HSP70 promotes tumor progression by stabilizing Skp2 expression in gastric cancer cells
Gastric cancer (GC) has one of the highest tumor incidences worldwide. Heat shock protein 70 (HSP70) is highly expressed and plays a critical role in the occurrence, progression, metastasis, poor prognosis, and drug resistance of GC. However, the underlying mechanisms of HSP70 are not clear. To expl...
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| Veröffentlicht in: | Molecular carcinogenesis 2021-12, Vol.60 (12), p.826-839 |
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| container_title | Molecular carcinogenesis |
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| creator | Lei, Ziying Xia, Xiaohong He, Qiaoling Luo, Jiali Xiong, Yan Wang, Jin Tang, Hongsheng Guan, Tianpei Tian, Yun Xu, Songhui Cui, Shuzhong |
| description | Gastric cancer (GC) has one of the highest tumor incidences worldwide. Heat shock protein 70 (HSP70) is highly expressed and plays a critical role in the occurrence, progression, metastasis, poor prognosis, and drug resistance of GC. However, the underlying mechanisms of HSP70 are not clear. To explore the regulatory role of HSP70 in GC, we performed cell counting kit‐8 (CCK‐8) and EdU staining assays to assess cell proliferation; immunohistochemistry and western blot analyses to assess protein expression; coimmunoprecipitation (Co‐IP) assays to assess interactions between two proteins; and immunofluorescence to assess protein expression and localization. HSP70 was highly expressed in clinical samples from patients with GC and indicated a poor prognosis. HSP70 inhibition enhanced the sensitivity of GC cells to thermochemotherapy. Furthermore, we found that S phase kinase‐associated protein 2 (Skp2) was highly expressed in GC and correlated with HSP70 in array data from The Cancer Genome Atlas (TCGA). Importantly, HSP70 inhibition promoted Skp2 degradation. Skp2 overexpression abrogated HSP70 inhibition‐induced cell cycle arrest, suggesting that the role of HSP70 in GC depends on Skp2 expression. Our results illustrate a possible regulatory mechanism of HSP70 and may provide a therapeutic strategy for overcoming resistance to thermochemotherapy. |
| doi_str_mv | 10.1002/mc.23346 |
| format | Article |
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Heat shock protein 70 (HSP70) is highly expressed and plays a critical role in the occurrence, progression, metastasis, poor prognosis, and drug resistance of GC. However, the underlying mechanisms of HSP70 are not clear. To explore the regulatory role of HSP70 in GC, we performed cell counting kit‐8 (CCK‐8) and EdU staining assays to assess cell proliferation; immunohistochemistry and western blot analyses to assess protein expression; coimmunoprecipitation (Co‐IP) assays to assess interactions between two proteins; and immunofluorescence to assess protein expression and localization. HSP70 was highly expressed in clinical samples from patients with GC and indicated a poor prognosis. HSP70 inhibition enhanced the sensitivity of GC cells to thermochemotherapy. Furthermore, we found that S phase kinase‐associated protein 2 (Skp2) was highly expressed in GC and correlated with HSP70 in array data from The Cancer Genome Atlas (TCGA). Importantly, HSP70 inhibition promoted Skp2 degradation. Skp2 overexpression abrogated HSP70 inhibition‐induced cell cycle arrest, suggesting that the role of HSP70 in GC depends on Skp2 expression. Our results illustrate a possible regulatory mechanism of HSP70 and may provide a therapeutic strategy for overcoming resistance to thermochemotherapy.