PIM2 promotes hepatocellular carcinoma tumorigenesis and progression through activating NF-κB signaling pathway
Inflammatory factors and activation of oncogenes both played critical roles in the development and progression of human hepatocellular carcinoma (HCC). However, the interplay between these two has not been well studied. In this study, we found that regulated by TNFα, Pim-2 proto-oncogene, serine/thr...
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| Veröffentlicht in: | Cell death & disease 2020-07, Vol.11 (7), p.510, Article 510 |
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| creator | Tang, Xuming Cao, Tingting Zhu, Yun Zhang, Liyi Chen, Jinna Liu, Tengfei Ming, Xiaoyan Fang, Shuo Yuan, Yun-fei Jiang, Lingxi Huang, Jian-Dong Guan, Xin-Yuan |
| description | Inflammatory factors and activation of oncogenes both played critical roles in the development and progression of human hepatocellular carcinoma (HCC). However, the interplay between these two has not been well studied. In this study, we found that regulated by TNFα, Pim-2 proto-oncogene, serine/threonine kinase (PIM2) was highly expressed in HCC and correlated with poor prognosis (
P
= 0.007) as well as tumor recurrence (
P
= 0.014). Functional studies showed that PIM2 could enhance abilities of cell proliferation, cell motility, angiogenesis, chemo-resistance, and in vivo tumorigenicity and HCC metastasis. Mechanistic studies revealed that PIM2 could activate NF-κB signaling pathway through upregulating phosphorylation level of RIPK2. Interestingly, TNFα treatment could induce the expression of PIM2, and overexpression of PIM2 could in turn upregulate the expression of TNFα in HCC cells. More importantly, we found the expression level of PIM2 increased with the progression of liver cirrhosis, and PIM kinase inhibitor AZD1208 treatment could effectively attenuate HCC cells’ tumorigenic ability both in vitro and in vivo. Collectively, our study revealed the interaction between an inflammatory factor and a proto-oncogene that contributed to tumorigenesis and progression of HCC, and PIM kinase inhibition may serve as a therapeutic target in the treatment of HCC. |
| doi_str_mv | 10.1038/s41419-020-2700-0 |
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| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7343807</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2421243435</sourcerecordid><originalsourceid>FETCH-LOGICAL-c470t-17af765b2b271e4e42f7def3644216420456fdd640584b681c3f2d024b5661063</originalsourceid><addsrcrecordid>eNp1kc1u1TAQhS0EolXpA7BBllgHxvbEzt0gQdVCpfKzgLXlJE7iKrGD7RT11XgInglf3VLKAm9sec45M6OPkOcMXjEQzeuEDNmuAg4VVwAVPCLHHJBV2DS7xw_eR-Q0pWsoRwjgtXxKjgSXyBTujsn65fIjp2sMS8g20cmuJofOzvM2m0g7Ezvnw2Jo3pYQ3Wi9TS5R4_u9Z4w2JRc8zVMM2zhR02V3Y7LzI_10Uf36-Y4mN3oz7z9K8PTD3D4jTwYzJ3t6d5-QbxfnX88-VFef31-evb2qOlSQK6bMoGTd8pYrZtEiH1RvByEROZNYlqvl0PcSoW6wlQ3rxMB74NjWUjKQ4oS8OeSuW7vYvrM-RzPrNbrFxFsdjNP_Vryb9BhutBIoGlAl4OVdQAzfN5uyvg5bLMskzcsMHIuuLip2UHUxpBTtcN-Bgd5z0gdOunDSe04aiufFw9HuHX-oFAE_CFIp-dHGv63_n_obykuf-Q</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2421243435</pqid></control><display><type>article</type><title>PIM2 promotes hepatocellular carcinoma tumorigenesis and progression through activating NF-κB signaling pathway</title><source>MEDLINE</source><source>Nature Free</source><source>DOAJ Directory of Open Access Journals</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>PubMed Central</source><source>Springer Nature OA Free Journals</source><creator>Tang, Xuming ; Cao, Tingting ; Zhu, Yun ; Zhang, Liyi ; Chen, Jinna ; Liu, Tengfei ; Ming, Xiaoyan ; Fang, Shuo ; Yuan, Yun-fei ; Jiang, Lingxi ; Huang, Jian-Dong ; Guan, Xin-Yuan</creator><creatorcontrib>Tang, Xuming ; Cao, Tingting ; Zhu, Yun ; Zhang, Liyi ; Chen, Jinna ; Liu, Tengfei ; Ming, Xiaoyan ; Fang, Shuo ; Yuan, Yun-fei ; Jiang, Lingxi ; Huang, Jian-Dong ; Guan, Xin-Yuan</creatorcontrib><description>Inflammatory factors and activation of oncogenes both played critical roles in the development and progression of human hepatocellular carcinoma (HCC). However, the interplay between these two has not been well studied. In this study, we found that regulated by TNFα, Pim-2 proto-oncogene, serine/threonine kinase (PIM2) was highly expressed in HCC and correlated with poor prognosis (
P
= 0.007) as well as tumor recurrence (
P
= 0.014). Functional studies showed that PIM2 could enhance abilities of cell proliferation, cell motility, angiogenesis, chemo-resistance, and in vivo tumorigenicity and HCC metastasis. Mechanistic studies revealed that PIM2 could activate NF-κB signaling pathway through upregulating phosphorylation level of RIPK2. Interestingly, TNFα treatment could induce the expression of PIM2, and overexpression of PIM2 could in turn upregulate the expression of TNFα in HCC cells. More importantly, we found the expression level of PIM2 increased with the progression of liver cirrhosis, and PIM kinase inhibitor AZD1208 treatment could effectively attenuate HCC cells’ tumorigenic ability both in vitro and in vivo. Collectively, our study revealed the interaction between an inflammatory factor and a proto-oncogene that contributed to tumorigenesis and progression of HCC, and PIM kinase inhibition may serve as a therapeutic target in the treatment of HCC.</description><identifier>ISSN: 2041-4889</identifier><identifier>EISSN: 2041-4889</identifier><identifier>DOI: 10.1038/s41419-020-2700-0</identifier><identifier>PMID: 32641749</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13 ; 13/1 ; 13/106 ; 13/109 ; 13/2 ; 13/31 ; 13/51 ; 13/95 ; 14 ; 38/35 ; 38/77 ; 631/67/1504/1610 ; 631/80/82/23 ; 631/80/84/2336 ; 64 ; 64/60 ; 82 ; 82/29 ; 82/80 ; 96 ; 96/44 ; Angiogenesis ; Antibodies ; Biochemistry ; Biomedical and Life Sciences ; Carcinogenesis - drug effects ; Carcinogenesis - genetics ; Carcinogenesis - pathology ; Carcinoma, Hepatocellular - drug therapy ; Carcinoma, Hepatocellular - genetics ; Carcinoma, Hepatocellular - metabolism ; Carcinoma, Hepatocellular - pathology ; Cell Biology ; Cell Culture ; Cell Line, Tumor ; Cell proliferation ; Cirrhosis ; Disease Progression ; Enzyme inhibitors ; Feedback, Physiological - drug effects ; Gene Expression Regulation, Neoplastic - drug effects ; Gene Knockdown Techniques ; Hepatocellular carcinoma ; Humans ; Immunology ; Inflammation ; Kinases ; Life Sciences ; Liver cancer ; Liver cirrhosis ; Liver Neoplasms - drug therapy ; Liver Neoplasms - genetics ; Liver Neoplasms - metabolism ; Liver Neoplasms - pathology ; Metastases ; Neoplasm Metastasis ; NF-kappa B - metabolism ; NF-κB protein ; Phosphorylation ; Prognosis ; Protein Kinase Inhibitors - pharmacology ; Protein-Serine-Threonine Kinases - antagonists & inhibitors ; Protein-Serine-Threonine Kinases - genetics ; Protein-Serine-Threonine Kinases - metabolism ; Protein-serine/threonine kinase ; Proto-Oncogene Proteins - antagonists & inhibitors ; Proto-Oncogene Proteins - genetics ; Proto-Oncogene Proteins - metabolism ; Signal transduction ; Signal Transduction - drug effects ; Therapeutic applications ; Tumor Necrosis Factor-alpha - metabolism ; Tumor necrosis factor-α ; Tumorigenesis ; Tumorigenicity ; Up-Regulation - drug effects ; Up-Regulation - genetics</subject><ispartof>Cell death & disease, 2020-07, Vol.11 (7), p.510, Article 510</ispartof><rights>The Author(s) 2020</rights><rights>The Author(s) 2020. