Killer cell lectin-like receptor G2 facilitates aggressive phenotypes of gastric cancer cells via dual activation of the ERK1/2 and JAK/STAT pathways
Background Advanced gastric cancer (GC) has a poor prognosis. This study aimed to identify novel GC-related genes as potential therapeutic targets. Methods Killer cell lectin-like receptor G2 ( KLRG2 ) was identified as a candidate gene by transcriptome analysis of metastatic GC tissues. Small inter...
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| Veröffentlicht in: | Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 2024-05, Vol.27 (3), p.506-518 |
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| creator | Ito, Yuki Kanda, Mitsuro Sasahara, Masahiro Tanaka, Chie Shimizu, Dai Umeda, Shinichi Inokawa, Yoshikuni Hattori, Norifumi Hayashi, Masamichi Nakayama, Goro Kodera, Yasuhiro |
| description | Background
Advanced gastric cancer (GC) has a poor prognosis. This study aimed to identify novel GC-related genes as potential therapeutic targets.
Methods
Killer cell lectin-like receptor G2 (
KLRG2
) was identified as a candidate gene by transcriptome analysis of metastatic GC tissues. Small interfering RNA-mediated
KLRG2
knockdown in human GC cell lines was used to investigate KLRG2 involvement in signaling pathways and functional behaviors in vitro and in vivo. Clinicopathological data were analyzed in patients stratified according to tumor
KLRG2
mRNA expression.
Results
KLRG2
knockdown in GC cells decreased cell proliferation, migration, and invasion; caused cell cycle arrest in G
2
/M phase; induced apoptosis via caspase activation; suppressed JAK/STAT and MAPK-ERK1/2 pathway activities; and upregulated p53 and p38 MAPK activities. In mouse xenograft models of peritoneal metastasis, the number and weight of disseminated GC nodules were decreased by
KLRG2
knockdown. High tumor levels of
KLRG2
mRNA were significantly associated with lower 5-year overall survival (OS) and relapse-free survival (RFS) rates in patients with Stage I–III GC (5-year OS rate: 64.4% vs. 80.0%,
P
= 0.009; 5-year RFS rate: 62.8% vs. 78.1%,
P
= 0.030).
Conclusions
KLRG2
knockdown attenuated the malignant phenotypes of GC cells via downregulation of JAK/STAT and MAPK-ERK1/2 pathway activity and upregulation of p38 MAPK and p53. Targeted suppression of KLRG2 may serve as a new treatment approach for GC. |
| doi_str_mv | 10.1007/s10120-024-01480-y |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_proquest_miscellaneous_2930475975</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>3038614956</sourcerecordid><originalsourceid>FETCH-LOGICAL-p213t-cb3a60480c505db54f3df66d1774e664a699e0cf837b45e646d789f6011a6c653</originalsourceid><addsrcrecordid>eNpdkd2O0zAQhS0EYn_gBbhAlrjhJnQc_yS5rFbLLnQlJCjXlutMWi9uEmynKA_C--LSrpC4mtHMp6OZcwh5w-ADA6gWkQEroYBSFMBEDcX8jFwywVXBOcjnT33ZsAtyFeMjAJMNUy_JBa95rUpeXZLfK-c9BmrRe-rRJtcX3v1AGtDimIZA70raGeu8SyZhpGa7DRijOyAdd9gPaR7zdOjo1sQUnKXW9PYsGOnBGdpOxlOTlQ8muaE_smmH9Pbrii1KavqWfl6uFt_WyzUdTdr9MnN8RV50xkd8fa7X5PvH2_XNffHw5e7TzfKhGEvGU2E33CjIn1sJst1I0fG2U6plVSVQKWFU0yDYrubVRkhUQrVV3XQKGDPKKsmvyfuT7hiGnxPGpPcuHi83PQ5T1GXDQVSyqY7ou__Qx2EKfb5Oc8huMtFIlam3Z2ra7LHVY3B7E2b9ZHgG-AmIedVvMfyTYaCPsepTrDrHqv_Gqmf-B4mSkoU</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>3038614956</pqid></control><display><type>article</type><title>Killer cell lectin-like receptor G2 facilitates aggressive phenotypes of gastric cancer cells via dual activation of