Pancreatic Cancer Stem-like Cells Display Aggressive Behavior Mediated via Activation of FoxQ1
Subpopulations of cancer stem cells (CSCs) or cancer stem-like cells (CSLCs) have been identified from most tumors, including pancreatic cancer (PC), and the existence of these cells is clinically relevant. Emerging evidence suggests that CSLCs participate in cell growth/proliferation, migration/inv...
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| Veröffentlicht in: | The Journal of biological chemistry 2014-05, Vol.289 (21), p.14520-14533 |
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| creator | Bao, Bin Azmi, Asfar S. Aboukameel, Amro Ahmad, Aamir Bolling-Fischer, Aliccia Sethi, Seema Ali, Shadan Li, Yiwei Kong, Dejuan Banerjee, Sanjeev Back, Jessica Sarkar, Fazlul H. |
| description | Subpopulations of cancer stem cells (CSCs) or cancer stem-like cells (CSLCs) have been identified from most tumors, including pancreatic cancer (PC), and the existence of these cells is clinically relevant. Emerging evidence suggests that CSLCs participate in cell growth/proliferation, migration/invasion, metastasis, and chemo-radiotherapy resistance, ultimately contributing to poor clinical outcome. However, the pathogenesis and biological significance of CSLCs in PC has not been well characterized. In the present study, we found that isolated triple-marker-positive (CD44+/CD133+/EpCAM+) cells of human PC MiaPaCa-2 and L3.6pl cells behave as CSLCs. These CSLCs exhibit aggressive behavior, such as increased cell growth, migration, clonogenicity, and self-renewal capacity. The mRNA expression profiling analysis showed that CSLCs (CD44+/CD133+/EpCAM+) exhibit differential expression of more than 1,600 mRNAs, including FoxQ1, compared with the triple-marker-negative (CD44−/CD133−/EpCAM−) cells. The knockdown of FoxQ1 by its siRNA in CSLCs resulted in the inhibition of aggressive behavior, consistent with the inhibition of EpCAM and Snail expression. Mouse xenograft tumor studies showed that CSLCs have a 100-fold higher potential for tumor formation and rapid tumor growth, consistent with overexpression of CSC-associated markers/mediators, including FoxQ1, compared with its parental MiaPaCa-2 cells. The inhibition of FoxQ1 attenuated tumor formation and growth, and expression of CSC markers in the xenograft tumor derived from CSLCs of MiaPaCa-2 cells. These data clearly suggest the role of differentially expressed genes in the regulation of CSLC characteristics, further suggesting that targeting some of these genes could be important for the development of novel therapies for achieving better treatment outcome of PC.
Cancer stem cells (CSCs) correlate to poorer clinical outcomes of many tumors.
We identified a highly aggressive (CD44+/CD133+/EpCAM+) CSC-like fraction from pancreatic cancer (PC) cell lines with differential expression of many genes, including FoxQ1.
FoxQ1 knockdown inhibited CSC aggressiveness.
Targeting differentially expressed CSC-related genes could provide a novel approach for better treatment outcomes of aggressive PC tumors. |
| doi_str_mv | 10.1074/jbc.M113.532887 |
| format | Article |
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Cancer stem cells (CSCs) correlate to poorer clinical outcomes of many tumors.
We identified a highly aggressive (CD44+/CD133+/EpCAM+) CSC-like fraction from pancreatic cancer (PC) cell lines with differential expression of many genes, including FoxQ1.
FoxQ1 knockdown inhibited CSC aggressiveness.