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c470t-17af765b2b271e4e42f7def3644216420456fdd640584b681c3f2d024b5661063</citedby><cites>FETCH-LOGICAL-c470t-17af765b2b271e4e42f7def3644216420456fdd640584b681c3f2d024b5661063</cites><orcidid>0000-0002-6244-8009 ; 0000-0002-8070-5275 ; 0000-0003-2467-3683 ; 0000-0002-4485-6017 ; 0000-0001-7531-2816</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343807/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343807/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27901,27902,41096,42165,51551,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32641749$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tang, Xuming</creatorcontrib><creatorcontrib>Cao, Tingting</creatorcontrib><creatorcontrib>Zhu, Yun</creatorcontrib><creatorcontrib>Zhang, Liyi</creatorcontrib><creatorcontrib>Chen, Jinna</creatorcontrib><creatorcontrib>Liu, Tengfei</creatorcontrib><creatorcontrib>Ming, Xiaoyan</creatorcontrib><creatorcontrib>Fang, Shuo</creatorcontrib><creatorcontrib>Yuan, Yun-fei</creatorcontrib><creatorcontrib>Jiang, Lingxi</creatorcontrib><creatorcontrib>Huang, Jian-Dong</creatorcontrib><creatorcontrib>Guan, Xin-Yuan</creatorcontrib><title>PIM2 promotes hepatocellular carcinoma tumorigenesis and progression through activating NF-κB signaling pathway</title><title>Cell death & disease</title><addtitle>Cell Death Dis</addtitle><addtitle>Cell Death Dis</addtitle><description>Inflammatory factors and activation of oncogenes both played critical roles in the development and progression of human hepatocellular carcinoma (HCC). However, the interplay between these two has not been well studied. In this study, we found that regulated by TNFα, Pim-2 proto-oncogene, serine/threonine kinase (PIM2) was highly expressed in HCC and correlated with poor prognosis (
P
= 0.007) as well as tumor recurrence (
P
= 0.014). Functional studies showed that PIM2 could enhance abilities of cell proliferation, cell motility, angiogenesis, chemo-resistance, and in vivo tumorigenicity and HCC metastasis. Mechanistic studies revealed that PIM2 could activate NF-κB signaling pathway through upregulating phosphorylation level of RIPK2. Interestingly, TNFα treatment could induce the expression of PIM2, and overexpression of PIM2 could in turn upregulate the expression of TNFα in HCC cells. More importantly, we found the expression level of PIM2 increased with the progression of liver cirrhosis, and PIM kinase inhibitor AZD1208 treatment could effectively attenuate HCC cells’ tumorigenic ability both in vitro and in vivo. Collectively, our study revealed the interaction between an inflammatory factor and a proto-oncogene that contributed to tumorigenesis and progression of HCC, and PIM kinase inhibition may serve as a therapeutic target in the treatment of HCC.</description><subject>13</subject><subject>13/1</subject><subject>13/106</subject><subject>13/109</subject><subject>13/2</subject><subject>13/31</subject><subject>13/51</subject><subject>13/95</subject><subject>14</subject><subject>38/35</subject><subject>38/77</subject><subject>631/67/1504/1610</subject><subject>631/80/82/23</subject><subject>631/80/84/2336</subject><subject>64</subject><subject>64/60</subject><subject>82</subject><subject>82/29</subject><subject>82/80</subject><subject>96</subject><subject>96/44</subject><subject>Angiogenesis</subject><subject>Antibodies</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Carcinogenesis - drug effects</subject><subject>Carcinogenesis - genetics</subject><subject>Carcinogenesis - 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drug effects</topic><topic>Carcinogenesis - genetics</topic><topic>Carcinogenesis - pathology</topic><topic>Carcinoma, Hepatocellular - drug therapy</topic><topic>Carcinoma, Hepatocellular - genetics</topic><topic>Carcinoma, Hepatocellular - metabolism</topic><topic>Carcinoma, Hepatocellular - pathology</topic><topic>Cell Biology</topic><topic>Cell Culture</topic><topic>Cell Line, Tumor</topic><topic>Cell proliferation</topic><topic>Cirrhosis</topic><topic>Disease Progression</topic><topic>Enzyme inhibitors</topic><topic>Feedback, Physiological - drug effects</topic><topic>Gene Expression Regulation, Neoplastic - drug effects</topic><topic>Gene Knockdown Techniques</topic><topic>Hepatocellular carcinoma</topic><topic>Humans</topic><topic>Immunology</topic><topic>Inflammation</topic><topic>Kinases</topic><topic>Life Sciences</topic><topic>Liver cancer</topic><topic>Liver cirrhosis</topic><topic>Liver Neoplasms - drug therapy</topic><topic>Liver Neoplasms - genetics</topic><topic>Liver Neoplasms - 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genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tang, Xuming</creatorcontrib><creatorcontrib>Cao, Tingting</creatorcontrib><creatorcontrib>Zhu, Yun</creatorcontrib><creatorcontrib>Zhang, Liyi</creatorcontrib><creatorcontrib>Chen, Jinna</creatorcontrib><creatorcontrib>Liu, Tengfei</creatorcontrib><creatorcontrib>Ming, Xiaoyan</creatorcontrib><creatorcontrib>Fang, Shuo</creatorcontrib><creatorcontrib>Yuan, Yun-fei</creatorcontrib><creatorcontrib>Jiang, Lingxi</creatorcontrib><creatorcontrib>Huang, Jian-Dong</creatorcontrib><creatorcontrib>Guan, Xin-Yuan</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science 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 Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>Publicly Available Content 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>ProQuest Central Basic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cell death & disease</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tang, Xuming</au><au>Cao, Tingting</au><au>Zhu, Yun</au><au>Zhang, Liyi</au><au>Chen, Jinna</au><au>Liu, Tengfei</au><au>Ming, Xiaoyan</au><au>Fang, Shuo</au><au>Yuan, Yun-fei</au><au>Jiang, Lingxi</au><au>Huang, Jian-Dong</au><au>Guan, Xin-Yuan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>PIM2 promotes hepatocellular carcinoma tumorigenesis and progression through activating NF-κB signaling pathway</atitle><jtitle>Cell death & disease</jtitle><stitle>Cell Death Dis</stitle><addtitle>Cell Death Dis</addtitle><date>2020-07-02</date><risdate>2020</risdate><volume>11</volume><issue>7</issue><spage>510</spage><pages>510-</pages><artnum>510</artnum><issn>2041-4889</issn><eissn>2041-4889</eissn><abstract>Inflammatory factors and activation of oncogenes both played critical roles in the development and progression of human hepatocellular carcinoma (HCC). However, the interplay between these two has not been well studied. In this study, we found that regulated by TNFα, Pim-2 proto-oncogene, serine/threonine kinase (PIM2) was highly expressed in HCC and correlated with poor prognosis (
P
= 0.007) as well as tumor recurrence (
P