the ERK1/2 and JAK/STAT pathways</title><source>SpringerNature Journals</source><creator>Ito, Yuki ; Kanda, Mitsuro ; Sasahara, Masahiro ; Tanaka, Chie ; Shimizu, Dai ; Umeda, Shinichi ; Inokawa, Yoshikuni ; Hattori, Norifumi ; Hayashi, Masamichi ; Nakayama, Goro ; Kodera, Yasuhiro</creator><creatorcontrib>Ito, Yuki ; Kanda, Mitsuro ; Sasahara, Masahiro ; Tanaka, Chie ; Shimizu, Dai ; Umeda, Shinichi ; Inokawa, Yoshikuni ; Hattori, Norifumi ; Hayashi, Masamichi ; Nakayama, Goro ; Kodera, Yasuhiro</creatorcontrib><description>Background
Advanced gastric cancer (GC) has a poor prognosis. This study aimed to identify novel GC-related genes as potential therapeutic targets.
Methods
Killer cell lectin-like receptor G2 (
KLRG2
) was identified as a candidate gene by transcriptome analysis of metastatic GC tissues. Small interfering RNA-mediated
KLRG2
knockdown in human GC cell lines was used to investigate KLRG2 involvement in signaling pathways and functional behaviors in vitro and in vivo. Clinicopathological data were analyzed in patients stratified according to tumor
KLRG2
mRNA expression.
Results
KLRG2
knockdown in GC cells decreased cell proliferation, migration, and invasion; caused cell cycle arrest in G
2
/M phase; induced apoptosis via caspase activation; suppressed JAK/STAT and MAPK-ERK1/2 pathway activities; and upregulated p53 and p38 MAPK activities. In mouse xenograft models of peritoneal metastasis, the number and weight of disseminated GC nodules were decreased by
KLRG2
knockdown. High tumor levels of
KLRG2
mRNA were significantly associated with lower 5-year overall survival (OS) and relapse-free survival (RFS) rates in patients with Stage I–III GC (5-year OS rate: 64.4% vs. 80.0%,
P
= 0.009; 5-year RFS rate: 62.8% vs. 78.1%,
P
= 0.030).
Conclusions
KLRG2
knockdown attenuated the malignant phenotypes of GC cells via downregulation of JAK/STAT and MAPK-ERK1/2 pathway activity and upregulation of p38 MAPK and p53. Targeted suppression of KLRG2 may serve as a new treatment approach for GC.</description><identifier>ISSN: 1436-3291</identifier><identifier>EISSN: 1436-3305</identifier><identifier>DOI: 10.1007/s10120-024-01480-y</identifier><identifier>PMID: 38386237</identifier><language>eng</language><publisher>Singapore: Springer Nature Singapore</publisher><subject>Abdominal Surgery ; Animal models ; Apoptosis ; Cancer Research ; Caspase ; Cell activation ; Cell adhesion & migration ; Cell cycle ; Cell migration ; Cell proliferation ; Down-regulation ; Extracellular signal-regulated kinase ; Gastric cancer ; Gastroenterology ; Gene expression ; Genetic engineering ; Genotype & phenotype ; Lectins ; MAP kinase ; Medical prognosis ; Medicine ; Medicine & Public Health ; Metastases ; Metastasis ; Oncology ; Original Article ; p53 Protein ; Phenotypes ; siRNA ; Surgical Oncology ; Targeted cancer therapy ; Therapeutic targets ; Transcriptomes ; Tumors</subject><ispartof>Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association, 2024-05, Vol.27 (3), p.506-518</ispartof><rights>The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.