Targeting differentially expressed CSC-related genes could provide a novel approach for better treatment outcomes of aggressive PC tumors.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M113.532887</identifier><identifier>PMID: 24719318</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>AC133 Antigen ; Animals ; Antigens, CD - metabolism ; Antigens, Neoplasm - metabolism ; Apoptosis - genetics ; Blotting, Western ; Cancer Stem Cells ; CD44 ; Cell Adhesion Molecules - metabolism ; Cell Biology ; Cell Cycle - genetics ; Cell Line, Tumor ; Cell Movement - genetics ; Cell Proliferation ; Epithelial Cell Adhesion Molecule ; Flow Cytometry ; Forkhead Transcription Factors - genetics ; Forkhead Transcription Factors - metabolism ; Gene Expression ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Glycoproteins - metabolism ; Humans ; Hyaluronan Receptors - metabolism ; Immunohistochemistry ; Mice ; Mice, SCID ; Microarray ; Microscopy, Confocal ; Neoplastic Stem Cells - metabolism ; Neoplastic Stem Cells - pathology ; Pancreatic Cancer ; Pancreatic Neoplasms - genetics ; Pancreatic Neoplasms - metabolism ; Pancreatic Neoplasms - pathology ; Peptides - metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; RNA Interference ; siRNA ; Transcriptional Activation ; Tumor Growth ; Xenograft Model Antitumor Assays</subject><ispartof>The Journal of biological chemistry, 2014-05, Vol.289 (21), p.14520-14533</ispartof><rights>2014 © 2014 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.</rights><rights>2014 by The American Society for Biochemistry and Molecular Biology, Inc.</rights><rights>2014 by The American Society for Biochemistry and Molecular Biology, Inc. 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c509t-8a0d7aca6847fa0cc827ab92fca3e438fb97a0194d5781878829fcac49b0f0683</citedby><cites>FETCH-LOGICAL-c509t-8a0d7aca6847fa0cc827ab92fca3e438fb97a0194d5781878829fcac49b0f0683</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4031510/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4031510/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24719318$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bao, Bin</creatorcontrib><creatorcontrib>Azmi, Asfar S.</creatorcontrib><creatorcontrib>Aboukameel, Amro</creatorcontrib><creatorcontrib>Ahmad, Aamir</creatorcontrib><creatorcontrib>Bolling-Fischer, Aliccia</creatorcontrib><creatorcontrib>Sethi, Seema</creatorcontrib><creatorcontrib>Ali, Shadan</creatorcontrib><creatorcontrib>Li, Yiwei</creatorcontrib><creatorcontrib>Kong, Dejuan</creatorcontrib><creatorcontrib>Banerjee, Sanjeev</creatorcontrib><creatorcontrib>Back, Jessica</creatorcontrib><creatorcontrib>Sarkar, Fazlul H.</creatorcontrib><title>Pancreatic Cancer Stem-like Cells Display Aggressive Behavior Mediated via Activation of FoxQ1</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>Subpopulations of cancer stem cells (CSCs) or cancer stem-like cells (CSLCs) have been identified from most tumors, including pancreatic cancer (PC), and the existence of these cells is clinically relevant. Emerging evidence suggests that CSLCs participate in cell growth/proliferation, migration/invasion, metastasis, and chemo-radiotherapy resistance, ultimately contributing to poor clinical outcome. However, the pathogenesis and biological significance of CSLCs in PC has not been well characterized. In the present study, we found that isolated triple-marker-positive (CD44+/CD133+/EpCAM+) cells of human PC MiaPaCa-2 and L3.6pl cells behave as CSLCs. These CSLCs exhibit aggressive behavior, such as increased cell growth, migration, clonogenicity, and self-renewal capacity. The mRNA expression profiling analysis showed that CSLCs (CD44+/CD133+/EpCAM+) exhibit differential expression of more than 1,600 mRNAs, including FoxQ1, compared with the triple-marker-negative (CD44−/CD133−/EpCAM−) cells. The knockdown of FoxQ1 by its siRNA in CSLCs resulted in the inhibition of aggressive behavior, consistent with the inhibition of EpCAM and Snail expression. Mouse xenograft tumor studies showed that CSLCs have a 100-fold higher potential for tumor formation and rapid tumor growth, consistent with overexpression of CSC-associated markers/mediators, including FoxQ1, compared with its parental MiaPaCa-2 cells. The inhibition of FoxQ1 attenuated tumor formation and growth, and expression of CSC markers in the xenograft tumor derived from CSLCs of MiaPaCa-2 cells. These data clearly suggest the role of differentially expressed genes in the regulation of CSLC characteristics, further suggesting that targeting some of these genes could be important for the development of novel therapies for achieving better treatment outcome of PC.