</description><identifier>ISSN: 0899-1987</identifier><identifier>EISSN: 1098-2744</identifier><identifier>DOI: 10.1002/mc.23346</identifier><identifier>PMID: 34499769</identifier><language>eng</language><publisher>United States: Wiley Subscription Services, Inc</publisher><subject>Cell cycle ; Cell Line, Tumor ; Cell proliferation ; Cell Proliferation - drug effects ; Cholecystokinin ; Disease Progression ; Drug resistance ; Female ; Gastric cancer ; Gene Expression Regulation, Neoplastic - drug effects ; Genomes ; Heat shock proteins ; HSP70 ; HSP70 Heat-Shock Proteins - metabolism ; Hsp70 protein ; Humans ; Immunofluorescence ; Immunohistochemistry ; Kinases ; Localization ; Male ; Metastases ; Oxaliplatin - pharmacology ; Prognosis ; Protein expression ; Protein Stability ; Proteins ; Purine Nucleosides - pharmacology ; S phase ; S-Phase Kinase-Associated Proteins - chemistry ; S-Phase Kinase-Associated Proteins - metabolism ; Skp2 ; Stomach Neoplasms - metabolism ; thermochemotherapy ; tumor progression ; Tumors ; Up-Regulation - drug effects</subject><ispartof>Molecular carcinogenesis, 2021-12, Vol.60 (12), p.826-839</ispartof><rights>2021 Wiley Periodicals LLC</rights><rights>2021 Wiley Periodicals LLC.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3496-e51dc1d824644a914a9948e8dca5cad5f897563c868327228a2832fdfe1126753</citedby><cites>FETCH-LOGICAL-c3496-e51dc1d824644a914a9948e8dca5cad5f897563c868327228a2832fdfe1126753</cites><orcidid>0000-0003-0269-9129</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fmc.23346$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fmc.23346$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,777,781,1412,27905,27906,45555,45556</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34499769$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lei, Ziying</creatorcontrib><creatorcontrib>Xia, Xiaohong</creatorcontrib><creatorcontrib>He, Qiaoling</creatorcontrib><creatorcontrib>Luo, Jiali</creatorcontrib><creatorcontrib>Xiong, Yan</creatorcontrib><creatorcontrib>Wang, Jin</creatorcontrib><creatorcontrib>Tang, Hongsheng</creatorcontrib><creatorcontrib>Guan, Tianpei</creatorcontrib><creatorcontrib>Tian, Yun</creatorcontrib><creatorcontrib>Xu, Songhui</creatorcontrib><creatorcontrib>Cui, Shuzhong</creatorcontrib><title>HSP70 promotes tumor progression by stabilizing Skp2 expression in gastric cancer cells</title><title>Molecular carcinogenesis</title><addtitle>Mol Carcinog</addtitle><description>Gastric cancer (GC) has one of the highest tumor incidences worldwide. Heat shock protein 70 (HSP70) is highly expressed and plays a critical role in the occurrence, progression, metastasis, poor prognosis, and drug resistance of GC. However, the underlying mechanisms of HSP70 are not clear. To explore the regulatory role of HSP70 in GC, we performed cell counting kit‐8 (CCK‐8) and EdU staining assays to assess cell proliferation; immunohistochemistry and western blot analyses to assess protein expression; coimmunoprecipitation (Co‐IP) assays to assess interactions between two proteins; and immunofluorescence to assess protein expression and localization. HSP70 was highly expressed in clinical samples from patients with GC and indicated a poor prognosis. HSP70 inhibition enhanced the sensitivity of GC cells to thermochemotherapy. Furthermore, we found that S phase kinase‐associated protein 2 (Skp2) was highly expressed in GC and correlated with HSP70 in array data from The Cancer Genome Atlas (TCGA). Importantly, HSP70 inhibition promoted Skp2 degradation. Skp2 overexpression abrogated HSP70 inhibition‐induced cell cycle arrest, suggesting that the role of HSP70 in GC depends on Skp2 expression. Our results illustrate a possible regulatory mechanism of HSP70 and may provide a therapeutic strategy for overcoming resistance to thermochemotherapy.