</rights><rights>2024. The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-p213t-cb3a60480c505db54f3df66d1774e664a699e0cf837b45e646d789f6011a6c653</cites><orcidid>0000-0001-5464-3819</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s10120-024-01480-y$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s10120-024-01480-y$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,780,784,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38386237$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ito, Yuki</creatorcontrib><creatorcontrib>Kanda, Mitsuro</creatorcontrib><creatorcontrib>Sasahara, Masahiro</creatorcontrib><creatorcontrib>Tanaka, Chie</creatorcontrib><creatorcontrib>Shimizu, Dai</creatorcontrib><creatorcontrib>Umeda, Shinichi</creatorcontrib><creatorcontrib>Inokawa, Yoshikuni</creatorcontrib><creatorcontrib>Hattori, Norifumi</creatorcontrib><creatorcontrib>Hayashi, Masamichi</creatorcontrib><creatorcontrib>Nakayama, Goro</creatorcontrib><creatorcontrib>Kodera, Yasuhiro</creatorcontrib><title>Killer cell lectin-like receptor G2 facilitates aggressive phenotypes of gastric cancer cells via dual activation of the ERK1/2 and JAK/STAT pathways</title><title>Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association</title><addtitle>Gastric Cancer</addtitle><addtitle>Gastric Cancer</addtitle><description>Background
Advanced gastric cancer (GC) has a poor prognosis. This study aimed to identify novel GC-related genes as potential therapeutic targets.
Methods
Killer cell lectin-like receptor G2 (
KLRG2
) was identified as a candidate gene by transcriptome analysis of metastatic GC tissues. Small interfering RNA-mediated
KLRG2
knockdown in human GC cell lines was used to investigate KLRG2 involvement in signaling pathways and functional behaviors in vitro and in vivo. Clinicopathological data were analyzed in patients stratified according to tumor
KLRG2
mRNA expression.
Results
KLRG2
knockdown in GC cells decreased cell proliferation, migration, and invasion; caused cell cycle arrest in G
2
/M phase; induced apoptosis via caspase activation; suppressed JAK/STAT and MAPK-ERK1/2 pathway activities; and upregulated p53 and p38 MAPK activities. In mouse xenograft models of peritoneal metastasis, the number and weight of disseminated GC nodules were decreased by
KLRG2
knockdown. High tumor levels of
KLRG2
mRNA were significantly associated with lower 5-year overall survival (OS) and relapse-free survival (RFS) rates in patients with Stage I–III GC (5-year OS rate: 64.4% vs. 80.0%,
P
= 0.009; 5-year RFS rate: 62.8% vs. 78.1%,
P
= 0.030).
Conclusions
KLRG2
knockdown attenuated the malignant phenotypes of GC cells via downregulation of JAK/STAT and MAPK-ERK1/2 pathway activity and upregulation of p38 MAPK and p53. Targeted suppression of KLRG2 may serve as a new treatment approach for GC.</description><subject>Abdominal Surgery</subject><subject>Animal models</subject><subject>Apoptosis</subject><subject>Cancer Research</subject><subject>Caspase</subject><subject>Cell activation</subject><subject>Cell adhesion & migration</subject><subject>Cell cycle</subject><subject>Cell migration</subject><subject>Cell proliferation</subject><subject>Down-regulation</subject><subject>Extracellular signal-regulated kinase</subject><subject>Gastric cancer</subject><subject>Gastroenterology</subject><subject>Gene expression</subject><subject>Genetic engineering</subject><subject>Genotype & phenotype</subject><subject>Lectins</subject><subject>MAP kinase</subject><subject>Medical prognosis</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Oncology</subject><subject>Original Article</subject><subject>p53 Protein</subject><subject>Phenotypes</subject><subject>siRNA</subject><subject>Surgical Oncology</subject><subject>Targeted cancer therapy</subject><subject>Therapeutic