Down‐regulation of RCC1 sensitizes immunotherapy by up‐regulating PD‐L1 via p27kip1/CDK4 axis in non‐small cell lung cancer
In recent years, although Immune Checkpoint Inhibitors (ICIs) significantly improves survival both in local advanced stage and advanced stage of non‐small cell lung cancer (NSCLC), the objective response rate of ICI monotherapy is still only about 20%. Thus, to identify the mechanisms of ICI resista...
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| Veröffentlicht in: | Journal of cellular and molecular medicine 2021-04, Vol.25 (8), p.4136-4147 |
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| creator | Zeng, Xiaozhu Zhong, Maoxi Yang, Yumeng Wang, Zhi Zhu, Yuxi |
| description | In recent years, although Immune Checkpoint Inhibitors (ICIs) significantly improves survival both in local advanced stage and advanced stage of non‐small cell lung cancer (NSCLC), the objective response rate of ICI monotherapy is still only about 20%. Thus, to identify the mechanisms of ICI resistance is critical to increase the efficacy of ICI treatments. By bioinformatics analysis, we found that the expression of regulator of chromosome condensation 1 (RCC1) in lung adenocarcinoma was significantly higher than that in normal lung tissue in TCGA and Oncomine databases. The survival analysis showed that high expression RCC1 was associated with the poor prognosis of NSCLC. And the expression of RCC1 was inversely related to the number of immune cell infiltration. In vitro, knockdown of RCC1 not only significantly inhibited the proliferation of lung adenocarcinoma cells but also increased the expression levels of p27kip1 and PD‐L1, and decreased the expression level of CDK4 and p‐Rb. In vivo, knockdown of RCC1 significantly slowed down the growth rate of tumour, and further reduced the volume and weight of tumour model after treated by PD‐L1 monoclonal antibody. Therefore, RCC1 could up‐regulate the expression level of PD‐L1 by regulating p27kip1/CDK4 pathway and decrease the resistance to ICIs. And this study might provide a new way to increase the efficacy of PD‐L1 monoclonal antibody by inhibiting RCC1. |
| doi_str_mv | 10.1111/jcmm.16383 |
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Thus, to identify the mechanisms of ICI resistance is critical to increase the efficacy of ICI treatments. By bioinformatics analysis, we found that the expression of regulator of chromosome condensation 1 (RCC1) in lung adenocarcinoma was significantly higher than that in normal lung tissue in TCGA and Oncomine databases. The survival analysis showed that high expression RCC1 was associated with the poor prognosis of NSCLC. And the expression of RCC1 was inversely related to the number of immune cell infiltration. In vitro, knockdown of RCC1 not only significantly inhibited the proliferation of lung adenocarcinoma cells but also increased the expression levels of p27kip1 and PD‐L1, and decreased the expression level of CDK4 and p‐Rb. In vivo, knockdown of RCC1 significantly slowed down the growth rate of tumour, and further reduced the volume and weight of tumour model after treated by PD‐L1 monoclonal antibody. Therefore, RCC1 could up‐regulate the expression level of PD‐L1 by regulating p27kip1/CDK4 pathway and decrease the resistance to ICIs. And this study might provide a new way to increase the efficacy of PD‐L1 monoclonal antibody by inhibiting RCC1.</description><identifier>ISSN: 1582-1838</identifier><identifier>EISSN: 1582-4934</identifier><identifier>DOI: 10.1111/jcmm.16383</identifier><identifier>PMID: 33630417</identifier><language>eng</language><publisher>Chichester: John Wiley & Sons, Inc</publisher><subject>Adenocarcinoma ; Apoptosis ; Bioinformatics ; Biotechnology ; Cell cycle ; Cell proliferation ; Cyclin-dependent kinase 4 ; Cyclin-dependent kinase inhibitor p27 ; Cyclin-dependent kinases ; Cytoplasm ; Flow cytometry ; Genes ; ICI ; Immune checkpoint inhibitors ; Immunotherapy ; Kinases ; Lung cancer ; Medical prognosis ; Metastases ; Monoclonal antibodies ; Non-small cell lung carcinoma ; non‐small cell lung cancer ; Original ; p27KIP1/CDK4 ; PD-L1 protein ; PD‐L1 ; Penicillin ; Proteins ; RCC1 ; Reagents ; Signal transduction ; Small cell lung carcinoma ; Tumors</subject><ispartof>Journal of cellular and molecular medicine, 2021-04, Vol.25 (8), p.4136-4147</ispartof><rights>2021 The Authors. published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.</rights><rights>2021. 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Thus, to identify the mechanisms of ICI resistance is critical to increase the efficacy of ICI treatments. By bioinformatics analysis, we found that the expression of regulator of chromosome condensation 1 (RCC1) in lung adenocarcinoma was significantly higher than that in normal lung tissue in TCGA and Oncomine databases. The survival analysis showed that high expression RCC1 was associated with the poor prognosis of NSCLC. And the expression of RCC1 was inversely related to the number of immune cell infiltration. In vitro, knockdown of RCC1 not only significantly inhibited the proliferation of lung adenocarcinoma cells but also increased the expression levels of p27kip1 and PD‐L1, and decreased the expression level of CDK4 and p‐Rb. In vivo, knockdown of RCC1 significantly slowed down the growth rate of tumour, and further reduced the volume and weight of tumour model after treated by PD‐L1 monoclonal antibody. Therefore, RCC1 could up‐regulate the expression level of PD‐L1 by regulating p27kip1/CDK4 pathway and decrease the resistance to ICIs. And this study might provide a new way to increase the efficacy of PD‐L1 monoclonal antibody by inhibiting RCC1.