= 0.014). Functional studies showed that PIM2 could enhance abilities of cell proliferation, cell motility, angiogenesis, chemo-resistance, and in vivo tumorigenicity and HCC metastasis. Mechanistic studies revealed that PIM2 could activate NF-κB signaling pathway through upregulating phosphorylation level of RIPK2. Interestingly, TNFα treatment could induce the expression of PIM2, and overexpression of PIM2 could in turn upregulate the expression of TNFα in HCC cells. More importantly, we found the expression level of PIM2 increased with the progression of liver cirrhosis, and PIM kinase inhibitor AZD1208 treatment could effectively attenuate HCC cells’ tumorigenic ability both in vitro and in vivo. Collectively, our study revealed the interaction between an inflammatory factor and a proto-oncogene that contributed to tumorigenesis and progression of HCC, and PIM kinase inhibition may serve as a therapeutic target in the treatment of HCC.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>32641749</pmid><doi>10.1038/s41419-020-2700-0</doi><orcidid>https://orcid.org/0000-0002-6244-8009</orcidid><orcidid>https://orcid.org/0000-0002-8070-5275</orcidid><orcidid>https://orcid.org/0000-0003-2467-3683</orcidid><orcidid>https://orcid.org/0000-0002-4485-6017</orcidid><orcidid>https://orcid.org/0000-0001-7531-2816</orcidid><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7343807 |
| source | MEDLINE; Nature Free; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Springer Nature OA Free Journals |
| subjects | 13 13/1 13/106 13/109 13/2 13/31 13/51 13/95 14 38/35 38/77 631/67/1504/1610 631/80/82/23 631/80/84/2336 64 64/60 82 82/29 82/80 96 96/44 Angiogenesis Antibodies Biochemistry Biomedical and Life Sciences Carcinogenesis - drug effects Carcinogenesis - genetics Carcinogenesis - pathology Carcinoma, Hepatocellular - drug therapy Carcinoma, Hepatocellular - genetics Carcinoma, Hepatocellular - metabolism Carcinoma, Hepatocellular - pathology Cell Biology Cell Culture Cell Line, Tumor Cell proliferation Cirrhosis Disease Progression Enzyme inhibitors Feedback, Physiological - drug effects Gene Expression Regulation, Neoplastic - drug effects Gene Knockdown Techniques Hepatocellular carcinoma Humans Immunology Inflammation Kinases Life Sciences Liver cancer Liver cirrhosis Liver Neoplasms - drug therapy Liver Neoplasms - genetics Liver Neoplasms - metabolism Liver Neoplasms - pathology Metastases Neoplasm Metastasis NF-kappa B - metabolism NF-κB protein Phosphorylation Prognosis Protein Kinase Inhibitors - pharmacology Protein-Serine-Threonine Kinases - antagonists & inhibitors Protein-Serine-Threonine Kinases - genetics Protein-Serine-Threonine Kinases - metabolism Protein-serine/threonine kinase Proto-Oncogene Proteins - antagonists & inhibitors Proto-Oncogene Proteins - genetics Proto-Oncogene Proteins - metabolism Signal transduction Signal Transduction - drug effects Therapeutic applications Tumor Necrosis Factor-alpha - metabolism Tumor necrosis factor-α Tumorigenesis Tumorigenicity Up-Regulation - drug effects Up-Regulation - genetics |
| title | PIM2 promotes hepatocellular carcinoma tumorigenesis and progression through activating NF-κB signaling pathway |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-08T09%3A35%3A37IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=PIM2%20promotes%20hepatocellular%20carcinoma%20tumorigenesis%20and%20progression%20through%20activating%20NF-%CE%BAB%20signaling%20pathway&rft.jtitle=Cell%20death%20&%20disease&rft.au=Tang,%20Xuming&rft.date=2020-07-02&rft.volume=11&rft.issue=7&rft.spage=510&rft.pages=510-&rft.artnum=510&rft.issn=2041-4889&rft.eissn=2041-4889&rft_id=info:doi/10.1038/s41419-020-2700-0&rft_dat=%3Cproquest_pubme%3E2421243435%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2421243435&rft_id=info:pmid/32641749&rfr_iscdi=true |