Functions and Clinical Significance of CACNA2D1 in Gastric Cancer
Background Voltage-gated calcium channels form as a complex of several subunits, among which the function of CACNA2D1, one of the genes encoding the α2δ subunit, remains unclear. The aim of our study was to investigate the role of CACNA2D1 and evaluate the efficacy of amlodipine, a blocker of CACNA2...
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| Veröffentlicht in: | Annals of surgical oncology 2022-07, Vol.29 (7), p.4522-4535 |
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| creator | Inoue, Hiroyuki Shiozaki, Atsushi Kosuga, Toshiyuki Shimizu, Hiroki Kudou, Michihiro Ohashi, Takuma Arita, Tomohiro Konishi, Hirotaka Komatsu, Shuhei Kubota, Takeshi Fujiwara, Hitoshi Okamoto, Kazuma Kishimoto, Mitsuo Konishi, Eiichi Otsuji, Eigo |
| description | Background
Voltage-gated calcium channels form as a complex of several subunits, among which the function of CACNA2D1, one of the genes encoding the α2δ subunit, remains unclear. The aim of our study was to investigate the role of CACNA2D1 and evaluate the efficacy of amlodipine, a blocker of CACNA2D1, in the treatment of gastric cancer (GC).
Methods
Knockdown experiments were performed on the human GC cell lines MKN7 and HGC27 using CACNA2D1 small interfering RNA (siRNA), and changes in cell proliferation, the cell cycle, apoptosis, migration, and invasion were assessed. The gene expression profiles of cells were examined using a microarray analysis. An immunohistochemical (IHC) analysis was conducted on samples obtained from 196 GC patients who underwent curative gastrectomy. In addition, the antitumor effects of amlodipine were investigated using a xenograft model.
Results
Cell proliferation, migration, and invasion were suppressed in CACNA2D1-depleted cells, and apoptosis was induced. The results of the microarray analysis showed that the apoptosis signaling pathway was enhanced via p53, BAX, and caspase 3 in CACNA2D1-depleted cells. A multivariate analysis identified high CACNA2D1 expression levels, confirmed by IHC, as an independent poor prognostic factor in GC patients. Moreover, subcutaneous tumor volumes were significantly smaller in a xenograft nude mouse model treated with a combination of amlodipine and cisplatin than in a model treated with cisplatin alone.
Conclusions
The present study indicates that CACNA2D1 regulates the apoptosis signaling pathway and may have potential as a biomarker for cancer growth and as a therapeutic target for GC. |
| doi_str_mv | 10.1245/s10434-022-11752-5 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_2653266776</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2673714466</sourcerecordid><originalsourceid>FETCH-LOGICAL-c426t-907d95e01ee8980fb110d71a493db924a5a12036dd2180df1c6decc9bc8205263</originalsourceid><addsrcrecordid>eNp9kD1PwzAQhi0Eonz9AQYUiYUl4PNnMlaBFiQEAzBbru0go9QpdjPw73FoAYmBySffc-_ZD0KngC-BMH6VADPKSkxICSA5KfkOOgCer5ioYDfXWFRlTQSfoMOU3jAGSTHfRxPKGeOUygM0nQ3BrH0fUqGDLZrOB290Vzz51-DbXAbjir4tmmnzMCXXUPhQzHVaR2-KZmzGY7TX6i65k-15hF5mN8_NbXn_OL9rpvelYUSsyxpLW3OHwbmqrnC7AMBWgmY1tYuaMM01EEyFtQQqbFswwjpj6oWpCOZE0CN0scldxf59cGmtlj4Z13U6uH5IKn-TEiGkHNHzP-hbP8SQX5cpSSUwJkaKbCgT-5Sia9Uq-qWOHwqwGgWrjWCVBasvwYrnobNt9LBYOvsz8m00A3QDpNwKry7-7v4n9hOrhIJz</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2673714466</pqid></control><display><type>article</type><title>Functions