PLEK2 promotes gallbladder cancer invasion and metastasis through EGFR/CCL2 pathway
Identifieur interne : 000555 ( Main/Exploration ); précédent : 000554; suivant : 000556PLEK2 promotes gallbladder cancer invasion and metastasis through EGFR/CCL2 pathway
Auteurs : Hui Shen [République populaire de Chine] ; Min He [République populaire de Chine] ; Ruirong Lin [République populaire de Chine] ; Ming Zhan [République populaire de Chine] ; Sunwang Xu [République populaire de Chine] ; Xince Huang [République populaire de Chine] ; Chu Xu [République populaire de Chine] ; Wei Chen [République populaire de Chine] ; Yanhua Yao [République populaire de Chine] ; Man Mohan [République populaire de Chine] ; Jian Wang [République populaire de Chine]Source :
- Journal of Experimental & Clinical Cancer Research : CR [ 0392-9078 ] ; 2019.
Abstract
Gallbladder cancer (GBC) is an extremely malignant tumor with a high mortality rate. Little is known about its invasion and metastasis mechanism so far.
To identify the driver genes in GBC metastasis, we performed a mRNA microarray of metastatic GBC and paired non-tumor samples, and found PLEK2 was markedly upregulated in GBC tissues. Next, the expression of PLEK2 in GBC were examined in a larger cohort of patients by qRT-PCR, western blot and IHC staining. The clinicopathologic correlation of PLEK2 was determined by statistical analyses. The biological involvement of PLEK2 in GBC metastasis and the underlying mechanisms were investigated.
In this study, we found that PLEK2 had higher expression in GBC tumor tissues compared to non-cancerous adjacent tissues and cholecystolithiasis tissues. The clinicopathologic analyses showed PLEK2 expression was positively correlated with tumor TNM stage, distant metastasis and PLEK2 was an independent predictor of overall survival (OS) in GBC patients. The cellular function assays showed PLEK2 promoted GBC cells migration, invasion and liver metastasis in mouse model via the regulation of epithelial-mesenchymal transition (EMT) process. Our mass spectrum and co-immunoprecipitation (co-IP) assays demonstrated that PLEK2 could interact with the kinase domain of EGFR and suppress EGFR ubiquitination mediated by c-CBL, leading to constitutive activation of EGFR signaling. Furthermore, RNA-sequencing and qRT-PCR results demonstrated chemokine (C-C motif) ligand 2 (CCL2), a target gene downstream of PLEK2/EGFR signaling, mediated the motility-promoting function of PLEK2.
On the basis of these collective data, we propose that PLEK2 promotes the invasion and metastasis of GBC by EGFR/CCL2 pathway and PLEK2 can serve as a potential therapeutic target for GBC treatment.
The online version of this article (10.1186/s13046-019-1250-8) contains supplementary material, which is available to authorized users.
Url:
DOI: 10.1186/s13046-019-1250-8
PubMed: 31182136
PubMed Central: 6558801
Affiliations:
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Chine</country><wicri:regionArea>Shanghai</wicri:regionArea></affiliation></author><author><name sortKey="Mohan, Man" sort="Mohan, Man" uniqKey="Mohan M" first="Man" last="Mohan">Man Mohan</name><affiliation wicri:level="1"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0368 8293</institution-id><institution-id institution-id-type="GRID">grid.16821.3c</institution-id><institution>Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Institutes of Medical Sciences, School of Medicine,</institution><institution>Shanghai Jiao Tong University,</institution></institution-wrap>Shanghai, 200025 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Shanghai</wicri:regionArea></affiliation></author><author><name sortKey="Wang, Jian" sort="Wang, Jian" uniqKey="Wang J" first="Jian" last="Wang">Jian Wang</name><affiliation wicri:level="1"><nlm:aff 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last="Shen">Hui Shen</name><affiliation wicri:level="1"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0368 8293</institution-id><institution-id institution-id-type="GRID">grid.16821.3c</institution-id><institution>Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine,</institution><institution>Shanghai Jiao Tong University,</institution></institution-wrap>160 Pujian Road, Shanghai, 200127 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>160 Pujian Road, Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author><author><name sortKey="He, Min" sort="He, Min" uniqKey="He M" first="Min" last="He">Min He</name><affiliation wicri:level="1"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0368 8293</institution-id><institution-id institution-id-type="GRID">grid.16821.3c</institution-id><institution>Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine,</institution><institution>Shanghai Jiao Tong University,</institution></institution-wrap>160 Pujian Road, Shanghai, 200127 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>160 Pujian Road, Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author><author><name