Cancer stem cells (CSCs) correlate to poorer clinical outcomes of many tumors.
We identified a highly aggressive (CD44+/CD133+/EpCAM+) CSC-like fraction from pancreatic cancer (PC) cell lines with differential expression of many genes, including FoxQ1.
FoxQ1 knockdown inhibited CSC aggressiveness.
Targeting differentially expressed CSC-related genes could provide a novel approach for better treatment outcomes of aggressive PC tumors.</description><subject>AC133 Antigen</subject><subject>Animals</subject><subject>Antigens, CD - metabolism</subject><subject>Antigens, Neoplasm - metabolism</subject><subject>Apoptosis - genetics</subject><subject>Blotting, Western</subject><subject>Cancer Stem Cells</subject><subject>CD44</subject><subject>Cell Adhesion Molecules - metabolism</subject><subject>Cell Biology</subject><subject>Cell Cycle - genetics</subject><subject>Cell Line, Tumor</subject><subject>Cell Movement - genetics</subject><subject>Cell Proliferation</subject><subject>Epithelial Cell Adhesion Molecule</subject><subject>Flow Cytometry</subject><subject>Forkhead Transcription Factors - genetics</subject><subject>Forkhead Transcription Factors - metabolism</subject><subject>Gene Expression</subject><subject>Gene Expression Profiling</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Glycoproteins - metabolism</subject><subject>Humans</subject><subject>Hyaluronan Receptors - metabolism</subject><subject>Immunohistochemistry</subject><subject>Mice</subject><subject>Mice, SCID</subject><subject>Microarray</subject><subject>Microscopy, Confocal</subject><subject>Neoplastic Stem Cells - metabolism</subject><subject>Neoplastic Stem Cells - pathology</subject><subject>Pancreatic Cancer</subject><subject>Pancreatic Neoplasms - genetics</subject><subject>Pancreatic Neoplasms - metabolism</subject><subject>Pancreatic Neoplasms - pathology</subject><subject>Peptides - metabolism</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>RNA Interference</subject><subject>siRNA</subject><subject>Transcriptional Activation</subject><subject>Tumor Growth</subject><subject>Xenograft Model Antitumor Assays</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kcFPHCEUh4mp0dV67q3h2MusMDALXEy226pNNNq0TXqSvGHerOjssMLsRP97MWtNeygXSN6PD977CPnA2ZQzJY_vaje95FxMK1FqrXbIhDMtClHx3-_IhLGSF6as9D45SOmO5SUN3yP7pVTcCK4n5OYaehcRBu_oIh8x0h8DrorO3yNdYNcl-sWndQdPdL5cRkzJj0g_4y2MPkR6iY2HARs6eqBzN_gxk0JPQ0tPw-N3_p7sttAlPHrdD8mv068_F-fFxdXZt8X8onAVM0OhgTUKHMy0VC0w53SpoDZl60CgFLqtjQLGjWwqpblWWpcm15w0NWvZTItDcrLlrjf1ChuH_RChs-voVxCfbABv_630_tYuw2glE7ziLAM-vQJieNhgGuzKJ5f7hx7DJlleSTMTTKtZjh5voy6GlCK2b89wZl-s2GzFvlixWyv5xse_f_eW_6MhB8w2gHlGo8dok_OYbTQ-ohtsE_x_4c9wuJ0L</recordid><startdate>20140523</startdate><enddate>20140523</enddate><creator>Bao, Bin</creator><creator>Azmi, Asfar S.</creator><creator>Aboukameel, Amro</creator><creator>Ahmad, Aamir</creator><creator>Bolling-Fischer, Aliccia</creator><creator>Sethi, Seema</creator><creator>Ali, Shadan</creator><creator>Li, Yiwei</creator><creator>Kong, Dejuan</creator><creator>Banerjee, Sanjeev</creator><creator>Back, Jessica</creator><creator>Sarkar, Fazlul H.</creator><general>Elsevier Inc</general><general>American Society for Biochemistry and Molecular Biology</general><scope>6I.</scope><scope>AAFTH</scope><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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20140523</creationdate><title>Pancreatic Cancer Stem-like Cells Display Aggressive Behavior Mediated via Activation of FoxQ1</title><author>Bao, Bin ; Azmi, Asfar S. ; Aboukameel, Amro ; Ahmad, Aamir ; Bolling-Fischer, Aliccia ; Sethi, Seema ; Ali, Shadan ; Li, Yiwei ; Kong, Dejuan ; Banerjee, Sanjeev ; Back, Jessica ; Sarkar, Fazlul H.