and Clinical Significance of CACNA2D1 in Gastric Cancer</title><source>Springer Nature Link eJournals</source><creator>Inoue, Hiroyuki ; Shiozaki, Atsushi ; Kosuga, Toshiyuki ; Shimizu, Hiroki ; Kudou, Michihiro ; Ohashi, Takuma ; Arita, Tomohiro ; Konishi, Hirotaka ; Komatsu, Shuhei ; Kubota, Takeshi ; Fujiwara, Hitoshi ; Okamoto, Kazuma ; Kishimoto, Mitsuo ; Konishi, Eiichi ; Otsuji, Eigo</creator><creatorcontrib>Inoue, Hiroyuki ; Shiozaki, Atsushi ; Kosuga, Toshiyuki ; Shimizu, Hiroki ; Kudou, Michihiro ; Ohashi, Takuma ; Arita, Tomohiro ; Konishi, Hirotaka ; Komatsu, Shuhei ; Kubota, Takeshi ; Fujiwara, Hitoshi ; Okamoto, Kazuma ; Kishimoto, Mitsuo ; Konishi, Eiichi ; Otsuji, Eigo</creatorcontrib><description>Background
Voltage-gated calcium channels form as a complex of several subunits, among which the function of CACNA2D1, one of the genes encoding the α2δ subunit, remains unclear. The aim of our study was to investigate the role of CACNA2D1 and evaluate the efficacy of amlodipine, a blocker of CACNA2D1, in the treatment of gastric cancer (GC).
Methods
Knockdown experiments were performed on the human GC cell lines MKN7 and HGC27 using CACNA2D1 small interfering RNA (siRNA), and changes in cell proliferation, the cell cycle, apoptosis, migration, and invasion were assessed. The gene expression profiles of cells were examined using a microarray analysis. An immunohistochemical (IHC) analysis was conducted on samples obtained from 196 GC patients who underwent curative gastrectomy. In addition, the antitumor effects of amlodipine were investigated using a xenograft model.
Results
Cell proliferation, migration, and invasion were suppressed in CACNA2D1-depleted cells, and apoptosis was induced. The results of the microarray analysis showed that the apoptosis signaling pathway was enhanced via p53, BAX, and caspase 3 in CACNA2D1-depleted cells. A multivariate analysis identified high CACNA2D1 expression levels, confirmed by IHC, as an independent poor prognostic factor in GC patients. Moreover, subcutaneous tumor volumes were significantly smaller in a xenograft nude mouse model treated with a combination of amlodipine and cisplatin than in a model treated with cisplatin alone.
Conclusions
The present study indicates that CACNA2D1 regulates the apoptosis signaling pathway and may have potential as a biomarker for cancer growth and as a therapeutic target for GC.</description><identifier>ISSN: 1068-9265</identifier><identifier>EISSN: 1534-4681</identifier><identifier>DOI: 10.1245/s10434-022-11752-5</identifier><identifier>PMID: 35445337</identifier><language>eng</language><publisher>Cham: Springer International Publishing</publisher><subject>Antitumor activity ; Apoptosis ; Calcium channels ; Calcium channels (voltage-gated) ; Caspase-3 ; Cell cycle ; Cell growth ; Cell migration ; Cell proliferation ; Cisplatin ; Clinical significance ; DNA microarrays ; Gastrectomy ; Gastric cancer ; Gene expression ; Medicine ; Medicine & Public Health ; Multivariate analysis ; Oncology ; p53 Protein ; Patients ; Signal transduction ; siRNA ; Surgery ; Surgical Oncology ; Therapeutic targets ; Translational Research ; Tumors ; Xenografts</subject><ispartof>Annals of surgical oncology, 2022-07, Vol.29 (7), p.4522-4535</ispartof><rights>Society of Surgical Oncology 2022</rights><rights>2022. Society of Surgical Oncology.