</description><subject>Adenocarcinoma</subject><subject>Apoptosis</subject><subject>Bioinformatics</subject><subject>Biotechnology</subject><subject>Cell cycle</subject><subject>Cell proliferation</subject><subject>Cyclin-dependent kinase 4</subject><subject>Cyclin-dependent kinase inhibitor p27</subject><subject>Cyclin-dependent kinases</subject><subject>Cytoplasm</subject><subject>Flow cytometry</subject><subject>Genes</subject><subject>ICI</subject><subject>Immune checkpoint inhibitors</subject><subject>Immunotherapy</subject><subject>Kinases</subject><subject>Lung cancer</subject><subject>Medical prognosis</subject><subject>Metastases</subject><subject>Monoclonal antibodies</subject><subject>Non-small cell lung carcinoma</subject><subject>non‐small cell lung cancer</subject><subject>Original</subject><subject>p27KIP1/CDK4</subject><subject>PD-L1 protein</subject><subject>PD‐L1</subject><subject>Penicillin</subject><subject>Proteins</subject><subject>RCC1</subject><subject>Reagents</subject><subject>Signal transduction</subject><subject>Small cell lung carcinoma</subject><subject>Tumors</subject><issn>1582-1838</issn><issn>1582-4934</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>BENPR</sourceid><recordid>eNpdUU1v1DAQtRCIlsKFX2CJC5dtPR4nsS9IKMv3ViAEZ8vxerdeEjuNk5blhMQf4DfyS3DaFQLm4BnL772Z8SPkMbBTyHG2s113CiVKvEOOoZB8IRSKu4caJMoj8iClHWNYAqr75AixRCagOiY_lvE6_Pr-c3DbqTWjj4HGDf1Y10CTC8mP_ptL1HfdFOJ44QbT72mzp1P_Fyds6Ydlvq-AXnlDe1598T2c1ct3gpqvPtMDDXHukjrTttS6fLRTplkTrBseknsb0yb36JBPyOeXLz7Vrxer96_e1M9Xix6UwIU1bGPLqhAFQ1yDMlxBUzoUpWt4s2YWpKoaAetCyaqxomhE4YwsQBiHm0rhCXl2q9tPTefW1oVxMK3uB9-ZYa-j8frfl-Av9DZeackKqJjMAk8PAkO8nFwadefTvI0JLk5J8_nfCyU4ZOiT_6C7OA0hr6e5FJJxRC4yCm5R1751-z-TANOzsXo2Vt8Yq9_W5-c3Ff4G8k6bSg</recordid><startdate>202104</startdate><enddate>202104</enddate><creator>Zeng, Xiaozhu</creator><creator>Zhong, Maoxi</creator><creator>Yang, Yumeng</creator><creator>Wang, Zhi</creator><creator>Zhu, Yuxi</creator><general>John Wiley & Sons, Inc</general><general>John Wiley and Sons Inc</general><scope>24P</scope><scope>3V.</scope><scope>7QP</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>88I</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>M7P</scope><scope>P64</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-7563-505X</orcidid></search><sort><creationdate>202104</creationdate><title>Down‐regulation of RCC1 sensitizes immunotherapy by up‐regulating PD‐L1 via p27kip1/CDK4 axis in non‐small cell lung cancer</title><author>Zeng, Xiaozhu ; 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Thus, to identify the mechanisms of ICI resistance is critical to increase the efficacy of ICI treatments. By bioinformatics analysis, we found that the expression of regulator of chromosome condensation 1 (RCC1) in lung adenocarcinoma was significantly higher than that in normal lung tissue in TCGA and Oncomine databases. The survival analysis showed that high expression RCC1 was associated with the poor prognosis of NSCLC. And the expression of RCC1 was inversely related to the number of immune cell infiltration. In vitro, knockdown of RCC1 not only significantly inhibited the proliferation of lung adenocarcinoma cells but also increased the expression levels of p27kip1 and PD‐L1, and decreased the expression level of CDK4 and p‐Rb. In vivo, knockdown of RCC1 significantly slowed down the growth rate of tumour, and further reduced the volume and weight of tumour model after treated by PD‐L1 monoclonal antibody. Therefore, RCC1 could up‐regulate the expression level of PD‐L1 by regulating p27kip1/CDK4 pathway and decrease the resistance to ICIs. And this study might provide a new way to increase the efficacy of PD‐L1 monoclonal antibody by inhibiting RCC1.</abstract><cop>Chichester</cop><pub>John Wiley & Sons, Inc</pub><pmid>33630417</pmid><doi>10.1111/jcmm.16383</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0001-7563-505X</orcidid><oa>free_for_read</oa></addata></record> |
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| source | Wiley-Blackwell Open Access Titles; DOAJ Directory of Open Access Journals; Wiley Online Library Journals Frontfile Complete; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Adenocarcinoma Apoptosis Bioinformatics Biotechnology Cell cycle Cell proliferation Cyclin-dependent kinase 4 Cyclin-dependent kinase inhibitor p27 Cyclin-dependent kinases Cytoplasm Flow cytometry Genes ICI Immune checkpoint inhibitors Immunotherapy Kinases Lung cancer Medical prognosis Metastases Monoclonal antibodies Non-small cell lung carcinoma non‐small cell lung cancer Original p27KIP1/CDK4 PD-L1 protein PD‐L1 Penicillin Proteins RCC1 Reagents Signal transduction Small cell lung carcinoma Tumors |
| title | Down‐regulation of RCC1 sensitizes immunotherapy by up‐regulating PD‐L1 via p27kip1/CDK4 axis in non‐small cell lung cancer |
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