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<front>
<journal-meta>
<journal-id journal-id-type="publisher-id">Front. Cell. Infect. Microbiol.</journal-id>
<journal-title>Frontiers in Cellular and Infection Microbiology</journal-title>
<abbrev-journal-title abbrev-type="pubmed">Front. Cell. Infect. Microbiol.</abbrev-journal-title>
<issn pub-type="epub">2235-2988</issn>
<publisher>
<publisher-name>Frontiers Media S.A.</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="doi">10.3389/fcimb.2023.1062803</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Cellular and Infection Microbiology</subject>
<subj-group>
<subject>Review</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group>
<article-title>A review of signal pathway induced by virulent protein CagA of <italic>Helicobacter pylori</italic>
</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name>
<surname>Wang</surname>
<given-names>Haiqiang</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
<xref ref-type="author-notes" rid="fn003">
<sup>&#x2020;</sup>
</xref>
<uri xlink:href="https://loop.frontiersin.org/people/1983440"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Zhao</surname>
<given-names>Mei</given-names>
</name>
<xref ref-type="aff" rid="aff2">
<sup>2</sup>
</xref>
<xref ref-type="author-notes" rid="fn003">
<sup>&#x2020;</sup>
</xref>
<uri xlink:href="https://loop.frontiersin.org/people/1783719"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Shi</surname>
<given-names>Fan</given-names>
</name>
<xref ref-type="aff" rid="aff2">
<sup>2</sup>
</xref>
<uri xlink:href="https://loop.frontiersin.org/people/1721249"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Zheng</surname>
<given-names>Shudan</given-names>
</name>
<xref ref-type="aff" rid="aff2">
<sup>2</sup>
</xref>
<uri xlink:href="https://loop.frontiersin.org/people/1983086"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Xiong</surname>
<given-names>Li</given-names>
</name>
<xref ref-type="aff" rid="aff2">
<sup>2</sup>
</xref>
<uri xlink:href="https://loop.frontiersin.org/people/1983254"/>
</contrib>
<contrib contrib-type="author" corresp="yes">
<name>
<surname>Zheng</surname>
<given-names>Lihong</given-names>
</name>
<xref ref-type="aff" rid="aff3">
<sup>3</sup>
</xref>
<xref ref-type="author-notes" rid="fn001">
<sup>*</sup>
</xref>
<uri xlink:href="https://loop.frontiersin.org/people/1721433"/>
</contrib>
</contrib-group>
<aff id="aff1">
<sup>1</sup>
<institution>Department of Internal Medicine, First Affiliated Hospital, Heilongjiang University of Chinese Medicine</institution>, <addr-line>Harbin</addr-line>, <country>China</country>
</aff>
<aff id="aff2">
<sup>2</sup>
<institution>Graduate School of Heilongjiang University of Chinese Medicine</institution>, <addr-line>Harbin</addr-line>, <country>China</country>
</aff>
<aff id="aff3">
<sup>3</sup>
<institution>Department of Internal Medicine, Fourth Affiliated Hospital, Heilongjiang University of Chinese Medicine</institution>, <addr-line>Harbin</addr-line>, <country>China</country>
</aff>
<author-notes>
<fn fn-type="edited-by">
<p>Edited by: Rossella Grande, University &#x201c;G. d&#x2019;Annunzio&#x201d; of Chieti-Pescara, Italy</p>
</fn>
<fn fn-type="edited-by">
<p>Reviewed by: Sungil Jang, Jeonbuk National University, Republic of Korea; Ling Hu, Guangzhou University of Chinese Medicine, China</p>
</fn>
<fn fn-type="corresp" id="fn001">
<p>*Correspondence: Lihong Zheng, <email xlink:href="mailto:zlhsunshine@126.com">zlhsunshine@126.com</email>
</p>
</fn>
<fn fn-type="other" id="fn003">
<p>&#x2020;These authors share first authorship</p>
</fn>
<fn fn-type="other" id="fn002">
<p>This article was submitted to Intestinal Microbiome, a section of the journal Frontiers in Cellular and Infection Microbiology</p>
</fn>
</author-notes>
<pub-date pub-type="epub">
<day>14</day>
<month>04</month>
<year>2023</year>
</pub-date>
<pub-date pub-type="collection">
<year>2023</year>
</pub-date>
<volume>13</volume>
<elocation-id>1062803</elocation-id>
<history>
<date date-type="received">
<day>06</day>
<month>10</month>
<year>2022</year>
</date>
<date date-type="accepted">
<day>24</day>
<month>03</month>
<year>2023</year>
</date>
</history>
<permissions>
<copyright-statement>Copyright &#xa9; 2023 Wang, Zhao, Shi, Zheng, Xiong and Zheng</copyright-statement>
<copyright-year>2023</copyright-year>
<copyright-holder>Wang, Zhao, Shi, Zheng, Xiong and Zheng</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/">
<p>This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</p>
</license>
</permissions>
<abstract>
<p>Gastric cancer (GC), a common and high-mortality disease, still occupies an important position in current cancer research, and <italic>Helicobacter pylori</italic> (<italic>H. pylori</italic>) infection as its important risk factor has been a hot and challenging research area. Among the numerous pathogenic factors of <italic>H. pylori</italic>, the virulence protein CagA has been widely studied as the only bacterial-derived oncoprotein. It was found that CagA entering into gastric epithelial cells (GECs) can induce the dysregulation of multiple cellular pathways such as MAPK signaling pathway, PI3K/Akt signaling pathway, NF-&#x3ba;B signaling pathway, Wnt/&#x3b2;-catenin signaling pathway, JAK-STAT signaling pathway, Hippo signaling pathway through phosphorylation and non-phosphorylation. These disordered pathways cause pathological changes in morphology, adhesion, polarity, proliferation, movement, and other processes of GECs, which eventually promotes the occurrence of GC. With the deepening of <italic>H. pylori</italic>-related research, the research on CagA-induced abnormal signaling pathway has been updated and deepened to some extent, so the key signaling pathways activated by CagA are used as the main stem to sort out the pathogenesis of CagA in this paper, aiming to provide new strategies for the <italic>H. pylori</italic> infection and treatment of GC in the future.</p>
</abstract>
<kwd-group>
<kwd>
<italic>H.pylori</italic> virulence protein CagA</kwd>
<kwd>MAPK signaling pathway</kwd>
<kwd>PI3K/Akt signaling pathway</kwd>
<kwd>NF-&#x3ba;B signaling pathway</kwd>
<kwd>JAK-STAT signaling pathway</kwd>
<kwd>Wnt/&#x3b2;-catenin signaling pathway</kwd>
<kwd>Hippo signaling pathway</kwd>
</kwd-group>
<counts>
<fig-count count="2"/>
<table-count count="0"/>
<equation-count count="0"/>
<ref-count count="97"/>