</rights><rights>Society of Surgical Oncology 2022.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c426t-907d95e01ee8980fb110d71a493db924a5a12036dd2180df1c6decc9bc8205263</citedby><cites>FETCH-LOGICAL-c426t-907d95e01ee8980fb110d71a493db924a5a12036dd2180df1c6decc9bc8205263</cites><orcidid>0000-0003-3739-160X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1245/s10434-022-11752-5$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1245/s10434-022-11752-5$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35445337$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Inoue, Hiroyuki</creatorcontrib><creatorcontrib>Shiozaki, Atsushi</creatorcontrib><creatorcontrib>Kosuga, Toshiyuki</creatorcontrib><creatorcontrib>Shimizu, Hiroki</creatorcontrib><creatorcontrib>Kudou, Michihiro</creatorcontrib><creatorcontrib>Ohashi, Takuma</creatorcontrib><creatorcontrib>Arita, Tomohiro</creatorcontrib><creatorcontrib>Konishi, Hirotaka</creatorcontrib><creatorcontrib>Komatsu, Shuhei</creatorcontrib><creatorcontrib>Kubota, Takeshi</creatorcontrib><creatorcontrib>Fujiwara, Hitoshi</creatorcontrib><creatorcontrib>Okamoto, Kazuma</creatorcontrib><creatorcontrib>Kishimoto, Mitsuo</creatorcontrib><creatorcontrib>Konishi, Eiichi</creatorcontrib><creatorcontrib>Otsuji, Eigo</creatorcontrib><title>Functions and Clinical Significance of CACNA2D1 in Gastric Cancer</title><title>Annals of surgical oncology</title><addtitle>Ann Surg Oncol</addtitle><addtitle>Ann Surg Oncol</addtitle><description>Background
Voltage-gated calcium channels form as a complex of several subunits, among which the function of CACNA2D1, one of the genes encoding the α2δ subunit, remains unclear. The aim of our study was to investigate the role of CACNA2D1 and evaluate the efficacy of amlodipine, a blocker of CACNA2D1, in the treatment of gastric cancer (GC).
Methods
Knockdown experiments were performed on the human GC cell lines MKN7 and HGC27 using CACNA2D1 small interfering RNA (siRNA), and changes in cell proliferation, the cell cycle, apoptosis, migration, and invasion were assessed. The gene expression profiles of cells were examined using a microarray analysis. An immunohistochemical (IHC) analysis was conducted on samples obtained from 196 GC patients who underwent curative gastrectomy. In addition, the antitumor effects of amlodipine were investigated using a xenograft model.
Results
Cell proliferation, migration, and invasion were suppressed in CACNA2D1-depleted cells, and apoptosis was induced. The results of the microarray analysis showed that the apoptosis signaling pathway was enhanced via p53, BAX, and caspase 3 in CACNA2D1-depleted cells. A multivariate analysis identified high CACNA2D1 expression levels, confirmed by IHC, as an independent poor prognostic factor in GC patients. Moreover, subcutaneous tumor volumes were significantly smaller in a xenograft nude mouse model treated with a combination of amlodipine and cisplatin than in a model treated with cisplatin alone.