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c509t-8a0d7aca6847fa0cc827ab92fca3e438fb97a0194d5781878829fcac49b0f0683</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>AC133 Antigen</topic><topic>Animals</topic><topic>Antigens, CD - metabolism</topic><topic>Antigens, Neoplasm - metabolism</topic><topic>Apoptosis - genetics</topic><topic>Blotting, Western</topic><topic>Cancer Stem Cells</topic><topic>CD44</topic><topic>Cell Adhesion Molecules - metabolism</topic><topic>Cell Biology</topic><topic>Cell Cycle - genetics</topic><topic>Cell Line, Tumor</topic><topic>Cell Movement - genetics</topic><topic>Cell Proliferation</topic><topic>Epithelial Cell Adhesion Molecule</topic><topic>Flow Cytometry</topic><topic>Forkhead Transcription Factors - genetics</topic><topic>Forkhead Transcription Factors - metabolism</topic><topic>Gene Expression</topic><topic>Gene Expression Profiling</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Glycoproteins - metabolism</topic><topic>Humans</topic><topic>Hyaluronan Receptors - metabolism</topic><topic>Immunohistochemistry</topic><topic>Mice</topic><topic>Mice, SCID</topic><topic>Microarray</topic><topic>Microscopy, Confocal</topic><topic>Neoplastic Stem Cells - metabolism</topic><topic>Neoplastic Stem Cells - pathology</topic><topic>Pancreatic Cancer</topic><topic>Pancreatic Neoplasms - genetics</topic><topic>Pancreatic Neoplasms - metabolism</topic><topic>Pancreatic Neoplasms - pathology</topic><topic>Peptides - metabolism</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>RNA Interference</topic><topic>siRNA</topic><topic>Transcriptional Activation</topic><topic>Tumor Growth</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bao, Bin</creatorcontrib><creatorcontrib>Azmi, Asfar S.</creatorcontrib><creatorcontrib>Aboukameel, Amro</creatorcontrib><creatorcontrib>Ahmad, Aamir</creatorcontrib><creatorcontrib>Bolling-Fischer, Aliccia</creatorcontrib><creatorcontrib>Sethi, Seema</creatorcontrib><creatorcontrib>Ali, Shadan</creatorcontrib><creatorcontrib>Li, Yiwei</creatorcontrib><creatorcontrib>Kong, Dejuan</creatorcontrib><creatorcontrib>Banerjee, Sanjeev</creatorcontrib><creatorcontrib>Back, Jessica</creatorcontrib><creatorcontrib>Sarkar, Fazlul H.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bao, Bin</au><au>Azmi, Asfar S.</au><au>Aboukameel, Amro</au><au>Ahmad, Aamir</au><au>Bolling-Fischer, Aliccia</au><au>Sethi, Seema</au><au>Ali, Shadan</au><au>Li, Yiwei</au><au>Kong, Dejuan</au><au>Banerjee, Sanjeev</au><au>Back, Jessica</au><au>Sarkar, Fazlul H.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pancreatic Cancer Stem-like Cells Display Aggressive Behavior Mediated via Activation of FoxQ1</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2014-05-23</date><risdate>2014</risdate><volume>289</volume><issue>21</issue><spage>14520</spage><epage>14533</epage><pages>14520-14533</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>Subpopulations of cancer stem cells (CSCs) or cancer stem-like cells (CSLCs) have been identified from most tumors, including pancreatic cancer (PC), and the existence of these cells is clinically relevant. Emerging evidence suggests that CSLCs participate in cell growth/proliferation, migration/invasion, metastasis, and