<page-count count="10"/>
<word-count count="5417"/>
</counts>
</article-meta>
</front>
<body>
<sec id="s1" sec-type="intro">
<label>1</label>
<title>Introduction</title>
<p>GC ranks as the fifth most common cancer and the third leading cause of cancer death in the world, so it is still important cancer worldwide today, and lots of previous studies have confirmed that <italic>H. pylori</italic> infection is a major risk factor for the development of GC and is classified as a class I carcinogen by the WHO (<xref ref-type="bibr" rid="B91">Watanabe et&#xa0;al., 1998</xref>; <xref ref-type="bibr" rid="B3">Backert and Tegtmeyer, 2012</xref>; <xref ref-type="bibr" rid="B64">Plummer et&#xa0;al., 2015</xref>). <italic>H. pylori</italic> contains various pathogenic factors such as cytotoxin-associated gene A (CagA), vacuolating cytotoxin A (VacA), neutrophil activating protein (NAP), outer membrane proteins (OpiA, HopQ) (<xref ref-type="bibr" rid="B60">Palframan et&#xa0;al., 2012</xref>), which activate various signaling pathways such as ERK/MAPK, PI3K/Akt, NF-&#x3ba;B, Wnt/&#x3b2;-Catenin, JAK-STAT, Hippo, etc. and promote aberrant transcription of downstream pro-inflammatory/anti-inflammatory, carcinogenic/anti-cancer target genes, which is the key mechanism of <italic>H. pylori</italic>-induced progression of chronic gastritis to GC. As the only bacterial-derived oncoprotein, CagA has been widely studied (<xref ref-type="bibr" rid="B58">Ohnishi et&#xa0;al., 2008</xref>; <xref ref-type="bibr" rid="B4">Belogolova et&#xa0;al., 2013</xref>; <xref ref-type="bibr" rid="B1">Alipour, 2021</xref>). Several studies have confirmed that CagA plays an indispensable role in the pathogenesis of <italic>H. pylori</italic> (<xref ref-type="bibr" rid="B15">Franco et&#xa0;al., 2008</xref>), so in this paper, the critical signaling pathways induced by CagA are used as the main stem to comb through the relevant studies on the pathogenesis of this protein, which further clarifies the pathogenesis of CagA-positive <italic>H. pylori</italic> and provides new ideas for clinical blockade of <italic>H. pylori</italic> infection and treatment of GC.</p>
</sec>
<sec id="s2">
<label>2</label>
<title>The structural basis of CagA</title>
<p>CagA is a 128-145 kDa protein (<xref ref-type="bibr" rid="B11">Covacci et&#xa0;al., 1993</xref>) that includes a folded N-terminal region (about 70% of the entire protein) and an intrinsically disordered C-terminal region (30% of the entire protein), where the folded N-terminal consists of three different structural domains (structural domains I-III) forming a new protein structure, while the disordered C-terminal region contains a glutamate-proline-isoleucine-tyrosine-alanine motif (Glu-Pro-Ile-Tyr-Ala, EPIYA) fragment and a CagA multimerization motif (CM motif) (<xref ref-type="fig" rid="f1">
<bold>Figure&#xa0;1</bold>
</xref>) (<xref ref-type="bibr" rid="B22">Hayashi et&#xa0;al., 2012</xref>; <xref ref-type="bibr" rid="B20">Hatakeyama, 2014</xref>). There is a small interacting surface region between structural domain I and structural domain II, but no interacting surface region with structural domain III, where the hydrophobic surface N-terminal binding sequence (NBS) of structural domain III interacts intramolecularly with the disordered C-terminal NBS homolog forming a lasso-like disordered loop that together enhances the hub function of CagA pathogenicity (<xref ref-type="bibr" rid="B3">Backert and Tegtmeyer, 2012</xref>; <xref ref-type="bibr" rid="B22">Hayashi et&#xa0;al., 2012</xref>).</p>
<p>The C-terminal variable region of CagA protein has a repetitive region of the EPIYA Motif, which plays a crucial role in membrane localization in non-polarized host cells and can be classified into four different types according to the amino acid sequence around each EPIYA motif: EPIYA-A, EPIYA-B, EPIYA-C, and EPIYA-D, which constitute the classical EPIYA-repeat region by different combinations and have evident regional variability (<xref ref-type="fig" rid="f1">
<bold>Figure&#xa0;1</bold>
</xref>) (<xref ref-type="bibr" rid="B69">Rudi et&#xa0;al., 1998</xref>; <xref ref-type="bibr" rid="B24">Higashi et&#xa0;al., 2002</xref>; <xref ref-type="bibr" rid="B54">Murata-Kamiya, 2011</xref>). The EPIYA repeat region of CagA in Western countries is composed of EPIYA-A/EPIYA-B/EPIYA-C fragments, which are known as Western CagA proteins or ABC-type CagA; while EPIYA-A/EPIYA-B/EPIYA-D fragments, named East Asian CagA proteins or ABD-type CagA, predominate in strains from East Asian countries (<xref ref-type="bibr" rid="B69">Rudi et&#xa0;al., 1998</xref>; <xref ref-type="bibr" rid="B24">Higashi et&#xa0;al., 2002</xref>; <xref ref-type="bibr" rid="B54">Murata-Kamiya, 2011</xref>). Moreover, EPIYA-C fragments are usually present in 1 to 3-fold quantities and in tandem in different Western CagA proteins (<xref ref-type="bibr" rid="B69">Rudi et&#xa0;al., 1998</xref>), and only tandem EPIYA-C can activate protein tyrosine phosphatase 2 (SHP2), whereas individually it cannot (<xref ref-type="bibr" rid="B90">Wang et&#xa0;al., 2021</xref>). The molecular dynamics simulation of SHP2 confirmed that the binding affinity of EPIYA-D to the N-SH2 domain of SHP2 is more potent than that of EPIYA-C, which explains that part of the reason why the incidence of GC in East Asian countries is much higher than that in western countries is due to the difference of CagA phosphorylation sites on both sides (<xref ref-type="bibr" rid="B19">Hatakeyama, 2004</xref>; <xref ref-type="bibr" rid="B90">Wang et&#xa0;al., 2021</xref>).</p>
<p>In addition to the EPIYA motif in the C-terminal region, the distal end contains a CM motif consisting of 16 amino acid residues to achieve its motif multimerization (dimerization) upon non-phosphorylation (<xref ref-type="bibr" rid="B70">Saadat et&#xa0;al., 2007</xref>); that is, two CagA molecules are recruited through the CM motif (<xref ref-type="bibr" rid="B21">Hatakeyama, 2017</xref>) and bind a polarity-regulated kinase 1b (PAR1b) to form the CagA-PAR1b complex, which induces host cell attachment and polarity defects and assists CagA molecules to enter the host cell (<xref ref-type="bibr" rid="B73">Segal et&#xa0;al., 1999</xref>; <xref ref-type="bibr" rid="B55">Murata-Kamiya et&#xa0;al., 2010</xref>). Although CM motifs are highly conserved in different strains, they are not identical and there is a difference of 5 amino acid changes in CagA of East Asian and Western strains, which are named as CM<sup>E</sup> sequence and CM<sup>W</sup> sequence respectively based on this difference. Most East Asian CagA proteins have only one CM sequence downstream of the EPIYA-D fragment. In contrast, in Western CagA, the CM sequence is located in the N-terminal part of the EPIYA-C fragment and downstream of the final EPIYA-C fragment, so the number of CM motifs in Western CagA increases along with the multiplication of the EPIYA-C fragment (<xref ref-type="fig" rid="f1">