sortKey="Lin, Ruirong" sort="Lin, Ruirong" uniqKey="Lin R" first="Ruirong" last="Lin">Ruirong Lin</name><affiliation wicri:level="1"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0368 8293</institution-id><institution-id institution-id-type="GRID">grid.16821.3c</institution-id><institution>Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine,</institution><institution>Shanghai Jiao Tong University,</institution></institution-wrap>160 Pujian Road, Shanghai, 200127 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>160 Pujian Road, Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author><author><name sortKey="Zhan, Ming" sort="Zhan, Ming" uniqKey="Zhan M" first="Ming" last="Zhan">Ming Zhan</name><affiliation wicri:level="1"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0368 8293</institution-id><institution-id institution-id-type="GRID">grid.16821.3c</institution-id><institution>Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine,</institution><institution>Shanghai Jiao Tong University,</institution></institution-wrap>160 Pujian Road, Shanghai, 200127 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>160 Pujian Road, Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author><author><name sortKey="Xu, Sunwang" sort="Xu, Sunwang" uniqKey="Xu S" first="Sunwang" last="Xu">Sunwang Xu</name><affiliation wicri:level="1"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0368 8293</institution-id><institution-id institution-id-type="GRID">grid.16821.3c</institution-id><institution>Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine,</institution><institution>Shanghai Jiao Tong University,</institution></institution-wrap>160 Pujian Road, Shanghai, 200127 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>160 Pujian Road, Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author><author><name sortKey="Huang, Xince" sort="Huang, Xince" uniqKey="Huang X" first="Xince" last="Huang">Xince Huang</name><affiliation wicri:level="1"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0368 8293</institution-id><institution-id institution-id-type="GRID">grid.16821.3c</institution-id><institution>Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine,</institution><institution>Shanghai Jiao Tong University,</institution></institution-wrap>160 Pujian Road, Shanghai, 200127 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>160 Pujian Road, Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author><author><name sortKey="Xu, Chu" sort="Xu, Chu" uniqKey="Xu C" first="Chu" last="Xu">Chu Xu</name><affiliation wicri:level="1"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0368 8293</institution-id><institution-id institution-id-type="GRID">grid.16821.3c</institution-id><institution>Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Institutes of Medical Sciences, School of Medicine,</institution><institution>Shanghai Jiao Tong University,</institution></institution-wrap>Shanghai, 200025 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Shanghai</wicri:regionArea></affiliation></author><author><name sortKey="Chen, Wei" sort="Chen, Wei" uniqKey="Chen W" first="Wei" last="Chen">Wei Chen</name><affiliation wicri:level="1"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0368 8293</institution-id><institution-id institution-id-type="GRID">grid.16821.3c</institution-id><institution>Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine,</institution><institution>Shanghai Jiao Tong University,</institution></institution-wrap>160 Pujian Road, Shanghai, 200127 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>160 Pujian Road, Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author><author><name sortKey="Yao, Yanhua" sort="Yao, Yanhua" uniqKey="Yao Y" first="Yanhua" last="Yao">Yanhua Yao</name><affiliation wicri:level="1"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0368 8293</institution-id><institution-id institution-id-type="GRID">grid.16821.3c</institution-id><institution>Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Institutes of Medical Sciences, School of Medicine,</institution><institution>Shanghai Jiao Tong University,</institution></institution-wrap>Shanghai, 200025 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Shanghai</wicri:regionArea></affiliation></author><author><name sortKey="Mohan, Man" sort="Mohan, Man" uniqKey="Mohan M" first="Man" last="Mohan">Man Mohan</name><affiliation wicri:level="1"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0368 8293</institution-id><institution-id institution-id-type="GRID">grid.16821.3c</institution-id><institution>Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Institutes of Medical Sciences, School of Medicine,</institution><institution>Shanghai Jiao Tong University,</institution></institution-wrap>Shanghai, 200025 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Shanghai</wicri:regionArea></affiliation></author><author><name sortKey="Wang, Jian" sort="Wang, Jian" uniqKey="Wang