Helicobacter pylori promotes gastric cancer progression by upregulating semaphorin 5A expression via ERK/MMP9 signaling

Abstract

Helicobacter pylori (H. pylori) infection is the strongest risk factor for the occurrence and development of gastric carcinoma. However, the molecular mechanism underlying H. pylori-induced pathogenesis has not yet been fully characterized. Here, we explored whether H. pylori upregulates semaphorin 5A to promote gastric cancer progression via the extracellular regulated protein kinases/matrix metalloproteinase (ERK/MMP9) signaling pathway. In this study, H. pylori upregulated semaphorin 5A expression in vitro and in vivo. Using the human gastric carcinoma cell lines SGC7901, SGC7901-siScrambled, and SGC7901-siSema 5A, our studies showed that H. pylori increased the proliferation, growth, migration, and invasiveness of gastric cancer cells via its effects on semaphorin 5A and that H. pylori increased the expression of MMP9 in gastric cancer cells via the semaphorin 5A-mediated ERK signaling pathway. Further analysis revealed that the ERK inhibitor PD98059 and MMP9 antibody (Ab) attenuated H. pylori-induced gastric cancer cell invasion and metastasis in vitro through a semaphorin 5A-dependent mechanism. In conclusion, H. pylori could promote gastric cancer progression in a semaphorin 5A-dependent manner via the ERK/MMP9 signaling pathway. Semaphorin 5A and its related signaling molecules potentially represent latent targets for H. pylori-related gastric cancer therapy. Helicobacter pylori (H. pylori) infection is the strongest risk factor for the occurrence and development of gastric carcinoma. However, the molecular mechanism underlying H. pylori-induced pathogenesis has not yet been fully characterized. Here, we explored whether H. pylori upregulates semaphorin 5A to promote gastric cancer progression via the extracellular regulated protein kinases/matrix metalloproteinase (ERK/MMP9) signaling pathway. In this study, H. pylori upregulated semaphorin 5A expression in vitro and in vivo. Using the human gastric carcinoma cell lines SGC7901, SGC7901-siScrambled, and SGC7901-siSema 5A, our studies showed that H. pylori increased the proliferation, growth, migration, and invasiveness of gastric cancer cells via its effects on semaphorin 5A and that H. pylori increased the expression of MMP9 in gastric cancer cells via the semaphorin 5A-mediated ERK signaling pathway. Further analysis revealed that the ERK inhibitor PD98059 and MMP9 antibody (Ab) attenuated H. pylori-induced gastric cancer cell invasion and metastasis in vitro through a semaphorin 5A-dependent mechanism. In conclusion, H. pylori could promote gastric cancer progression in a semaphorin 5A-dependent manner via the ERK/MMP9 signaling pathway. Semaphorin 5A and its related signaling molecules potentially represent latent targets for H. pylori-related gastric cancer therapy. IntroductionGastric cancer is one of the most common malignant tumors and seriously threatens human health. Based on global cancer statistics in 2018, an estimated 1,030,000 new stomach cancer cases were diagnosed, and 782,685 deaths occurred.1Bray F. Ferlay J. Soerjomataram I. Siegel R.L. Torre L.A. Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J. Clin. 2018; 68: 394-424Crossref PubMed Scopus (47594) Google Scholar Although great achievements have been made in gastric cancer research and clinical treatment in recent years, patients with advanced gastric cancer have a poor prognosis, with a 5-year survival rate lower than 20%.2Lazăr D.C. Avram M.F. Romoșan I. Cornianu M. Tăban S. Goldiș A. Prognostic significance of tumor immune microenvironment and immunotherapy: Novel insights and future perspectives in gastric cancer.World J. Gastroenterol. 2018; 24: 3583-3616Crossref PubMed Scopus (77) Google Scholar,3Yaprak G. Tataroglu D. Dogan B. Pekyurek M. Prognostic factors for survival in patients with gastric cancer: Single-centre experience.North. Clin. Istanb. 