<bold>Figure&#xa0;1</bold>
</xref>) (<xref ref-type="bibr" rid="B67">Ren et&#xa0;al., 2006</xref>; <xref ref-type="bibr" rid="B70">Saadat et&#xa0;al., 2007</xref>).</p>
<fig id="f1" position="float">
<label>Figure&#xa0;1</label>
<caption>
<p>The chematic structure of the <italic>H. pylori</italic> CagA.</p>
</caption>
<graphic mimetype="image" mime-subtype="tiff" xlink:href="fcimb-13-1062803-g001.tif"/>
</fig>
</sec>
<sec id="s3">
<label>3</label>
<title>The translocation and activation of CagA</title>
<p>Upon attachment of <italic>H. pylori</italic> to GECs, CagA enters the host cell through the synergistic action of various molecules such as the type IV secretion system encoded by the Cag pathogenicity island (Cag PAI), externalized phosphatidylserine (PS), multiple adhesion factors (BabA, SabA, OpiA, HopQ, and other outer membrane proteins) and the host cell integrin &#x251;5&#x3b2;1 (<xref ref-type="bibr" rid="B2">Backert et&#xa0;al., 2011</xref>; <xref ref-type="bibr" rid="B61">Palrasu et&#xa0;al., 2020</xref>). Once <italic>H. pylori</italic> enters GECs, CagA is anchored to the inner leaflet of the plasma membrane by different mechanisms depending on the polarity of the cell. In polarized host cells, the interaction of basic amino acids of the Lys-Xn-Arg-X-Arg (K-X-R-X-R) motif with PS plays a major role in the membrane binding of CagA, whereas in non-polarized cells, it is the EPIYA motif that is critical for CagA membrane binding (<xref ref-type="bibr" rid="B20">Hatakeyama, 2014</xref>; <xref ref-type="bibr" rid="B21">Hatakeyama, 2017</xref>). In addition, <italic>H. pylori</italic> can shed Outer Membrane Vesicles (OMVs) from its outer membrane surface and enter human gastric adenocarcinoma (AGS) cells by macropinocytosis/phagocytosis, like other Gram-negative bacilli (<xref ref-type="bibr" rid="B9">Chew et&#xa0;al., 2021</xref>). The OMVs of <italic>H. pylori</italic> were shown to contain adhesins, lipopolysaccharides, and virulence factors (CagA, VacA, and UreA) (<xref ref-type="bibr" rid="B53">Mullaney et&#xa0;al., 2009</xref>; <xref ref-type="bibr" rid="B59">Olofsson et&#xa0;al., 2010</xref>; <xref ref-type="bibr" rid="B87">Turner et&#xa0;al., 2018</xref>), so OMVs are another way for CagA to enter the host cells instead of a functional type IV secretion system (<xref ref-type="bibr" rid="B9">Chew et&#xa0;al., 2021</xref>). Studies suggest that CagA is located only on the surface of OMV isolated from <italic>H. pylori</italic> and occurs phosphorylated upon entry into AGS cells, which interferes with cellular signaling pathways leading to inflammation and carcinogenesis (<xref ref-type="bibr" rid="B27">Jarzab et&#xa0;al., 2020</xref>), although it is not present in high levels in infected cells (<xref ref-type="bibr" rid="B9">Chew et&#xa0;al., 2021</xref>).</p>
<p>CagA immobilized at the plasma membrane undergoes selective tyrosine phosphorylation at the EPIYA site mediated by src family kinase (SFK) and c-Abl tyrosine kinase, where EPIYA-C or EPIYA-D is phosphorylated by SFK at the onset of infection (0.5-2h), followed by rapid inactivation of SFK by phosphorylated CagA and C-terminal Src kinase (Csk) (<xref ref-type="bibr" rid="B82">Tegtmeyer and Backert, 2011</xref>), and post-infection (2-8h) c-Abl phosphorylates EPIYA-A or EPIYA-B (<xref ref-type="bibr" rid="B69">Rudi et&#xa0;al., 1998</xref>; <xref ref-type="bibr" rid="B79">Tammer et&#xa0;al., 2007</xref>; <xref ref-type="bibr" rid="B52">Mueller et&#xa0;al., 2012</xref>). So, the phosphorylation process of CagA is not only time-dependent but also kinase selective for motifs. Scholars have also found that the c-Src kinase phosphorylated only EPIYA-C and EPIYA-D, while c-Abl kinase can phosphorylate all repetitive fragments of CagA (<xref ref-type="bibr" rid="B79">Tammer et&#xa0;al., 2007</xref>; <xref ref-type="bibr" rid="B52">Mueller et&#xa0;al., 2012</xref>). In Western strains, the kinase can preferentially phosphorylate EPIYA-A and EPIYA-C motifs across two CagA molecules or on one CagA molecule at the same time, and it was found that phosphorylation of CagA mostly occurs through one or two EPIYA repeat fragments and rarely three motifs simultaneously (<xref ref-type="bibr" rid="B52">Mueller et&#xa0;al., 2012</xref>). Certainly, the phosphorylation of one EPIYA motif alone is not sufficient to induce scattering and elongation in GECs (<xref ref-type="bibr" rid="B78">Takahashi-Kanemitsu et&#xa0;al., 2020</xref>). Phosphorylated CagA interacts with SHP2, Csk, Crk junction protein, and other proteins to trigger the ERK/MAPK signaling pathway, leading to abnormal expression of epithelial genes and inducing morphological changes in the &#x201c;hummingbird phenotype&#x201d; (<xref ref-type="bibr" rid="B70">Saadat et&#xa0;al., 2007</xref>). However, not all pathological changes caused by CagA require the prerequisite of phosphorylation. The CM motif can bind to PARIb, Ecadherin/&#x3b2;-catenin, C-met, growth factor receptor-bound protein 2 (Grb2), or other proteins to disrupt intracellular signaling pathways such as PI3K/Akt signaling pathway and Wnt/&#x3b2;catenin signaling pathway (<xref ref-type="bibr" rid="B61">Palrasu et&#xa0;al., 2020</xref>), so non-phosphorylation plays an equally important role as phosphorylation in the pathogenesis of CagA.</p>
</sec>
<sec id="s4">
<label>4</label>
<title>Signaling pathways activated by CagA</title>
<sec id="s4_1">
<label>4.1</label>
<title>The MAPK signaling pathway</title>