</description><subject>Cell cycle</subject><subject>Cell Line, Tumor</subject><subject>Cell proliferation</subject><subject>Cell Proliferation - drug effects</subject><subject>Cholecystokinin</subject><subject>Disease Progression</subject><subject>Drug resistance</subject><subject>Female</subject><subject>Gastric cancer</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>Genomes</subject><subject>Heat shock proteins</subject><subject>HSP70</subject><subject>HSP70 Heat-Shock Proteins - metabolism</subject><subject>Hsp70 protein</subject><subject>Humans</subject><subject>Immunofluorescence</subject><subject>Immunohistochemistry</subject><subject>Kinases</subject><subject>Localization</subject><subject>Male</subject><subject>Metastases</subject><subject>Oxaliplatin - pharmacology</subject><subject>Prognosis</subject><subject>Protein expression</subject><subject>Protein Stability</subject><subject>Proteins</subject><subject>Purine Nucleosides - pharmacology</subject><subject>S phase</subject><subject>S-Phase Kinase-Associated Proteins - chemistry</subject><subject>S-Phase Kinase-Associated Proteins - metabolism</subject><subject>Skp2</subject><subject>Stomach Neoplasms - metabolism</subject><subject>thermochemotherapy</subject><subject>tumor progression</subject><subject>Tumors</subject><subject>Up-Regulation - drug effects</subject><issn>0899-1987</issn><issn>1098-2744</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kE1LAzEQhoMotlbBXyABL162Jtl8HqWoFSoKVTyGNJstqftlsovWX-_Wtt48DDMhD88MLwDnGI0xQuS6tGOSppQfgCFGSiZEUHoIhkgqlWAlxQCcxLhCCGPB0DEYpJQqJbgagrfp_Fkg2IS6rFsXYduVddg8l8HF6OsKLtYwtmbhC__tqyWcvzcEuq9m_-0ruDSxDd5CayrrArSuKOIpOMpNEd3Zro_A693ty2SazJ7uHyY3s8SmVPHEMZxZnElCOaVG4b4UlU5m1jBrMpZLJRhPreQyJYIQaUg_5FnuMCZcsHQELrfe_uSPzsVWr-ouVP1KTZhinCGBSE9dbSkb6hiDy3UTfGnCWmOkNwnq0urfBHv0YifsFqXL_sB9ZD2QbIFPX7j1vyL9ONkKfwAhPnhY</recordid><startdate>202112</startdate><enddate>202112</enddate><creator>Lei, Ziying</creator><creator>Xia, Xiaohong</creator><creator>He, Qiaoling</creator><creator>Luo, Jiali</creator><creator>Xiong, Yan</creator><creator>Wang, Jin</creator><creator>Tang, Hongsheng</creator><creator>Guan, Tianpei</creator><creator>Tian, Yun</creator><creator>Xu, Songhui</creator><creator>Cui, Shuzhong</creator><general>Wiley Subscription Services, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TM</scope><scope>7TO</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>RC3</scope><orcidid>https://orcid.org/0000-0003-0269-9129</orcidid></search><sort><creationdate>202112</creationdate><title>HSP70 promotes tumor progression by stabilizing Skp2 expression in gastric cancer cells</title><author>Lei, Ziying ; Xia, Xiaohong ; He, Qiaoling ; Luo, Jiali ; Xiong, Yan ; Wang, Jin ; Tang, Hongsheng ; Guan, Tianpei ; Tian, Yun ; Xu, Songhui ; Cui, Shuzhong</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3496-e51dc1d824644a914a9948e8dca5cad5f897563c868327228a2832fdfe1126753</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Cell cycle</topic><topic>Cell Line, Tumor</topic><topic>Cell proliferation</topic><topic>Cell Proliferation - drug effects</topic><topic>Cholecystokinin</topic><topic>Disease Progression</topic><topic>Drug resistance</topic><topic>Female</topic><topic>Gastric cancer</topic><topic>Gene Expression Regulation, Neoplastic - drug effects</topic><topic>Genomes</topic><topic>Heat shock proteins</topic><topic>HSP70</topic><topic>HSP70 Heat-Shock Proteins - metabolism</topic><topic>Hsp70 protein</topic><topic>Humans</topic><topic>Immunofluorescence</topic><topic>Immunohistochemistry</topic><topic>Kinases</topic><topic>Localization</topic><topic>Male</topic><topic>Metastases</topic><topic>Oxaliplatin - pharmacology</topic><topic>Prognosis</topic><topic>Protein expression</topic><topic>Protein Stability</topic><topic>Proteins</topic><topic>Purine Nucleosides - pharmacology</topic><topic>S phase</topic><topic>S-Phase Kinase-Associated Proteins - chemistry</topic><topic>S-Phase Kinase-Associated Proteins - metabolism</topic><topic>Skp2</topic><topic>Stomach Neoplasms - metabolism</topic><topic>thermochemotherapy</topic><topic>tumor