J" first="Jian" last="Wang">Jian Wang</name><affiliation wicri:level="1"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0368 8293</institution-id><institution-id institution-id-type="GRID">grid.16821.3c</institution-id><institution>Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine,</institution><institution>Shanghai Jiao Tong University,</institution></institution-wrap>160 Pujian Road, Shanghai, 200127 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>160 Pujian Road, Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author></analytic><series><title level="j">Journal of Experimental & Clinical Cancer Research : CR</title><idno type="ISSN">0392-9078</idno><idno type="eISSN">1756-9966</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Background</title><p id="Par1">Gallbladder cancer (GBC) is an extremely malignant tumor with a high mortality rate. Little is known about its invasion and metastasis mechanism so far.</p></sec><sec><title>Methods</title><p id="Par2">To identify the driver genes in GBC metastasis, we performed a mRNA microarray of metastatic GBC and paired non-tumor samples, and found PLEK2 was markedly upregulated in GBC tissues. Next, the expression of PLEK2 in GBC were examined in a larger cohort of patients by qRT-PCR, western blot and IHC staining. The clinicopathologic correlation of PLEK2 was determined by statistical analyses. The biological involvement of PLEK2 in GBC metastasis and the underlying mechanisms were investigated.</p></sec><sec><title>Results</title><p id="Par3">In this study, we found that PLEK2 had higher expression in GBC tumor tissues compared to non-cancerous adjacent tissues and cholecystolithiasis tissues. The clinicopathologic analyses showed PLEK2 expression was positively correlated with tumor TNM stage, distant metastasis and PLEK2 was an independent predictor of overall survival (OS) in GBC patients. The cellular function assays showed PLEK2 promoted GBC cells migration, invasion and liver metastasis in mouse model via the regulation of epithelial-mesenchymal transition (EMT) process. Our mass spectrum and co-immunoprecipitation (co-IP) assays demonstrated that PLEK2 could interact with the kinase domain of EGFR and suppress EGFR ubiquitination mediated by c-CBL, leading to constitutive activation of EGFR signaling. Furthermore, RNA-sequencing and qRT-PCR results demonstrated chemokine (C-C motif) ligand 2 (CCL2), a target gene downstream of PLEK2/EGFR signaling, mediated the motility-promoting function of PLEK2.</p></sec><sec><title>Conclusions</title><p id="Par4">On the basis of these collective data, we propose that PLEK2 promotes the invasion and metastasis of GBC by EGFR/CCL2 pathway and PLEK2 can serve as a potential therapeutic target for GBC treatment.</p></sec><sec><title>Electronic supplementary material</title><p>The online version of this article (10.1186/s13046-019-1250-8) contains supplementary material, which is available to authorized users.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Jemal, A" uniqKey="Jemal A">A Jemal</name></author><author><name sortKey="Siegel, R" uniqKey="Siegel R">R Siegel</name></author><author><name sortKey="Xu, J" uniqKey="Xu J">J Xu</name></author><author><name sortKey="Ward, E" 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H">H Li</name></author><author><name sortKey="Wu, H" uniqKey="Wu H">H Wu</name></author><author><name sortKey="Li, J" uniqKey="Li J">J Li</name></author><author><name sortKey="Wang, L" uniqKey="Wang L">L Wang</name></author><author><name sortKey="Li, M" uniqKey="Li M">M Li</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>République populaire de Chine</li></country></list><tree><country name="République populaire de Chine"><noRegion><name sortKey="Shen, Hui" sort="Shen, Hui" uniqKey="Shen H" first="Hui" last="Shen">Hui Shen</name></noRegion><name sortKey="Chen, Wei" sort="Chen, Wei" uniqKey="Chen W" first="Wei" last="Chen">Wei Chen</name><name sortKey="He, Min" sort="He, Min" uniqKey="He M" first="Min" last="He">Min He</name><name sortKey="Huang, Xince" sort="Huang, Xince" uniqKey="Huang X" first="Xince" last="Huang">Xince Huang</name><name sortKey="Lin, Ruirong" sort="Lin, Ruirong" uniqKey="Lin R" first="Ruirong" last="Lin">Ruirong Lin</name><name sortKey="Mohan, Man" sort="Mohan, Man" uniqKey="Mohan M" first="Man" last="Mohan">Man Mohan</name><name sortKey="Wang, Jian" sort="Wang, Jian" uniqKey="Wang J" first="Jian" last="Wang">Jian Wang</name><name sortKey="Xu, Chu" sort="Xu, Chu" uniqKey="Xu C" first="Chu" last="Xu">Chu Xu</name><name sortKey="Xu, Sunwang" sort="Xu, Sunwang" uniqKey="Xu S" first="Sunwang" last="Xu">Sunwang Xu</name><name sortKey="Yao, Yanhua" sort="Yao, Yanhua" uniqKey="Yao Y" first="Yanhua" last="Yao">Yanhua Yao</name><name sortKey="Zhan, Ming" sort="Zhan, Ming" uniqKey="Zhan M" first="Ming" last="Zhan">Ming Zhan</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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