Conclusions
The present study indicates that CACNA2D1 regulates the apoptosis signaling pathway and may have potential as a biomarker for cancer growth and as a therapeutic target for GC.</description><subject>Antitumor activity</subject><subject>Apoptosis</subject><subject>Calcium channels</subject><subject>Calcium channels (voltage-gated)</subject><subject>Caspase-3</subject><subject>Cell cycle</subject><subject>Cell growth</subject><subject>Cell migration</subject><subject>Cell proliferation</subject><subject>Cisplatin</subject><subject>Clinical significance</subject><subject>DNA microarrays</subject><subject>Gastrectomy</subject><subject>Gastric cancer</subject><subject>Gene expression</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Multivariate analysis</subject><subject>Oncology</subject><subject>p53 Protein</subject><subject>Patients</subject><subject>Signal transduction</subject><subject>siRNA</subject><subject>Surgery</subject><subject>Surgical Oncology</subject><subject>Therapeutic targets</subject><subject>Translational Research</subject><subject>Tumors</subject><subject>Xenografts</subject><issn>1068-9265</issn><issn>1534-4681</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>BENPR</sourceid><recordid>eNp9kD1PwzAQhi0Eonz9AQYUiYUl4PNnMlaBFiQEAzBbru0go9QpdjPw73FoAYmBySffc-_ZD0KngC-BMH6VADPKSkxICSA5KfkOOgCer5ioYDfXWFRlTQSfoMOU3jAGSTHfRxPKGeOUygM0nQ3BrH0fUqGDLZrOB290Vzz51-DbXAbjir4tmmnzMCXXUPhQzHVaR2-KZmzGY7TX6i65k-15hF5mN8_NbXn_OL9rpvelYUSsyxpLW3OHwbmqrnC7AMBWgmY1tYuaMM01EEyFtQQqbFswwjpj6oWpCOZE0CN0scldxf59cGmtlj4Z13U6uH5IKn-TEiGkHNHzP-hbP8SQX5cpSSUwJkaKbCgT-5Sia9Uq-qWOHwqwGgWrjWCVBasvwYrnobNt9LBYOvsz8m00A3QDpNwKry7-7v4n9hOrhIJz</recordid><startdate>20220701</startdate><enddate>20220701</enddate><creator>Inoue, Hiroyuki</creator><creator>Shiozaki, Atsushi</creator><creator>Kosuga, Toshiyuki</creator><creator>Shimizu, Hiroki</creator><creator>Kudou, Michihiro</creator><creator>Ohashi, Takuma</creator><creator>Arita, Tomohiro</creator><creator>Konishi, Hirotaka</creator><creator>Komatsu, Shuhei</creator><creator>Kubota, Takeshi</creator><creator>Fujiwara, Hitoshi</creator><creator>Okamoto, Kazuma</creator><creator>Kishimoto, Mitsuo</creator><creator>Konishi, Eiichi</creator><creator>Otsuji, Eigo</creator><general>Springer International Publishing</general><general>Springer Nature B.V</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7TO</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-3739-160X</orcidid></search><sort><creationdate>20220701</creationdate><title>Functions and Clinical Significance of CACNA2D1 in Gastric Cancer</title><author>Inoue, Hiroyuki ; Shiozaki, Atsushi ; Kosuga, Toshiyuki ; Shimizu, Hiroki ; Kudou, Michihiro ; Ohashi, Takuma ; Arita, Tomohiro ; Konishi, Hirotaka ; Komatsu, Shuhei ; Kubota, Takeshi ; Fujiwara, Hitoshi ; Okamoto, Kazuma ; Kishimoto, Mitsuo ; Konishi, Eiichi ; Otsuji, Eigo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c426t-907d95e01ee8980fb110d71a493db924a5a12036dd2180df1c6decc9bc8205263</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Antitumor activity</topic><topic>Apoptosis</topic><topic>Calcium channels</topic><topic>Calcium channels (voltage-gated)</topic><topic>Caspase-3</topic><topic>Cell cycle</topic><topic>Cell growth</topic><topic>Cell migration</topic><topic>Cell proliferation</topic><topic>Cisplatin</topic><topic>Clinical significance</topic><topic>DNA microarrays</topic><topic>Gastrectomy</topic><topic>Gastric cancer</topic><topic>Gene expression</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Multivariate analysis</topic><topic>Oncology</topic><topic>p53 Protein</topic><topic>Patients</topic><topic>Signal transduction</topic><topic>siRNA</topic><topic>Surgery</topic><topic>Surgical Oncology</topic><topic>Therapeutic targets</topic><topic>Translational