2019; 7: 146-152PubMed Google Scholar Therefore, the identification of risk factors is of great clinical value to understand their pathogenic effects.Helicobacter pylori (H. pylori) is an important pathogen contributing to the occurrence and progression of gastric cancer. Chronic infection with H. pylori leads to atrophic gastritis, along with the development of intestinal metaplasia, dysplasia, and gastric cancer. Therefore, H. pylori has been defined as a class I carcinogenic factor in the human stomach by the World Health Organization (WHO) since 1994.4Han F. Ren J. Zhang J. Sun Y. Ma F. Liu Z. Yu H. Jia J. Li W. JMJD2B is required for Helicobacter pylori-induced gastric carcinogenesis via regulating COX-2 expression.Oncotarget. 2016; 7: 38626-38637Crossref PubMed Scopus (25) Google Scholar, 5McClain M.S. Beckett A.C. Cover T.L. Helicobacter pylori Vacuolating Toxin and Gastric Cancer.Toxins (Basel). 2017; 9: E316Crossref PubMed Scopus (66) Google Scholar, 6Li G. Yu S. Xu J. Zhang X. Ye J. Wang Z. He Y. The prognostic role of Helicobacter pylori in gastric cancer patients: A meta-analysis.Clin. Res. Hepatol. Gastroenterol. 2019; 43: 216-224Crossref PubMed Scopus (10) Google Scholar However, the mechanism underlying the H. pylori-induced pathogenesis of gastric cancer remains to be fully elucidated.Semaphorin 5A, a class 5 semaphorin, is an integral membrane protein with seven characteristic thrombospondin-specific repeats (TSP-1). Initially, the gene was identified to play a crucial role in the guidance of growing axons to their targets during the development of the central nervous system.7Lordick F. Shitara K. Janjigian Y.Y. New agents on the horizon in gastric cancer.Ann. Oncol. 2017; 28: 1767-1775Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar, 8Nienhüser H. Schmidt T. Angiogenesis and Anti-Angiogenic Therapy in Gastric Cancer.Int. J. Mol. Sci. 2017; 19: E43Crossref PubMed Scopus (61) Google Scholar, 9Vrána D. Matzenauer M. Neoral Č. Aujeský R. Vrba R. Melichar B. Rušarová N. Bartoušková M. Jankowski J. From Tumor Immunology to Immunotherapy in Gastric and Esophageal Cancer.Int. J. Mol. Sci. 2018; 20: E13Crossref PubMed Scopus (62) Google Scholar, 10Alto L.T. Terman J.R. Semaphorins and their Signaling Mechanisms.Methods Mol. Biol. 2017; 1493: 1-25Crossref PubMed Scopus (143) Google Scholar, 11Koropouli E. Kolodkin A.L. Semaphorins and the dynamic regulation of synapse assembly, refinement, and function.Curr. Opin. Neurobiol. 2014; 27: 1-7Crossref PubMed Scopus (66) Google Scholar As shown in our previous studies, semaphorin 5A is overexpressed in gastric cancer tissue, which may be closely related to the tumorigenesis and metastasis of gastric cancer.12Pan G. Lv H. Ren H. Wang Y. Liu Y. Jiang H. Wen J. Elevated expression of semaphorin 5A in human gastric cancer and its implication in carcinogenesis.Life Sci. 2010; 86: 139-144Crossref PubMed Scopus (25) Google Scholar, 13Pan G. Zhu Z. Huang J. Yang C. Yang Y. Wang Y. Tuo X. Su G. Zhang X. Yang Z. Liu T. Semaphorin 5A promotes gastric cancer invasion/metastasis via urokinase-type plasminogen activator/phosphoinositide 3-kinase/protein kinase B.Dig. Dis. Sci. 2013; 58: 2197-2204Crossref PubMed Scopus (24) Google Scholar, 14Pan G. Zhang X. Ren J. Lu J. Li W. Fu H. Zhang S. Li J. Semaphorin 5A, an axon guidance molecule, enhances the invasion and metastasis of human gastric cancer through activation of MMP9.Pathol. Oncol. Res. 2013; 19: 11-18Crossref PubMed Scopus (25) Google Scholar In our recent study, semaphorin 5A expression was identified as a potentially important contributor to the occurrence and development of H. pylori-related gastric precancerous lesions.15Pan G. Su G. Wang Y. Xue F. Yang Y. Yang Z. Zhang Q. Liu T. Hong M. Zheng J. Effect of Helicobacter pylori on the expression of semaphorin 5A in patients with gastric precancerous lesions and its clinical significance.Int. J. Clin. Exp. Pathol. 