<p>MAPK signaling pathway is a cellular pathway that regulates cell growth, differentiation, stress, inflammation, immunity, and other important physiopathological responses through sequential activation of MAP kinase (MAPK), MAPK kinase (MEK, MKK or MAPK kinase) and MEK kinase (MEKK, MKKK or MAPK kinase kinase) (<xref ref-type="bibr" rid="B66">Raman et&#xa0;al., 2007</xref>; <xref ref-type="bibr" rid="B6">Cargnello and Roux, 2011</xref>). Among the four major branches of ERK, JNK, p38 MAPK, and ERK5, CagA is dominated by the activation of ERK and JNK subgroups, among which ERK is in charge of cell growth and differentiation, and its upstream signal is the well-known Ras/Raf protein, while JNK is mostly involved in cell inflammation and apoptosis, both of which are critical for CagA-induced GC progression (<xref ref-type="bibr" rid="B6">Cargnello and Roux, 2011</xref>).</p>
<sec id="s4_1_1">
<label>4.1.1</label>
<title>The MAPK classical signaling pathway</title>
<p>CagA acts as a scaffold to recruit SHP2 at the plasma membrane of host cells in a Tyr site tyrosine phosphorylation-dependent manner (<xref ref-type="bibr" rid="B81">Tartaglia et&#xa0;al., 2001</xref>). SHP2 is the first known phosphatase to act as a human oncoprotein, which contains two tandem Src homologous structural domains (N-terminal Src-homology domain 2, N-SH2; C-terminal Src-homology domain 2, C-SH2) also is a major molecule in determining the virulence of CagA-positive <italic>H. pylori</italic> (<xref ref-type="bibr" rid="B19">Hatakeyama, 2004</xref>; <xref ref-type="bibr" rid="B54">Murata-Kamiya, 2011</xref>). CagA can bind to a single SHP2 through two structural domains, N-SH2 and C-SH2, to form a CagA-SHP2 complex, either in cis or trans (<xref ref-type="bibr" rid="B19">Hatakeyama, 2004</xref>). Activated SHP2 stimulates ERK through both RAS-dependent and non-dependent pathways, which in turn activates the Ras/Raf/MEK/ERK signaling pathway, thereby deregulating cell proliferation, triggering an abnormal mitotic response, inducing cell elongation to form needle-like protrusions that constitute the morphological changes of the &#x201c;hummingbird phenotype&#x201d; (<xref ref-type="fig" rid="f2">
<bold>Figure&#xa0;2A</bold>
</xref>) (<xref ref-type="bibr" rid="B23">Higashi et&#xa0;al., 2004</xref>; <xref ref-type="bibr" rid="B86">Tsutsumi et&#xa0;al., 2006</xref>; <xref ref-type="bibr" rid="B43">Liu et&#xa0;al., 2012</xref>; <xref ref-type="bibr" rid="B20">Hatakeyama, 2014</xref>). The phenotype is characterized by increased cell viability and scattered elongated cell shape, similar to changes in cell scattering, elongation and diffusion induced by hepatocyte growth factor (HGF) (<xref ref-type="bibr" rid="B73">Segal et&#xa0;al., 1999</xref>). It was shown that SHP2 not only participated in the positive regulation of ERK/MAPK activity by CagA but also prolonged the duration of ERK activation, and the morphogenetic activity of CagA was dependent on ERK/MAPK activity, so tyrosine phosphorylation of CagA in this process was necessary to induce the hummingbird phenotype and cell scattering phenotype in GECs (<xref ref-type="bibr" rid="B23">Higashi et&#xa0;al., 2004</xref>). Moreover, the CagA-SHP2 complex induces dephosphorylation of various phosphorylation sites of focal adhesion kinase (FAK), an important tyrosine kinase, that controls cell adhesion, spreading, differentiation, motility, and death (<xref ref-type="bibr" rid="B48">Mitra et&#xa0;al., 2005</xref>; <xref ref-type="bibr" rid="B86">Tsutsumi et&#xa0;al., 2006</xref>), thereby affecting the host cytoskeleton, local adhesion sites bound by extracellular matrix molecules, and structural changes in membrane protrusions through different molecular binding (<xref ref-type="bibr" rid="B83">Tegtmeyer et&#xa0;al., 2017</xref>), resulting in alterations in cell motility and cell morphology. The interaction between CagA and PAR1b inhibits the activity of FAK resulting in junction defects and polarity defects in host cells, which promotes the formation of CagA-SHP2 complexes and further induces hummingbird phenotypes (<xref ref-type="bibr" rid="B70">Saadat et&#xa0;al., 2007</xref>). Some recent studies have found that CagA can downregulate downstream tumor suppressors genes such as GKN1 and Runx3 after triggering this pathway, thus inducing a decrease in suppressor activity in GECs and ultimately promoting the development of GC (<xref ref-type="bibr" rid="B84">Tsang et&#xa0;al., 2010</xref>; <xref ref-type="bibr" rid="B18">Guo et&#xa0;al., 2020</xref>).</p>
<fig id="f2" position="float">
<label>Figure&#xa0;2</label>
<caption>
<p>The Summary of CagA-induced signaling pathways. <bold>(A)</bold> The MAPK classical signaling pathway; <bold>(B)</bold> The NF-&#x3ba;B signaling pathway; <bold>(C)</bold> The PI3K/Akt signaling pathway; <bold>(D)</bold> The JAK-STAT signaling pathway; <bold>(E)</bold> The Hippo signaling pathway; <bold>(F)</bold> The Wnt/&#x3b2;-catenin signaling pathway.</p>
</caption>
<graphic mimetype="image" mime-subtype="tiff" xlink:href="fcimb-13-1062803-g002.tif"/>
</fig>
<p>The phase interaction of CagA-SHP2 was mediated by the phosphorylation of EPIYA-C or EPIYA-D fragments, while the phosphorylation of EPIYA-A or EPIYA-B fragments participates in the interaction of CagA-Csk, which is similar to the complex formed after SHP2 activates Csk (<xref ref-type="bibr" rid="B54">Murata-Kamiya, 2011</xref>). The CagA-Csk formation competitively inhibits CagA-SHP2 binding and down-regulates CagA-SHP2 signaling by decreasing the phosphorylation level of CagA (<xref ref-type="fig" rid="f2">
<bold>Figure&#xa0;2A</bold>
</xref>) (<xref ref-type="bibr" rid="B85">Tsutsumi et&#xa0;al., 2003</xref>). Therefore, the interaction of CagA with Csk may establish a negative feedback regulatory loop to prevent excessive cell damage caused by excessive activation of phosphorylation-dependent CagA activity (<xref ref-type="bibr" rid="B20">Hatakeyama, 2014</xref>), which is conducive to persistent infection of CagA-positive <italic>H. pylori</italic> while avoiding excessive toxicity to host cells, so Csk is considered as a negative regulator of SFK (<xref ref-type="bibr" rid="B56">Nada et&#xa0;al., 1991</xref>; <xref ref-type="bibr" rid="B85">Tsutsumi et&#xa0;al., 2003</xref>). The inhibition of SFK kinase activity by the CagA-Csk complex also affects the phosphorylation status of actin-binding proteins (cortactin, vinculin, etc.) (<xref ref-type="bibr" rid="B20">Hatakeyama, 2014</xref>), leading to an overall rearrangement of the actin cytoskeleton, which promotes cell motility, scattering, and elongation (<xref ref-type="bibr" rid="B82">Tegtmeyer and Backert, 2011</xref>), further contributing to the &#x201c;hummingbird phenotype&#x201d; of cell morphology changes. In addition, phosphorylated CagA interacts with Crk junction proteins (Crk-I, Crk-II, Crk-L) to induce other downstream signaling pathways such as SoS1/H-Ras-Raf-MEK and C3G-Rap1/B-Raf-MEK (<xref ref-type="bibr" rid="B76">Suzuki et&#xa0;al., 2005</xref>), which plays an important role in promoting cell scattering (<xref ref-type="bibr" rid="B8">Chen et&#xa0;al., 2016</xref>). In the non-phosphorylated state, the CM motif of CagA interacts with Grb2 to activate the RAS/MEK/ERK pathway and lead to cell dispersion and proliferation, but the EPIYA fragments required for tyrosine phosphorylation are indispensable in Grb2 binding and cellular response (<xref ref-type="fig" rid="f2">
