Activation of Laminin γ2 by Helicobacter pylori Promotes Invasion and Survival of Gastric Cancer Cells With E-Cadherin Defects

Helicobacter pylori infection induces cellular phenotypes relevant for cancer progression, namely cell motility and invasion. We hypothesized that the extracellular matrix (ECM) could be involved in these deleterious effects. Microarrays were used to uncover ECM interactors in cells infected with H....

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Veröffentlicht in:	The Journal of infectious diseases 2022-12, Vol.226 (12), p.2226-2237
Hauptverfasser:	Ferreira, Rui M, Figueiredo, Joana, Pinto-Ribeiro, Ines, Gullo, Irene, Sgouras, Dionyssios N, Carreto, Laura, Castro, Patricia, Santos, Manuel A, Carneiro, Fatima, Seruca, Raquel, Figueiredo, Ceu
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Sprache:	eng
Schlagworte:	Antigens, Bacterial - genetics Bacterial Proteins - genetics Bacterial Proteins - metabolism Cadherins - metabolism Cell Line, Tumor Helicobacter Infections - microbiology Helicobacter pylori - genetics Humans Laminin - metabolism Stomach Neoplasms
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creator	Ferreira, Rui M Figueiredo, Joana Pinto-Ribeiro, Ines Gullo, Irene Sgouras, Dionyssios N Carreto, Laura Castro, Patricia Santos, Manuel A Carneiro, Fatima Seruca, Raquel Figueiredo, Ceu
description	Helicobacter pylori infection induces cellular phenotypes relevant for cancer progression, namely cell motility and invasion. We hypothesized that the extracellular matrix (ECM) could be involved in these deleterious effects. Microarrays were used to uncover ECM interactors in cells infected with H. pylori. LAMC2, encoding laminin γ2, was selected as a candidate gene and its expression was assessed in vitro and in vivo. The role of LAMC2 was investigated by small interference RNA (siRNA) combined with a set of functional assays. Laminin γ2 and E-cadherin expression patterns were evaluated in gastric cancer cases. Laminin γ2 was found significantly overexpressed in gastric cancer cells infected with H. pylori. This finding was validated in vitro by infection with clinical isolates and in vivo by using gastric biopsies of infected and noninfected individuals. We showed that laminin γ2 overexpression is dependent on the bacterial type IV secretion system and on the CagA. Functionally, laminin γ2 promotes cell invasion and resistance to apoptosis, through modulation of Src, JNK, and AKT activity. These effects were abrogated in cells with functional E-cadherin. These data highlight laminin γ2 and its downstream effectors as potential therapeutic targets, and the value of H. pylori eradication to delay gastric cancer onset and progression.
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We hypothesized that the extracellular matrix (ECM) could be involved in these deleterious effects. Microarrays were used to uncover ECM interactors in cells infected with H. pylori. LAMC2, encoding laminin γ2, was selected as a candidate gene and its expression was assessed in vitro and in vivo. The role of LAMC2 was investigated by small interference RNA (siRNA) combined with a set of functional assays. Laminin γ2 and E-cadherin expression patterns were evaluated in gastric cancer cases. Laminin γ2 was found significantly overexpressed in gastric cancer cells infected with H. pylori. This finding was validated in vitro by infection with clinical isolates and in vivo by using gastric biopsies of infected and noninfected individuals. We showed that laminin γ2 overexpression is dependent on the bacterial type IV secretion system and on the CagA. Functionally, laminin γ2 promotes cell invasion and resistance to apoptosis, through modulation of Src, JNK, and AKT activity. These effects were abrogated in cells with functional E-cadherin. These data highlight laminin γ2 and its downstream effectors as potential therapeutic targets, and the value of H. pylori eradication to delay gastric cancer onset and progression.</description><identifier>ISSN: 0022-1899</identifier><identifier>EISSN: 1537-6613</identifier><identifier>DOI: 10.1093/infdis/jiac397</identifier><identifier>PMID: 36173814</identifier><language>eng</language><publisher>United States</publisher><subject>Antigens, Bacterial - genetics ; Bacterial Proteins - genetics ; Bacterial Proteins - metabolism ; Cadherins - metabolism ; Cell Line, Tumor ; Helicobacter Infections - microbiology ; Helicobacter pylori - genetics ; Humans ; Laminin - metabolism ; Stomach Neoplasms</subject><ispartof>The Journal of infectious diseases, 2022-12, Vol.226 (12), p.2226-2237</ispartof><rights>The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. 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subjects	Antigens, Bacterial - genetics Bacterial Proteins - genetics Bacterial Proteins - metabolism Cadherins - metabolism Cell Line, Tumor Helicobacter Infections - microbiology Helicobacter pylori - genetics Humans Laminin - metabolism Stomach Neoplasms
title	Activation of Laminin γ2 by Helicobacter pylori Promotes Invasion and Survival of Gastric Cancer Cells With E-Cadherin Defects
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