2017; 10: 1403-1409Google Scholar However, researchers have not yet determined whether semaphorin 5A is associated with H. pylori-related gastric carcinoma. In the present study, we investigated the role of semaphorin 5A in H. pylori-induced gastric carcinogenesis and identified a novel intracellular signaling pathway involving semaphorin 5A in H. pylori-mediated pathogenesis.ResultsH. pylori Infection is related to the clinicopathological features of gastric cancerWe first observed H. pylori colonization in 200 gastric cancer samples to explore the relationship between H. pylori infection and the clinicopathological features of patients with gastric cancer. As shown in Table 1, H. pylori colonization was present in 50.5% (101/200) of gastric carcinoma specimens. An analysis of the interrelation between H. pylori infection and the clinicopathological features showed that H. pylori infection in patients with gastric cancer was not related to sex or age, while it was associated with the Lauren of and metastasis that H. pylori infection is with an advanced of gastric of H. pylori infection and clinicopathological features of gastric cancer pylori pylori of in a new Semaphorin 5A expression in gastric cancer with the H. pylori infection first investigated semaphorin 5A expression in H. gastric cancer to explore the mechanism underlying H. pylori-induced gastric The expression of the semaphorin 5A protein was in 200 human gastric cancer of gastric carcinoma showed that the of semaphorin 5A was in H. gastric cancer than in H. and Table that H. pylori infection upregulates semaphorin 5A which play a crucial role in H. pylori-induced gastric cancer 5A expression is associated with H. pylori 5A in a new Effect of H. pylori on semaphorin 5A and protein in and investigated the of H. pylori infection on semaphorin 5A expression in gastric cancer cells to semaphorin 5A in H. gastric cancer. and of with H. of the semaphorin 5A was observed in and cells whether H. pylori-mediated of semaphorin 5A the protein we semaphorin 5A expression and in H. or cells H. pylori increased of the semaphorin 5A protein in gastric cancer cell that H. pylori upregulates semaphorin 5A pylori infection upregulates semaphorin 5A expression in and cells in and cells were with H. pylori a of for and The expression of the semaphorin 5A was The semaphorin 5A protein expression was and was as an The shown in the a of pylori infection upregulates semaphorin 5A expression in an gastric H. pylori infection with H. pylori was to the relationship between semaphorin 5A expression and H. pylori The that in the infection were with H. pylori The gastric of the in the infection showed cell were not observed in the and revealed a of that the of the gastric in the infection and and were in the the of the of gastric H. pylori semaphorin 5A was in the gastric of the infection than in the that semaphorin 5A is in H. pylori infection pylori infection upregulates semaphorin 5A expression in an gastric H. pylori infection and Gastric with and The gastric of with H. pylori infection showed cell were observed in the and were to H. pylori H. pylori colonization was observed in the of the gastric semaphorin 5A was identified in the gastric of with H. pylori infection Semaphorin 5A was not observed in the gastric of the which was by The shown in the a of pylori infection the proliferation, growth, migration, and invasion of gastric cancer cells via semaphorin SGC7901-siScrambled, and SGC7901-siSema 5A cells were with H. pylori a of for was and is shown in a were for in were and with were to the of cells H. pylori infection in were and 36 The invasion of gastric cancer cells was by a invasion cells were with and were The shown in the a of ERK signaling pathway is for H. pylori-induced gastric cancer progression by semaphorin SGC7901-siScrambled, and cells were with H. pylori a of for The of H. pylori infection on the of and was and was as an The ERK inhibitor PD98059 the invasion of H. SGC7901, SGC7901-siScrambled, and cells in a semaphorin 5A-dependent The shown in the a of pylori infection enhances the of gastric cancer cells via its effects on semaphorin 5A in shown semaphorin 5A is overexpressed in gastric cancer and gastric