<bold>Figure&#xa0;2A</bold>
</xref>) (<xref ref-type="bibr" rid="B47">Mimuro et&#xa0;al., 2002</xref>).</p>
<p>The ERK/MAPK signaling pathway is the core of the signaling network that regulates cell growth, development, and division (<xref ref-type="bibr" rid="B80">Tang et&#xa0;al., 2017</xref>), and timely blockage of the pathway may be a potential way to prevent GC. Berberine inhibits the proliferation and tumorigenicity of GECs by inactivating the MAPK signaling pathway, and reduces the secretion of IL-8, thus playing a good role in the treatment of gastric cancer (<xref ref-type="bibr" rid="B40">Li et&#xa0;al., 2016</xref>).</p>
</sec>
<sec id="s4_1_2">
<label>4.1.2</label>
<title>The JNK signaling pathway</title>
<p>The JNK signaling pathway is an important branch of the MAPK signaling pathway that plays an important role in a variety of physiological and pathological processes, including cell cycle, reproduction, apoptosis, and cellular stress (<xref ref-type="bibr" rid="B17">Gozdecka et&#xa0;al., 2014</xref>). It has been proved that the JNK signaling pathway cannot only inhibit tumors but also promote tumors in different cell types and organs (<xref ref-type="bibr" rid="B13">Epstein Shochet et&#xa0;al., 2014</xref>). Through the experiments of transgenic fruit flies, some scholars have found that CagA can trigger the activation of the JNK signal pathway and induce apoptosis of epithelial cells (<xref ref-type="bibr" rid="B88">Wandler and Guillemin, 2012</xref>). JNK-mediated apoptosis may play a role in limiting pathogenicity and protecting GECs during early infection, but the accumulation of genetic mutations may occur under the combined influence of persistent <italic>H. pylori</italic> infection and other factors, which will promote tumor progression when carcinogenic mutations are acquired (<xref ref-type="bibr" rid="B96">Yong et&#xa0;al., 2015</xref>).</p>
<p>The new study also suggests that early in <italic>H. pylori</italic> infection, phosphorylated CagA promotes cortical actin overexpression through activation of JNK and stimulates actin-cytoskeleton, cell adhesion, and motility changes, which affect cell structure and epithelial barrier function in the development of GC (<xref ref-type="bibr" rid="B74">Sharafutdinov et&#xa0;al., 2021</xref>).</p>
</sec>
</sec>
<sec id="s4_2">
<label>4.2</label>
<title>The PI3K/Akt signaling pathway</title>
<p>The PI3K/Akt signaling pathway is mainly involved in protein synthesis, cell survival, migration, and growth (<xref ref-type="bibr" rid="B16">Franke, 2008</xref>). The activation of the pathway is in response to growth factors, such as epidermal growth factor and hepatocyte growth factor (<xref ref-type="bibr" rid="B96">Yong et&#xa0;al., 2015</xref>). The classical cascade reaction is to activate the heterodimer (Phosphatidylinositol-3-kinase, PI3K), which is composed of the p85 regulatory subunit and p110 catalytic subunit, through specific receptors (EGFR, C-met) and other molecules (<xref ref-type="bibr" rid="B16">Franke, 2008</xref>; <xref ref-type="bibr" rid="B96">Yong et&#xa0;al., 2015</xref>). The activated PI3K can phosphorylate the second messenger phosphatidylinositol (3,4)-biphosphate (PIP2) to generate phosphatidylinositol (3,4,5)-trisphosphate (PIP3) and cause Akt kinase phosphorylation at the Ser473 or Thr308 sites, which in turn activates or inhibits downstream targets such as glycogen synthase kinase 3&#x3b2; (GSK-3&#x3b2;) and forkhead box protein o (FOXO), and this pathway signaling was found to be active in tumor cells such as GC (<xref ref-type="bibr" rid="B16">Franke, 2008</xref>; <xref ref-type="bibr" rid="B71">Saijilafu et&#xa0;al., 2013</xref>; <xref ref-type="bibr" rid="B96">Yong et&#xa0;al., 2015</xref>). Under the regulation of the PI3K/Akt pathway, CagA induces the phosphorylation of X-linked inhibitor of apoptosis protein (XIAP) E3 ubiquitin ligase at position 87 and initiates ubiquitination and proteasome dissociation of the pro-apoptotic factor Siva1, which leads to the inhibition of apoptosis and DNA damage response (<xref ref-type="fig" rid="f2">
<bold>Figure&#xa0;2C</bold>
</xref>) (<xref ref-type="bibr" rid="B61">Palrasu et&#xa0;al., 2020</xref>). CagA also promotes GC by mediating autophagy through the C-met/Akt signaling pathway and promoting the expression of downstream inflammatory cytokines (<xref ref-type="bibr" rid="B39">Li et&#xa0;al., 2017a</xref>).</p>
<p>The PI3K/Akt signaling pathway is essential in the pathogenesis of CagA, which can be activated through the following three pathways: (1) When CagA is not phosphorylated, the CM motif interacts with the hepatocyte growth factor receptor-C-met (<xref ref-type="bibr" rid="B75">Suzuki et&#xa0;al., 2009</xref>), representing activation of PI3K/Akt signaling <italic>via</italic> a phospholipase C&#x3b3; (PLC&#x3b3;)-related junction protein (<xref ref-type="bibr" rid="B8">Chen et&#xa0;al., 2016</xref>), causing inactivation of the downstream target gene GSK-3&#x3b2; and subsequently inducing crosstalk of the Wnt/&#x3b2;-catenin signaling pathway and NF-&#x3ba;B signaling pathway to promote the cell proliferation and enhance the inflammatory response (<xref ref-type="bibr" rid="B75">Suzuki et&#xa0;al., 2009</xref>; <xref ref-type="bibr" rid="B77">Tabassam et&#xa0;al., 2009</xref>). (2) CagA interacts with PI3K <italic>via</italic> the tyrosine phosphorylation motif (B-TPM) of EPIYA-B repeat region, thereby inducing the PI3K/Akt signaling pathway (<xref ref-type="bibr" rid="B96">Yong et&#xa0;al., 2015</xref>; <xref ref-type="bibr" rid="B97">Zhang et&#xa0;al., 2015</xref>). The B-TPM has the A/T polymorphism of EPIYA and EPIYT and has an apparent non-random geographical