chemo-radiotherapy resistance, ultimately contributing to poor clinical outcome. However, the pathogenesis and biological significance of CSLCs in PC has not been well characterized. In the present study, we found that isolated triple-marker-positive (CD44+/CD133+/EpCAM+) cells of human PC MiaPaCa-2 and L3.6pl cells behave as CSLCs. These CSLCs exhibit aggressive behavior, such as increased cell growth, migration, clonogenicity, and self-renewal capacity. The mRNA expression profiling analysis showed that CSLCs (CD44+/CD133+/EpCAM+) exhibit differential expression of more than 1,600 mRNAs, including FoxQ1, compared with the triple-marker-negative (CD44−/CD133−/EpCAM−) cells. The knockdown of FoxQ1 by its siRNA in CSLCs resulted in the inhibition of aggressive behavior, consistent with the inhibition of EpCAM and Snail expression. Mouse xenograft tumor studies showed that CSLCs have a 100-fold higher potential for tumor formation and rapid tumor growth, consistent with overexpression of CSC-associated markers/mediators, including FoxQ1, compared with its parental MiaPaCa-2 cells. The inhibition of FoxQ1 attenuated tumor formation and growth, and expression of CSC markers in the xenograft tumor derived from CSLCs of MiaPaCa-2 cells. These data clearly suggest the role of differentially expressed genes in the regulation of CSLC characteristics, further suggesting that targeting some of these genes could be important for the development of novel therapies for achieving better treatment outcome of PC.
Cancer stem cells (CSCs) correlate to poorer clinical outcomes of many tumors.
We identified a highly aggressive (CD44+/CD133+/EpCAM+) CSC-like fraction from pancreatic cancer (PC) cell lines with differential expression of many genes, including FoxQ1.
FoxQ1 knockdown inhibited CSC aggressiveness.
Targeting differentially expressed CSC-related genes could provide a novel approach for better treatment outcomes of aggressive PC tumors.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>24719318</pmid><doi>10.1074/jbc.M113.532887</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | The Journal of biological chemistry, 2014-05, Vol.289 (21), p.14520-14533 |
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| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; PubMed Central; Alma/SFX Local Collection |
| subjects | AC133 Antigen Animals Antigens, CD - metabolism Antigens, Neoplasm - metabolism Apoptosis - genetics Blotting, Western Cancer Stem Cells CD44 Cell Adhesion Molecules - metabolism Cell Biology Cell Cycle - genetics Cell Line, Tumor Cell Movement - genetics Cell Proliferation Epithelial Cell Adhesion Molecule Flow Cytometry Forkhead Transcription Factors - genetics Forkhead Transcription Factors - metabolism Gene Expression Gene Expression Profiling Gene Expression Regulation, Neoplastic Glycoproteins - metabolism Humans Hyaluronan Receptors - metabolism Immunohistochemistry Mice Mice, SCID Microarray Microscopy, Confocal Neoplastic Stem Cells - metabolism Neoplastic Stem Cells - pathology Pancreatic Cancer Pancreatic Neoplasms - genetics Pancreatic Neoplasms - metabolism Pancreatic Neoplasms - pathology Peptides - metabolism Reverse Transcriptase Polymerase Chain Reaction RNA Interference siRNA Transcriptional Activation Tumor Growth Xenograft Model Antitumor Assays |
| title | Pancreatic Cancer Stem-like Cells Display Aggressive Behavior Mediated via Activation of FoxQ1 |
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