cancer However, we have not determined whether semaphorin 5A is in H. pylori-mediated gastric cancer As shown in semaphorin 5A the H. pylori-induced in gastric cancer cell the that semaphorin 5A to a of of with H. pylori and were in vitro to the of H. pylori on the and invasion of SGC7901, SGC7901-siScrambled, and SGC7901-siSema 5A As in and semaphorin 5A in cell and invasion by H. that H. pylori enhances the of gastric cancer cells via its effects on semaphorin 5A in ERK signaling pathway is for H. pylori-induced gastric cancer progression by semaphorin semaphorin 5A promotes the invasion and of gastric cancer cells via activation of the extracellular regulated protein kinase signaling pathway. Here, we investigated whether the ERK signaling pathway was in H. pylori-induced gastric cancer progression by semaphorin we the of H. pylori on the of in SGC7901, SGC7901-siScrambled, and SGC7901-siSema 5A cells with H. pylori for As shown in 5A, the of in H. and cells was than that in SGC7901-siSema 5A the of the were not we a invasion to whether an ERK inhibitor gastric cancer cell invasion by H. SGC7901, SGC7901-siScrambled, and SGC7901-siSema 5A cells were with H. pylori in the or of the ERK inhibitor As in the ERK inhibitor PD98059 the invasion of H. The of PD98059 on the of and cells were than of SGC7901-siSema 5A the ERK signaling pathway may be for H. pylori-induced gastric cancer progression through a semaphorin 5A-dependent was in H. pylori-induced gastric cancer progression by semaphorin of metalloproteinase in tumors associated with cancer cell invasiveness and in and (Basel). 2014; PubMed Scopus Google Scholar Here, we explored whether MMP9 was in H. pylori-induced gastric cancer progression by semaphorin the effects of H. pylori on the expression of MMP9 were in SGC7901, SGC7901-siScrambled, and SGC7901-siSema 5A cells a with H. pylori for As shown in the of MMP9 expression in and cells was than that in SGC7901-siSema 5A we an invasion to the of an MMP9 antibody (Ab) on the invasion of SGC7901, SGC7901-siScrambled, and SGC7901-siSema 5A As in treatment with the MMP9 the H. pylori-induced of The by the MMP9 in and cells were than in SGC7901-siSema 5A our that MMP9 is in H. pylori-induced gastric cancer progression by semaphorin is in H. pylori-induced gastric cancer progression by semaphorin SGC7901-siScrambled, and cells were with H. pylori a of for H. pylori upregulated the expression of the MMP9 protein in gastric cancer An invasion MMP9 SGC7901, SGC7901-siScrambled, and cells was to the of the MMP9 on the invasion of cells were with and The shown in the a of pylori infection MMP9 expression via the semaphorin 5A-mediated activation of the ERK signaling to our previous study, semaphorin 5A upregulates MMP9 expression in gastric cancer cells by the ERK signaling pathway. whether activation of MMP9 by H. pylori infection was on semaphorin 5A-mediated ERK SGC7901, SGC7901-siScrambled, and SGC7901-siSema 5A cells were with H. pylori in the or of the ERK inhibitor PD98059 to whether the of MMP9 expression by H. pylori infection on semaphorin 5A-mediated activation of ERK As shown in PD98059 of the MMP9 protein and in gastric cancer cells with H. were in and cells than in SGC7901-siSema 5A Based on H. pylori increased the expression of MMP9 by semaphorin 5A expression and the activation of the ERK signaling pylori infection MMP9 expression via the ERK signaling pathway in a semaphorin 5A-dependent SGC7901-siScrambled, and SGC7901-siSema 5A cells were with H. pylori in the or of the ERK inhibitor MMP9 expression the and protein was and shown in the a of and semaphorin 5A expression in gastric cancer with H. pylori gastric cancer and the expression of MMP9 and semaphorin 5A protein to whether in samples were H. pylori and the were H. pylori As shown in the of semaphorin 5A and MMP9 was in H. samples than in H. for MMP9 and semaphorin 5A in gastric cancer of semaphorin 5A and MMP9 expression was increased in H. and with H. and shown in the a of pylori is one of the factors