distribution, with EPIYT B-TPM being more predominant in Western <italic>H. pylori</italic> isolates, and structural modeling revealed that this is due to the side chain hydrogen bond formed by the threonine residue at the pY<sup>+1</sup> position with PI3-kinase N-417 increasing its affinity for PI3K binding (<xref ref-type="bibr" rid="B96">Yong et&#xa0;al., 2015</xref>; <xref ref-type="bibr" rid="B97">Zhang et&#xa0;al., 2015</xref>). However, EPIYA is more dominant in East Asian <italic>H. pylori</italic> isolates, does not have this affinity (<xref ref-type="bibr" rid="B46">Matsunari et&#xa0;al., 2012</xref>). So CagA regulates the interaction with PI3K through the A/T polymorphism of B-TMP, which regulates the activity of the oncogenic-related PI3K/Akt signaling pathway and enhances the risk of GC (<xref ref-type="bibr" rid="B25">Huang et&#xa0;al., 2008</xref>; <xref ref-type="bibr" rid="B96">Yong et&#xa0;al., 2015</xref>; <xref ref-type="bibr" rid="B97">Zhang et&#xa0;al., 2015</xref>). (3) Scholars have found that CagA can phosphorylate Akt 1 (Protein Kinase B, PKB) and activate the ubiquitin ligase Hdm2 to induce degradation of the tumor suppressor p53 in GECs from <italic>H. pylori</italic>-infected Mongolian gerbils (<xref ref-type="bibr" rid="B92">Wei et&#xa0;al., 2010</xref>), which is triggered by the direct interaction of ectopically expressed CagA with AKT (<xref ref-type="fig" rid="f2">
<bold>Figure&#xa0;2C</bold>
</xref>) (<xref ref-type="bibr" rid="B83">Tegtmeyer et&#xa0;al., 2017</xref>). The PI3K/Akt signaling pathway contributes to the progression of GC through epithelial-mesenchymal transition (EMT) stimulation, and resveratrol was able to inhibit Doxorubicin treatment EMT-mediated resistance by significantly reducing the Akt signaling pathway (<xref ref-type="bibr" rid="B32">Kiu and Nicholson, 2012</xref>). So, the PI3K/AKt may also serve as a target for the treatment of <italic>H. pylori</italic> infection.</p>
</sec>
<sec id="s4_3">
<label>4.3</label>
<title>The NF-&#x3ba;B signaling pathway and JAK-STAT signaling pathway</title>
<sec id="s4_3_1">
<label>4.3.1</label>
<title>The NF-&#x3ba;B signaling pathway</title>
<p>Downstream of the PI3K/Akt signal pathway, NF-&#x3ba;B is an important inflammatory target, which acts as an essential nuclear transcription factor regulating the inflammatory response/immune response of bodies and apoptotic, stress response of cells (<xref ref-type="bibr" rid="B96">Yong et&#xa0;al., 2015</xref>). NF-&#x3ba;B is a heterodimer composed of p65/p50 and forms a complex with I&#x3ba;B&#x3b1;, the intracellular inhibitory proteins, in the classical pathway, and the phosphorylation of the p65 subunit in NF-&#x3ba;B plays a crucial role in its own transnuclear process (<xref ref-type="bibr" rid="B96">Yong et&#xa0;al., 2015</xref>). The resting I&#x3ba;B kinase (IKK) is activated by some extracellular signals mediated by membrane receptors, and then phosphorylates, ubiquitinates and detaches I&#x3ba;B&#x3b1; protein from the complex, which is eventually cleaved by proteasomes and releases NF-&#x3ba;B dimer (<xref ref-type="bibr" rid="B57">Neumann and Naumann, 2007</xref>). The activated NF-&#x3ba;B is transferred to the nucleus of cells and binds to specific sequences of DNA to further promote the transcription of the target gene (<xref ref-type="bibr" rid="B57">Neumann and Naumann, 2007</xref>).</p>
<p>The PI3K/Akt signal pathway usually promotes the degradation of I&#x3ba;B&#x3b1; protein and the nuclear transfer of NF-&#x3ba;B through the order of CagA-C-met-PI3K-AKt axis (<xref ref-type="bibr" rid="B78">Takahashi-Kanemitsu et&#xa0;al., 2020</xref>), and ubiquitination of transforming growth factor-activated kinase 1 (TAK1) plays a crucial role in this process (<xref ref-type="fig" rid="f2">
<bold>Figure&#xa0;2B</bold>
</xref>) (<xref ref-type="bibr" rid="B35">Lamb et&#xa0;al., 2009</xref>). CagA binds to TAK1 in the pathway and mediates Lys 63-linked TAK1 ubiquitination <italic>via</italic> tumor necrosis factor receptor-associated molecule 6 (TRAF6) (<xref ref-type="bibr" rid="B89">Wang et&#xa0;al., 2001</xref>). The activated TAK1 induces phosphorylation of the IKK complex, which ultimately activates the NF-&#x3ba;B signaling pathway (<xref ref-type="bibr" rid="B35">Lamb et&#xa0;al., 2009</xref>), releases the inflammatory cytokine interleukin-8 (IL-8) (<xref ref-type="bibr" rid="B5">Brandt et&#xa0;al., 2005</xref>), and induces phospholipase D1 (PLD1) expression (<xref ref-type="bibr" rid="B29">Kang et&#xa0;al., 2013</xref>). Investigators also found that the phosphorylated EPIYA-C motif of CagA also induced the activation of NF-&#x3ba;B and up-regulated IL-8, but it was not related to the number of repetitions of EPIYA-C fragments (<xref ref-type="bibr" rid="B62">Papadakos et&#xa0;al., 2013</xref>). The activation of NF-&#x3ba;B and the release of IL-8 were also found to be related to the activation of the ERK signaling pathway by CagA, but the effect is modest (<xref ref-type="bibr" rid="B30">Kim et&#xa0;al., 2006</xref>). This pathway mediates the direct binding of NF-&#x3ba;B to the Rev-erb&#x3b1; promoter, thereby increasing bacterial colonization within the gastric mucosa (<xref ref-type="bibr" rid="B44">Mao et&#xa0;al., 2021</xref>). CagA-activated NF-&#x3ba;B can induce aberrant expression of cytidine deaminase (AID), a key gene for antibody gene diversification in GECs, resulting in a high mutation frequency of the tumor suppressor p53 (<xref ref-type="bibr" rid="B45">Matsumoto et&#xa0;al., 2007</xref>). NF-&#x3ba;B also directly binds to the promoter of miR-223-3p in a CagA-dependent manner and stimulates the up-regulation of miR-223-3p, which induces ARID1A gene expression to decrease and promotes the proliferation and migration of GC cells (<xref ref-type="bibr" rid="B95">Yang et&#xa0;al., 2018</xref>). Therefore, it is well documented that CagA-activated NF-&#x3ba;B plays an important role in the development of GC. Inhibiting NF-&#x3ba;B can modulate the expression of inflammatory factors to alter the microenvironment, which can also regulate the expression of oncogenes to slow down the progression of GC, and berberine can treat stomach cancer by this (<xref ref-type="bibr" rid="B42">Liu et&#xa0;al., 2022</xref>).</p>
</sec>
<sec id="s4_3_2">
<label>4.3.2</label>
<title>The JAK-STAT signaling pathway</title>