targets</subject><subject>Transcriptomes</subject><subject>Tumors</subject><issn>1436-3291</issn><issn>1436-3305</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><recordid>eNpdkd2O0zAQhS0EYn_gBbhAlrjhJnQc_yS5rFbLLnQlJCjXlutMWi9uEmynKA_C--LSrpC4mtHMp6OZcwh5w-ADA6gWkQEroYBSFMBEDcX8jFwywVXBOcjnT33ZsAtyFeMjAJMNUy_JBa95rUpeXZLfK-c9BmrRe-rRJtcX3v1AGtDimIZA70raGeu8SyZhpGa7DRijOyAdd9gPaR7zdOjo1sQUnKXW9PYsGOnBGdpOxlOTlQ8muaE_smmH9Pbrii1KavqWfl6uFt_WyzUdTdr9MnN8RV50xkd8fa7X5PvH2_XNffHw5e7TzfKhGEvGU2E33CjIn1sJst1I0fG2U6plVSVQKWFU0yDYrubVRkhUQrVV3XQKGDPKKsmvyfuT7hiGnxPGpPcuHi83PQ5T1GXDQVSyqY7ou__Qx2EKfb5Oc8huMtFIlam3Z2ra7LHVY3B7E2b9ZHgG-AmIedVvMfyTYaCPsepTrDrHqv_Gqmf-B4mSkoU</recordid><startdate>20240501</startdate><enddate>20240501</enddate><creator>Ito, Yuki</creator><creator>Kanda, Mitsuro</creator><creator>Sasahara, Masahiro</creator><creator>Tanaka, Chie</creator><creator>Shimizu, Dai</creator><creator>Umeda, Shinichi</creator><creator>Inokawa, Yoshikuni</creator><creator>Hattori, Norifumi</creator><creator>Hayashi, Masamichi</creator><creator>Nakayama, Goro</creator><creator>Kodera, Yasuhiro</creator><general>Springer Nature Singapore</general><general>Springer Nature B.V</general><scope>NPM</scope><scope>7T5</scope><scope>H94</scope><scope>K9.</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-5464-3819</orcidid></search><sort><creationdate>20240501</creationdate><title>Killer cell lectin-like receptor G2 facilitates aggressive phenotypes of gastric cancer cells via dual activation of the ERK1/2 and JAK/STAT pathways</title><author>Ito, Yuki ; Kanda, Mitsuro ; Sasahara, Masahiro ; Tanaka, Chie ; Shimizu, Dai ; Umeda, Shinichi ; Inokawa, Yoshikuni ; Hattori, Norifumi ; Hayashi, Masamichi ; Nakayama, Goro ; Kodera, Yasuhiro</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p213t-cb3a60480c505db54f3df66d1774e664a699e0cf837b45e646d789f6011a6c653</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Abdominal Surgery</topic><topic>Animal models</topic><topic>Apoptosis</topic><topic>Cancer Research</topic><topic>Caspase</topic><topic>Cell activation</topic><topic>Cell adhesion & migration</topic><topic>Cell cycle</topic><topic>Cell migration</topic><topic>Cell proliferation</topic><topic>Down-regulation</topic><topic>Extracellular signal-regulated kinase</topic><topic>Gastric cancer</topic><topic>Gastroenterology</topic><topic>Gene expression</topic><topic>Genetic engineering</topic><topic>Genotype & phenotype</topic><topic>Lectins</topic><topic>MAP kinase</topic><topic>Medical prognosis</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Metastases</topic><topic>Metastasis</topic><topic>Oncology</topic><topic>Original Article</topic><topic>p53 Protein</topic><topic>Phenotypes</topic><topic>siRNA</topic><topic>Surgical Oncology</topic><topic>Targeted cancer therapy</topic><topic>Therapeutic targets</topic><topic>Transcriptomes</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ito, Yuki</creatorcontrib><creatorcontrib>Kanda, Mitsuro</creatorcontrib><creatorcontrib>Sasahara, Masahiro</creatorcontrib><creatorcontrib>Tanaka, Chie</creatorcontrib><creatorcontrib>Shimizu, Dai</creatorcontrib><creatorcontrib>Umeda, Shinichi</creatorcontrib><creatorcontrib>Inokawa, Yoshikuni</creatorcontrib><creatorcontrib>Hattori, Norifumi</creatorcontrib><creatorcontrib>Hayashi, Masamichi</creatorcontrib><creatorcontrib>Nakayama, Goro</creatorcontrib><creatorcontrib>Kodera, Yasuhiro</creatorcontrib><collection>PubMed</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><jtitle>Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ito, Yuki</au><au>Kanda, Mitsuro</au><au>Sasahara, Masahiro</au><au>Tanaka, Chie</au><au>Shimizu, Dai</au><au>Umeda, Shinichi</au><au>Inokawa, Yoshikuni</au><au>Hattori, Norifumi</au><au>Hayashi, Masamichi</au><au>Nakayama, Goro</au><au>Kodera, Yasuhiro</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Killer