contributing to the occurrence and development of gastric carcinoma. In our study, H. pylori infection was associated with the progression of gastric cancer in and the and invasion of gastric cancer cells in Although a of studies have been to H. pylori pathogenesis and the molecular mechanism remains In the present study, we the first that H. pylori promotes the invasion and metastasis of gastric cancer by semaphorin 5A expression via the ERK/MMP9 signaling 5A, a protein with seven characteristic thrombospondin-specific repeats to the development of the central nervous D. Matzenauer M. Neoral Č. Aujeský R. Vrba R. Melichar B. Rušarová N. Bartoušková M. Jankowski J. From Tumor Immunology to Immunotherapy in Gastric and Esophageal Cancer.Int. J. Mol. Sci. 2018; 20: E13Crossref PubMed Scopus (62) Google Scholar In our previous studies, we that semaphorin 5A a crucial role in the development and progression of gastric and that H. pylori infection upregulates semaphorin 5A expression in gastric precancerous lesions and gastric G. Lv H. Ren H. Wang Y. Liu Y. Jiang H. Wen J. Elevated expression of semaphorin 5A in human gastric cancer and its implication in carcinogenesis.Life Sci. 2010; 86: 139-144Crossref PubMed Scopus (25) Google Scholar, 13Pan G. Zhu Z. Huang J. Yang C. Yang Y. Wang Y. Tuo X. Su G. Zhang X. Yang Z. Liu T. Semaphorin 5A promotes gastric cancer invasion/metastasis via urokinase-type plasminogen activator/phosphoinositide 3-kinase/protein kinase B.Dig. Dis. Sci. 2013; 58: 2197-2204Crossref PubMed Scopus (24) Google Scholar, 14Pan G. Zhang X. Ren J. Lu J. Li W. Fu H. Zhang S. Li J. Semaphorin 5A, an axon guidance molecule, enhances the invasion and metastasis of human gastric cancer through activation of MMP9.Pathol. Oncol. Res. 2013; 19: 11-18Crossref PubMed Scopus (25) Google Scholar, G. Su G. Wang Y. Xue F. Yang Y. Yang Z. Zhang Q. Liu T. Hong M. Zheng J. Effect of Helicobacter pylori on the expression of semaphorin 5A in patients with gastric precancerous lesions and its clinical significance.Int. J. Clin. Exp. Pathol. 2017; 10: 1403-1409Google Scholar However, we not yet whether semaphorin 5A is in H. pylori-related gastric this study, we the of H. pylori infection on semaphorin 5A expression in gastric cancer and gastric cancer semaphorin 5A expression was in H. gastric cancer than in H. gastric cancer and H. pylori infection increased the of the semaphorin 5A and protein in gastric cancer cells in a In we a with H. pylori and observed semaphorin 5A expression in the gastric of the H. pylori infection than in the that semaphorin 5A expression is in H. pylori that semaphorin 5A activation may be in H. pylori However, the mechanism underlying the of semaphorin 5A in H. pylori-mediated gastric cancer progression remains to be the present study, we in vitro gastric cancer cells with H. which may to the carcinogenic of semaphorin 5A attenuated the H. pylori-induced proliferation, growth, and of gastric cancer that semaphorin 5A may play an important role in the development and progression of H. pylori-related gastric cancer. However, the by is for tumor cell invasion and In this study, H. pylori MMP9 expression in SGC7901, SGC7901-siScrambled, and SGC7901-siSema 5A In the in vitro showed that the of MMP9 with an antibody the of H. pylori on the invasion of SGC7901, SGC7901-siScrambled, and SGC7901-siSema 5A Therefore, MMP9 was in H. pylori-induced gastric cancer progression by semaphorin ERK signaling pathway has been shown to be an important of tumor cell invasion and E. E. J. C. ERK is a of in Cancer.Int. J. Mol. Sci. 2019; 20: PubMed Scopus Google Wang Z. Signaling (Basel). 