<p>The JAK-STAT signaling pathway consists of three components: tyrosine kinase-associated receptors that receive the signal, tyrosine kinase JAK that transmits the signal, and transcription factor STAT that produces the effect (<xref ref-type="bibr" rid="B96">Yong et&#xa0;al., 2015</xref>). As a stress inflammatory signal pathway, this pathway is an effective mechanism to limit the pathogenic effect and protect GECs in early CagA infection (<xref ref-type="bibr" rid="B23">Higashi et&#xa0;al., 2004</xref>). However, when CagA excess activates NF-&#x3ba;B and/or STAT3, it could induce the production of pro-inflammatory cytokines and anti-apoptotic proteins to promote the expansion of cancer-susceptible cells and prevent their apoptosis, which also induces ROS to increase DNA damage and accelerate the accumulation of mutations (<xref ref-type="bibr" rid="B20">Hatakeyama, 2014</xref>; <xref ref-type="bibr" rid="B96">Yong et&#xa0;al., 2015</xref>). When carcinogenic mutations are obtained, JAK-STAT signaling pathways are activated and accelerate the progression of a variety of tumors, including GC (<xref ref-type="fig" rid="f2">
<bold>Figure&#xa0;2D</bold>
</xref>).</p>
<p>After infection with CagA-positive <italic>H. pylori</italic>, the upregulation of IL-6 and IL-11 expression in GECs depends on non-phosphorylated CagA, and induces STAT3 tyrosine phosphorylation through the gp130 subunit of the IL-6 receptor to manipulate host immunity and promote immune evasion (<xref ref-type="bibr" rid="B26">Jackson et&#xa0;al., 2007</xref>; <xref ref-type="bibr" rid="B68">Rizzuti et&#xa0;al., 2015</xref>; <xref ref-type="bibr" rid="B21">Hatakeyama, 2017</xref>). The gp130 subunit plays a central role in regulating the balance between SHP2/ERK signaling and JAK-STAT3 signaling, and the phosphorylation status of CagA further affects GC progression by affecting the signaling switch between the SHP2/ERK and JAK/STAT3 pathways <italic>via</italic> gp130 (<xref ref-type="bibr" rid="B37">Lee et&#xa0;al., 2010</xref>). It was shown that the STAT3 signaling pathway activated by CagA increases the expression of the bactericidal agglutinin REG3&#x3b3; (<xref ref-type="bibr" rid="B36">Lee et&#xa0;al., 2012</xref>), and CagA can also regulate the secretion of IL-10 and the phosphorylation of STAT3 to damage the function of dendritic cells and manipulate T cell immune response, which is conducive to persistent <italic>H. pylori</italic> infection and increases the probability of GC (<xref ref-type="bibr" rid="B28">Kaebisch et&#xa0;al., 2014</xref>). Immune drugs are widely used in GC treatment, which inhibit JAK-STAT signaling can achieve both targeted blockade and avoid creating an immunosuppressive environment, so JAK and START inhibitors have good application prospects in cancer research, and combined immunosuppressants provide new therapeutic ideas for GC patients (<xref ref-type="bibr" rid="B32">Kiu and Nicholson, 2012</xref>; <xref ref-type="bibr" rid="B40">Li et&#xa0;al., 2016</xref>).</p>
</sec>
</sec>
<sec id="s4_4">
<label>4.4</label>
<title>The Wnt/&#x3b2;-catenin signaling pathway</title>
<p>The Wnt/&#x3b2;-catenin signaling pathway is a class of highly conserved signaling pathways during species evolution, which plays a critical role in early embryonic development, organogenesis, tissue regeneration, and other physiological processes in animal embryos (<xref ref-type="bibr" rid="B20">Hatakeyama, 2014</xref>; <xref ref-type="bibr" rid="B96">Yong et&#xa0;al., 2015</xref>). The core of this pathway is the multi-functional protein &#x3b2;-catenin encoded by CTNNB1 (<xref ref-type="bibr" rid="B20">Hatakeyama, 2014</xref>). Under physiological conditions, &#x3b2;-catenin interacts with the cytoplasmic tail of E-cadherin to form adhesion junctions between epithelial cells, and if this protein is affected, it is likely to trigger abnormal activation of the pathway and thus induce cancer development (<xref ref-type="bibr" rid="B10">Clevers, 2006</xref>). When GECs are infected by CagA-positive <italic>H. pylori</italic>, CagA and E-cadherin become competitive binding proteins, which destroys the formation of the complex between E-cadherin and &#x3b2;-catenin, leading to the accumulation of &#x3b2;-catenin in the cytoplasm and nucleus and subsequently triggering the Wnt/&#x3b2;-catenin signaling pathway, which requires the EPIYA repeat region of CagA but does not depend on CagA&#x2019;s own tyrosine phosphorylation (<xref ref-type="fig" rid="f2">
<bold>Figure&#xa0;2F</bold>
</xref>) (<xref ref-type="bibr" rid="B34">Kurashima et&#xa0;al., 2008</xref>; <xref ref-type="bibr" rid="B96">Yong et&#xa0;al., 2015</xref>).</p>
<p>The classical Wnt/&#x3b2;-catenin signaling pathway is triggered by the binding of extracellular Wnt ligands to the transmembrane receptor Frizzled family protein (FZD) and its accessory receptor low-density lipoprotein receptor-related protein (LRP) (<xref ref-type="bibr" rid="B31">Kimelman and Xu, 2006</xref>). Activated FZD receptors initiate intracellular signal cascades and phosphorylated LRP activates Dvl proteins, which together phosphorylate the N-terminal end of &#x3b2;-catenin through the destruction complex (consisting of GSK3&#x3b2;, core protein (Axin), colon cancer-associated oncogene (APC), and casein kinase-1 (CK-1)), and the phosphorylated &#x3b2;-catenin is ubiquitinated by &#x3b2;-transducin repeats-containing proteins (&#x3b2;-TrCP) and covalently modified by the intracellular proteasome, which keeps the amount of intracytoplasmic &#x3b2;-catenin at a low level (<xref ref-type="bibr" rid="B31">Kimelman and Xu, 2006</xref>; <xref ref-type="bibr" rid="B33">Klaus and Birchmeier, 2008</xref>). However, when GECs were infected with CagA-positive <italic>H. pylori</italic>, Wnt signaling leads to the inactivation of the destruction complex and thus fails to phosphorylate intracellular &#x3b2;-catenin, causing a large accumulation of &#x3b2;-catenin in the cytoplasm and entering the nucleus to interact with T-cell factor/lymphatic enhancer factor (TCF/LEF) family transcription factors, which induces the expression of cancer-related genes such as Cyclin D1 and c-myc to affect cell differentiation, proliferation, migration, and adhesion, leading to tumorigenesis (<xref ref-type="fig" rid="f2">
<bold>Figure&#xa0;2F</bold>