progression</topic><topic>Tumors</topic><topic>Up-Regulation - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lei, Ziying</creatorcontrib><creatorcontrib>Xia, Xiaohong</creatorcontrib><creatorcontrib>He, Qiaoling</creatorcontrib><creatorcontrib>Luo, Jiali</creatorcontrib><creatorcontrib>Xiong, Yan</creatorcontrib><creatorcontrib>Wang, Jin</creatorcontrib><creatorcontrib>Tang, Hongsheng</creatorcontrib><creatorcontrib>Guan, Tianpei</creatorcontrib><creatorcontrib>Tian, Yun</creatorcontrib><creatorcontrib>Xu, Songhui</creatorcontrib><creatorcontrib>Cui, Shuzhong</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><jtitle>Molecular carcinogenesis</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lei, Ziying</au><au>Xia, Xiaohong</au><au>He, Qiaoling</au><au>Luo, Jiali</au><au>Xiong, Yan</au><au>Wang, Jin</au><au>Tang, Hongsheng</au><au>Guan, Tianpei</au><au>Tian, Yun</au><au>Xu, Songhui</au><au>Cui, Shuzhong</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>HSP70 promotes tumor progression by stabilizing Skp2 expression in gastric cancer cells</atitle><jtitle>Molecular carcinogenesis</jtitle><addtitle>Mol Carcinog</addtitle><date>2021-12</date><risdate>2021</risdate><volume>60</volume><issue>12</issue><spage>826</spage><epage>839</epage><pages>826-839</pages><issn>0899-1987</issn><eissn>1098-2744</eissn><abstract>Gastric cancer (GC) has one of the highest tumor incidences worldwide. Heat shock protein 70 (HSP70) is highly expressed and plays a critical role in the occurrence, progression, metastasis, poor prognosis, and drug resistance of GC. However, the underlying mechanisms of HSP70 are not clear. To explore the regulatory role of HSP70 in GC, we performed cell counting kit‐8 (CCK‐8) and EdU staining assays to assess cell proliferation; immunohistochemistry and western blot analyses to assess protein expression; coimmunoprecipitation (Co‐IP) assays to assess interactions between two proteins; and immunofluorescence to assess protein expression and localization. HSP70 was highly expressed in clinical samples from patients with GC and indicated a poor prognosis. HSP70 inhibition enhanced the sensitivity of GC cells to thermochemotherapy. Furthermore, we found that S phase kinase‐associated protein 2 (Skp2) was highly expressed in GC and correlated with HSP70 in array data from The Cancer Genome Atlas (TCGA). Importantly, HSP70 inhibition promoted Skp2 degradation. Skp2 overexpression abrogated HSP70 inhibition‐induced cell cycle arrest, suggesting that the role of HSP70 in GC depends on Skp2 expression. Our results illustrate a possible regulatory mechanism of HSP70 and may provide a therapeutic strategy for overcoming resistance to thermochemotherapy.</abstract><cop>United States</cop><pub>Wiley Subscription Services, Inc</pub><pmid>34499769</pmid><doi>10.1002/mc.23346</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0003-0269-9129</orcidid></addata></record> |
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| subjects | Cell cycle Cell Line, Tumor Cell proliferation Cell Proliferation - drug effects Cholecystokinin Disease Progression Drug resistance Female Gastric cancer Gene Expression Regulation, Neoplastic - drug effects Genomes Heat shock proteins HSP70 HSP70 Heat-Shock Proteins - metabolism Hsp70 protein Humans Immunofluorescence Immunohistochemistry Kinases Localization Male Metastases Oxaliplatin - pharmacology Prognosis Protein expression Protein Stability Proteins Purine Nucleosides - pharmacology S phase S-Phase Kinase-Associated Proteins - chemistry S-Phase Kinase-Associated Proteins - metabolism Skp2 Stomach Neoplasms - metabolism thermochemotherapy tumor progression Tumors Up-Regulation - drug effects |
| title | HSP70 promotes tumor progression by stabilizing Skp2 expression in gastric cancer cells |
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