2017; 9: PubMed Scopus Google Scholar Therefore, we whether the ERK signaling pathway was for H. pylori-mediated gastric cancer Using the human gastric cancer cell lines SGC7901, SGC7901-siScrambled, and SGC7901-siSema 5A, we that H. pylori increased the of PD98059 the of H. pylori to MMP9 migration, and with the gastric cancer MMP9 expression with semaphorin 5A expression in gastric cancer H. pylori promotes the and invasion of gastric cancer by semaphorin 5A expression via the ERK/MMP9 signaling the of our this is the first to the of semaphorin 5A and its molecular mechanism in H. pylori-mediated gastric cancer which not a novel of semaphorin 5A the nervous our of semaphorin H. pylori is to be an important contributing factor to the development of gastric cancer. Therefore, this may for the and treatment for gastric and gastric cancer were patients with gastric cancer between and the of the The patients were by a and not and tumor for the of their for clinical which was by our The was on the by the the were to be H. by and human gastric cancer cell lines SGC7901, and SGC7901-siScrambled, which was with the semaphorin 5A, and SGC7901-siSema 5A, which was with semaphorin 5A G. Lv H. Ren H. Wang Y. Liu Y. Jiang H. Wen J. Elevated expression of semaphorin 5A in human gastric cancer and its implication in carcinogenesis.Life Sci. 2010; 86: 139-144Crossref PubMed Scopus (25) Google Scholar were in with and in a of and pylori and infection of gastric cancer pylori were on and H. pylori were and in The H. pylori were by the and H. pylori was with SGC7901, SGC7901-siScrambled, and SGC7901-siSema 5A cells a of for to or in the gastric samples were which were and to were with a antibody semaphorin 5A by a antibody Semaphorin 5A expression was determined by the of tumor cells with a The of cells with expression was determined by the of cells in in the with a of cells and 5 The was cell membrane and cell membrane and cell membrane and and cell membrane and The were to a Semaphorin 5A expression were and of a with H. were in this the infection and the The infection 5 H. pylori for The of on the were and gastric in the were for semaphorin 5A A and were to H. pylori infection in the The was by our and was samples was to the The were for semaphorin and semaphorin and and and was for 5 by of for for and for with a as a The were for semaphorin semaphorin and and The expression of the was to the expression of the cells were in of protein were by and to which were with and with semaphorin 5A, and for with with the were with a by as an and cells were in of and for and the was to the and for an in a cell 200 of was to The was on a for and were a a of to cell the cells were in of with H. cells were with and with were a and were was to gastric cancer cell A of of cell were on a with cells than were a and was by the with were and 36 cells were in with to The in the while the in the lower In inhibitor and were to the for in a the cells that through the were with and with was determined by the cells that the a as the The were The analysis was and was IntroductionGastric cancer is one of the most common malignant tumors and seriously threatens human health. Based on global cancer statistics in 2018, an estimated 1,030,000 new stomach cancer cases were diagnosed, and 782,685 deaths occurred.1Bray F. Ferlay J. Soerjomataram I. Siegel R.L. Torre L.A. Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J. Clin. 2018; 68: 394-424Crossref PubMed Scopus (47594) Google Scholar Although great achievements have been made in gastric cancer research and clinical treatment in recent years, patients with advanced gastric cancer have a poor prognosis, with a 5-year survival rate lower than 20%.2Lazăr D.C. Avram M.F. Romoșan I. Cornianu M. Tăban S. Goldiș A. Prognostic significance of tumor immune microenvironment and immunotherapy: Novel insights and future perspectives in gastric cancer.World J. Gastroenterol. 2018; 24: 3583-3616Crossref PubMed Scopus (77) Google Scholar,3Yaprak G. Tataroglu D. Dogan B. Pekyurek M. Prognostic factors for survival in patients with gastric cancer: Single-centre experience.North. Clin. Istanb. 