.…”

Section: Microbial Agents In Gastric Cancermentioning

confidence: 99%

Review: Gastric malignancies: Basic aspects

2019

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Gastric cancer is the third deadliest cancer in the world, and the absolute number of cases is increasing every year due to aging and growing of high‐risk populations. This disease is a consequence of the complex interaction of microbial agents, with environmental and host factors, resulting in the dysregulation of multiple oncogenic and tumor‐suppressing signaling pathways. Despite the advances in our understanding of carcinogenesis, there are still reduced therapeutic options for patients with gastric cancer. In recent years, genomic analyses of gastric tumors have emphasized their molecular heterogeneity. The distinction of gastric cancer molecular subtypes may be a key to identify novel therapeutic targets, to predict patient outcome and response to therapy, and to guide early diagnosis strategies. In this review, we summarize the most recent updates on the relationship between microbial agents and gastric cancer, in particular, Helicobacter pylori, the non‐H pylori microbiome, and Epstein‐Barr virus. We also highlight the main advances made in the past year regarding the molecular characterization of gastric cancer, especially the signatures with potential clinical utility.

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“…The signalling functions of integrins are conducted through the formation of signalling complexes at the cytoplasmic face of the plasma membrane with its cofactors, for example focal adhesion kinase (FAK) (18) and receptor of activated protein C kinase 1 (RACK1) (19,20). RACK1 , a 36-kDa protein comprising of seven WD-40 repeats, is well known as a scaffolder protein (21) and plays its unique functions in various cancers (22)(23)(24) and infections (24)(25)(26)(27)(28). RACK1 serves as an adaptor molecule for the binding of key signaling molecules (19,(22)(23)(24)(29)(30)(31),with elaborate involvement in the regulation of multiple signal pathways (24,30,32).…”

mentioning

confidence: 99%

“…RACK1 , a 36-kDa protein comprising of seven WD-40 repeats, is well known as a scaffolder protein (21) and plays its unique functions in various cancers (22)(23)(24) and infections (24)(25)(26)(27)(28). RACK1 serves as an adaptor molecule for the binding of key signaling molecules (19,(22)(23)(24)(29)(30)(31),with elaborate involvement in the regulation of multiple signal pathways (24,30,32). RACK1 is reported to interact with β integrins to stabilize the focal adhesion through cell-ECM interaction with the entanglement of integrin-induced FAK autophosphoryation (19,31,33).…”

mentioning

confidence: 99%

Integrin β3, a RACK1 interacting protein, is critical for porcine reproductive and respiratory syndrome virus infection and NF-κB activation in Marc-145 cells

et al. 2020

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show abstract

Downregulation of tumor suppressor RACK1 by Helicobacter pylori infection promotes gastric carcinogenesis through the integrin β-1/NF-κB signaling pathway

Cited by 29 publications

References 35 publications

Integrin β3, a RACK1 interacting protein, is required for porcine reproductive and respiratory syndrome virus infection and NF-κB activation in Marc-145 cells

Integrin β3, a RACK1 interacting protein, is required for porcine reproductive and respiratory syndrome virus infection and NF-κB activation in Marc-145 cells

Review: Gastric malignancies: Basic aspects

Integrin β3, a RACK1 interacting protein, is critical for porcine reproductive and respiratory syndrome virus infection and NF-κB activation in Marc-145 cells

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