</xref>) (<xref ref-type="bibr" rid="B14">Franco et&#xa0;al., 2005</xref>; <xref ref-type="bibr" rid="B33">Klaus and Birchmeier, 2008</xref>; <xref ref-type="bibr" rid="B93">White et&#xa0;al., 2012</xref>). <italic>H. pylori</italic> can activate the Wnt/&#x3b2;-catenin signaling pathway in GC cells, which enhances cell invasion and angiogenesis. Inhibiting the activation of this pathway can achieve anti-tumor effects, such as Wnt/&#x3b2;-catenin signaling pathway inhibitors and berberine, which can play a similar role in regulating GC cells (<xref ref-type="bibr" rid="B42">Liu et&#xa0;al., 2022</xref>), so the Wnt/&#x3b2;-catenin signaling pathway has the potential to become an effective way to prevent and treat GC.</p>
</sec>
<sec id="s4_5">
<label>4.5</label>
<title>The Hippo signaling pathway</title>
<p>The Hippo signaling pathway, as a conserved pathway originally defined through Drosophila protein kinase (Hippo), mostly controls organ size by regulating cell proliferation and apoptosis, and acts as a key role in embryonic development, organ growth, tissue regeneration, stem cell pluripotency, and tumorigenesis (<xref ref-type="bibr" rid="B7">Chen et&#xa0;al., 2019</xref>). There is no doubt that Hippo signaling pathway also plays a crucial role in the development of GC (<xref ref-type="bibr" rid="B65">Qiao et&#xa0;al., 2018</xref>). The pathways include Sav1 protein, MOB1, MST1/2, LATS1/2, and two downstream effectors containing WW domain (YAP and TAZ) (<xref ref-type="bibr" rid="B72">Salah and Aqeilan, 2011</xref>; <xref ref-type="bibr" rid="B63">Piccolo et&#xa0;al., 2014</xref>). YAP is a core component of the Hippo pathway and its increased expression is closely associated with different human tumor progression. When receiving conventional signals, MST1/2 phosphorylates the Thr1079/Thr1041 site of LATS1/2 upon stimulation by SAV1 and MOB1, and activated LATS1 directly phosphorylates YAP, which generates cytoplasmic isolation from the nucleus by binding to 14-3-3 proteins, ultimately limiting tissue overgrowth (<xref ref-type="bibr" rid="B51">Moroishi et&#xa0;al., 2015</xref>; <xref ref-type="bibr" rid="B12">Denic et&#xa0;al., 2020</xref>). However, when the signaling pathway is closed, the activated YAP enters the nucleus in the presence of transcription factors TEADs to induce the expression of oncoproteins such as connective tissue growth factor (CTGF) and cysteine-rich angiogenic inducer 61 (CYR61), which further promoting cancer development (<xref ref-type="bibr" rid="B51">Moroishi et&#xa0;al., 2015</xref>; <xref ref-type="bibr" rid="B41">Li et&#xa0;al., 2017b</xref>; <xref ref-type="bibr" rid="B38">Li et&#xa0;al., 2018</xref>).</p>
<p>Several studies have demonstrated that CagA-positive <italic>H. pylori</italic> infection induces abnormal Hippo signaling in GECs and promotes the activation and nucleation of the critical effector molecule YAP, during which CagA upregulates LATS2 and significantly increases the expression of YAP and TAZ, which induces the expression of downstream target genes, thereby inducing EMT and intestinal epithelial to increase the risk of early GC (<xref ref-type="fig" rid="f2">
<bold>Figure&#xa0;2E</bold>
</xref>) (<xref ref-type="bibr" rid="B49">Mo et&#xa0;al., 2015</xref>; <xref ref-type="bibr" rid="B50">Molina-Castro et&#xa0;al., 2020</xref>). Studies have shown that the activation of YAP into the nucleus increases in <italic>H. pylori</italic>-positive chronic gastritis, the expression of E-cadherin decreases and the expression of CTGF and CYR61 increases, which ultimately leads to the invasion and migration of gastric adenocarcinoma cells and promotes oncogenic EMT transformation (<xref ref-type="bibr" rid="B38">Li et&#xa0;al., 2018</xref>). Blocking the abnormal activation of the Hippo signaling pathway through inhibiting YAP is also one of the ways to treat GC (<xref ref-type="bibr" rid="B94">Xiao et&#xa0;al., 2023</xref>).</p>
</sec>
</sec>
<sec id="s5" sec-type="conclusions">
<label>5</label>
<title>Conclusions and perspectives</title>
<p>GC is one type of cancer that develops gradually through a multi-step histopathological cascade reaction over a long period of time (<xref ref-type="bibr" rid="B20">Hatakeyama, 2014</xref>). Breaking through its treatment bottleneck is still one of the challenges in the medical field today, and <italic>H. pylori</italic> infection as a key factor inducing GC is naturally a key breakthrough point. CagA is undoubtedly the most critical entry point as the best of many pathogenic factors of <italic>H. pylori</italic>. It is not difficult to find that disrupting key cell signaling pathways and inducing various pathological changes in host cells is the key to the oncogenicity of CagA by synthesizing the exposition in this paper. Abnormally transduced signaling pathways induce the following changes in the host, among others: (1) Promoting morphological changes (Hummingbird phenotype, EMT); (2) Facilitating immune dysregulation and exacerbating inflammatory responses; (3) Inducing gene mutations and inhibiting apoptosis, releasing sustained proliferative signals to increase cancer risk; (4) Regulate gene transcription, downregulate multiple tumor suppressors such as RUNX3, p53, and Siva1, and reduce oncogenic activity. These findings systematically demonstrate the mechanism of CagA in <italic>H. pylori</italic>-induced transformation of chronic gastritis to GC, so blocking the expression of key factors in MAPK signaling pathway, PI3K/Akt signaling pathway, NF-&#x3ba;B signaling pathway, JAK-STAT signaling pathway, Wnt/&#x3b2;-catenin signaling pathway, and Hippo signaling pathway, will be a new strategy to eradicate <italic>H. pylori</italic> and treat GC.</p>
</sec>
<sec id="s6" sec-type="author-contributions">
<title>Author contributions</title>
<p>HW, MZ, and LZ concepted and designed the review. MZ, FS and SZ wrote the manuscript. HW, LX, and LZ revised the manuscript. HW and MZ should be considered joint first author. All authors contributed to the article and approved the submitted version.</p>
</sec>
</body>
<back>
<sec id="s7" sec-type="COI-statement">
<title>Conflict of interest</title>
<p>The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</p>
</sec>
<sec id="s8" sec-type="disclaimer">
<title>Publisher&#x2019;s note</title>
<p>All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.</p>
</sec>
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<title>References</title>
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