2019; 7: 146-152PubMed Google Scholar Therefore, the identification of risk factors is of great clinical value to understand their pathogenic effects.Helicobacter pylori (H. pylori) is an important pathogen contributing to the occurrence and progression of gastric cancer. Chronic infection with H. pylori leads to atrophic gastritis, along with the development of intestinal metaplasia, dysplasia, and gastric cancer. Therefore, H. pylori has been defined as a class I carcinogenic factor in the human stomach by the World Health Organization (WHO) since 1994.4Han F. Ren J. Zhang J. Sun Y. Ma F. Liu Z. Yu H. Jia J. Li W. JMJD2B is required for Helicobacter pylori-induced gastric carcinogenesis via regulating COX-2 expression.Oncotarget. 2016; 7: 38626-38637Crossref PubMed Scopus (25) Google Scholar, 5McClain M.S. Beckett A.C. Cover T.L. Helicobacter pylori Vacuolating Toxin and Gastric Cancer.Toxins (Basel). 2017; 9: E316Crossref PubMed Scopus (66) Google Scholar, 6Li G. Yu S. Xu J. Zhang X. Ye J. Wang Z. He Y. The prognostic role of Helicobacter pylori in gastric cancer patients: A meta-analysis.Clin. Res. Hepatol. Gastroenterol. 2019; 43: 216-224Crossref PubMed Scopus (10) Google Scholar However, the mechanism underlying the H. pylori-induced pathogenesis of gastric cancer remains to be fully elucidated.Semaphorin 5A, a class 5 semaphorin, is an integral membrane protein with seven characteristic thrombospondin-specific repeats (TSP-1). Initially, the gene was identified to play a crucial role in the guidance of growing axons to their targets during the development of the central nervous system.7Lordick F. Shitara K. Janjigian Y.Y. New agents on the horizon in gastric cancer.Ann. Oncol. 2017; 28: 1767-1775Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar, 8Nienhüser H. Schmidt T. Angiogenesis and Anti-Angiogenic Therapy in Gastric Cancer.Int. J. Mol. Sci. 2017; 19: E43Crossref PubMed Scopus (61) Google Scholar, 9Vrána D. Matzenauer M. Neoral Č. Aujeský R. Vrba R. Melichar B. Rušarová N. Bartoušková M. Jankowski J. From Tumor Immunology to Immunotherapy in Gastric and Esophageal Cancer.Int. J. Mol. Sci. 2018; 20: E13Crossref PubMed Scopus (62) Google Scholar, 10Alto L.T. Terman J.R. Semaphorins and their Signaling Mechanisms.Methods Mol. Biol. 2017; 1493: 1-25Crossref PubMed Scopus (143) Google Scholar, 11Koropouli E. Kolodkin A.L. Semaphorins and the dynamic regulation of synapse assembly, refinement, and function.Curr. Opin. Neurobiol. 2014; 27: 1-7Crossref PubMed Scopus (66) Google Scholar As shown in our previous studies, semaphorin 5A is overexpressed in gastric cancer tissue, which may be closely related to the tumorigenesis and metastasis of gastric cancer.12Pan G. Lv H. Ren H. Wang Y. Liu Y. Jiang H. Wen J. Elevated expression of semaphorin 5A in human gastric cancer and its implication in carcinogenesis.Life Sci. 2010; 86: 139-144Crossref PubMed Scopus (25) Google Scholar, 13Pan G. Zhu Z. Huang J. Yang C. Yang Y. Wang Y. Tuo X. Su G. Zhang X. Yang Z. Liu T. Semaphorin 5A promotes gastric cancer invasion/metastasis via urokinase-type plasminogen activator/phosphoinositide 3-kinase/protein kinase B.Dig. Dis. Sci. 2013; 58: 2197-2204Crossref PubMed Scopus (24) Google Scholar, 14Pan G. Zhang X. Ren J. Lu J. Li W. Fu H. Zhang S. Li J. Semaphorin 5A, an axon guidance molecule, enhances the invasion and metastasis of human gastric cancer through activation of MMP9.Pathol. Oncol. Res. 2013; 19: 11-18Crossref PubMed Scopus (25) Google Scholar In our recent study, semaphorin 5A expression was identified as a potentially important contributor to the occurrence and development of H. pylori-related gastric precancerous lesions.15Pan G. Su G. Wang Y. Xue F. Yang Y. Yang Z. Zhang Q. Liu T. Hong M. Zheng J. Effect of Helicobacter pylori on the expression of semaphorin 5A in patients with gastric precancerous lesions and its clinical significance.Int. J. Clin. Exp. Pathol. 2017; 10: 1403-1409Google Scholar However, researchers have not yet determined whether semaphorin 5A is associated with H. pylori-related gastric carcinoma. In the present study, we investigated the role of semaphorin 5A in H. pylori-induced gastric carcinogenesis and identified a novel intracellular signaling pathway involving semaphorin 5A in H. pylori-mediated

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