cell lectin-like receptor G2 facilitates aggressive phenotypes of gastric cancer cells via dual activation of the ERK1/2 and JAK/STAT pathways</atitle><jtitle>Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association</jtitle><stitle>Gastric Cancer</stitle><addtitle>Gastric Cancer</addtitle><date>2024-05-01</date><risdate>2024</risdate><volume>27</volume><issue>3</issue><spage>506</spage><epage>518</epage><pages>506-518</pages><issn>1436-3291</issn><eissn>1436-3305</eissn><abstract>Background
Advanced gastric cancer (GC) has a poor prognosis. This study aimed to identify novel GC-related genes as potential therapeutic targets.
Methods
Killer cell lectin-like receptor G2 (
KLRG2
) was identified as a candidate gene by transcriptome analysis of metastatic GC tissues. Small interfering RNA-mediated
KLRG2
knockdown in human GC cell lines was used to investigate KLRG2 involvement in signaling pathways and functional behaviors in vitro and in vivo. Clinicopathological data were analyzed in patients stratified according to tumor
KLRG2
mRNA expression.
Results
KLRG2
knockdown in GC cells decreased cell proliferation, migration, and invasion; caused cell cycle arrest in G
2
/M phase; induced apoptosis via caspase activation; suppressed JAK/STAT and MAPK-ERK1/2 pathway activities; and upregulated p53 and p38 MAPK activities. In mouse xenograft models of peritoneal metastasis, the number and weight of disseminated GC nodules were decreased by
KLRG2
knockdown. High tumor levels of
KLRG2
mRNA were significantly associated with lower 5-year overall survival (OS) and relapse-free survival (RFS) rates in patients with Stage I–III GC (5-year OS rate: 64.4% vs. 80.0%,
P
= 0.009; 5-year RFS rate: 62.8% vs. 78.1%,
P
= 0.030).
Conclusions
KLRG2
knockdown attenuated the malignant phenotypes of GC cells via downregulation of JAK/STAT and MAPK-ERK1/2 pathway activity and upregulation of p38 MAPK and p53. Targeted suppression of KLRG2 may serve as a new treatment approach for GC.</abstract><cop>Singapore</cop><pub>Springer Nature Singapore</pub><pmid>38386237</pmid><doi>10.1007/s10120-024-01480-y</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0001-5464-3819</orcidid></addata></record> |
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| subjects | Abdominal Surgery Animal models Apoptosis Cancer Research Caspase Cell activation Cell adhesion & migration Cell cycle Cell migration Cell proliferation Down-regulation Extracellular signal-regulated kinase Gastric cancer Gastroenterology Gene expression Genetic engineering Genotype & phenotype Lectins MAP kinase Medical prognosis Medicine Medicine & Public Health Metastases Metastasis Oncology Original Article p53 Protein Phenotypes siRNA Surgical Oncology Targeted cancer therapy Therapeutic targets Transcriptomes Tumors |
| title | Killer cell lectin-like receptor G2 facilitates aggressive phenotypes of gastric cancer cells via dual activation of the ERK1/2 and JAK/STAT pathways |
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