Research</topic><topic>Tumors</topic><topic>Xenografts</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Inoue, Hiroyuki</creatorcontrib><creatorcontrib>Shiozaki, Atsushi</creatorcontrib><creatorcontrib>Kosuga, Toshiyuki</creatorcontrib><creatorcontrib>Shimizu, Hiroki</creatorcontrib><creatorcontrib>Kudou, Michihiro</creatorcontrib><creatorcontrib>Ohashi, Takuma</creatorcontrib><creatorcontrib>Arita, Tomohiro</creatorcontrib><creatorcontrib>Konishi, Hirotaka</creatorcontrib><creatorcontrib>Komatsu, Shuhei</creatorcontrib><creatorcontrib>Kubota, Takeshi</creatorcontrib><creatorcontrib>Fujiwara, Hitoshi</creatorcontrib><creatorcontrib>Okamoto, Kazuma</creatorcontrib><creatorcontrib>Kishimoto, Mitsuo</creatorcontrib><creatorcontrib>Konishi, Eiichi</creatorcontrib><creatorcontrib>Otsuji, Eigo</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>ProQuest - Health & Medical Complete保健、医学与药学数据库</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><jtitle>Annals of surgical oncology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Inoue, Hiroyuki</au><au>Shiozaki, Atsushi</au><au>Kosuga, Toshiyuki</au><au>Shimizu, Hiroki</au><au>Kudou, Michihiro</au><au>Ohashi, Takuma</au><au>Arita, Tomohiro</au><au>Konishi, Hirotaka</au><au>Komatsu, Shuhei</au><au>Kubota, Takeshi</au><au>Fujiwara, Hitoshi</au><au>Okamoto, Kazuma</au><au>Kishimoto, Mitsuo</au><au>Konishi, Eiichi</au><au>Otsuji, Eigo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Functions and Clinical Significance of CACNA2D1 in Gastric Cancer</atitle><jtitle>Annals of surgical oncology</jtitle><stitle>Ann Surg Oncol</stitle><addtitle>Ann Surg Oncol</addtitle><date>2022-07-01</date><risdate>2022</risdate><volume>29</volume><issue>7</issue><spage>4522</spage><epage>4535</epage><pages>4522-4535</pages><issn>1068-9265</issn><eissn>1534-4681</eissn><abstract>Background
Voltage-gated calcium channels form as a complex of several subunits, among which the function of CACNA2D1, one of the genes encoding the α2δ subunit, remains unclear. The aim of our study was to investigate the role of CACNA2D1 and evaluate the efficacy of amlodipine, a blocker of CACNA2D1, in the treatment of gastric cancer (GC).
Methods
Knockdown experiments were performed on the human GC cell lines MKN7 and HGC27 using CACNA2D1 small interfering RNA (siRNA), and changes in cell proliferation, the cell cycle, apoptosis, migration, and invasion were assessed. The gene expression profiles of cells were examined using a microarray analysis. An immunohistochemical (IHC) analysis was conducted on samples obtained from 196 GC patients who underwent curative gastrectomy. In addition, the antitumor effects of amlodipine were investigated using a xenograft model.
Results
Cell proliferation, migration, and invasion were suppressed in CACNA2D1-depleted cells, and apoptosis was induced. The results of the microarray analysis showed that the apoptosis signaling pathway was enhanced via p53, BAX, and caspase 3 in CACNA2D1-depleted cells. A multivariate analysis identified high CACNA2D1 expression levels, confirmed by IHC, as an independent poor prognostic factor in GC patients. Moreover, subcutaneous tumor volumes were significantly smaller in a xenograft nude mouse model treated with a combination of amlodipine and cisplatin than in a model treated with cisplatin alone.
Conclusions
The present study indicates that CACNA2D1 regulates the apoptosis signaling pathway and may have potential as a biomarker for cancer growth and as a therapeutic target for GC.</abstract><cop>Cham</cop><pub>Springer International Publishing</pub><pmid>35445337</pmid><doi>10.1245/s10434-022-11752-5</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0003-3739-160X</orcidid></addata></record> |
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| subjects | Antitumor activity Apoptosis Calcium channels Calcium channels (voltage-gated) Caspase-3 Cell cycle Cell growth Cell migration Cell proliferation Cisplatin Clinical significance DNA microarrays Gastrectomy Gastric cancer Gene expression Medicine Medicine & Public Health Multivariate analysis Oncology p53 Protein Patients Signal transduction siRNA Surgery Surgical Oncology Therapeutic targets Translational Research Tumors Xenografts |
| title | Functions and Clinical Significance of CACNA2D1 in Gastric Cancer |
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