An N-terminal truncated carboxypeptidase E splice isoform induces tumor growth and is a biomarker for predicting future metastasis in human cancers
Metastasis is a major cause of mortality in cancer patients. However, the mechanisms governing the metastatic process remain elusive, and few accurate biomarkers exist for predicting whether metastasis will occur, something that would be invaluable for guiding therapy. We report here that the carbox...
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Veröffentlicht in: | The Journal of clinical investigation 2011-03, Vol.121 (3), p.880-892 |
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creator | Lee, Terence K Murthy, Saravana R K Cawley, Niamh X Dhanvantari, Savita Hewitt, Stephen M Lou, Hong Lau, Tracy Ma, Stephanie Huynh, Thanh Wesley, Robert A Ng, Irene O Pacak, Karel Poon, Ronnie T Loh, Y Peng |
description | Metastasis is a major cause of mortality in cancer patients. However, the mechanisms governing the metastatic process remain elusive, and few accurate biomarkers exist for predicting whether metastasis will occur, something that would be invaluable for guiding therapy. We report here that the carboxypeptidase E gene (CPE) is alternatively spliced in human tumors to yield an N-terminal truncated protein (CPE-ΔN) that drives metastasis. mRNA encoding CPE-ΔN was found to be elevated in human metastatic colon, breast, and hepatocellular carcinoma (HCC) cell lines. In HCC cells, cytosolic CPE-ΔN was translocated to the nucleus and interacted with histone deacetylase 1/2 to upregulate expression of the gene encoding neural precursor cell expressed, developmentally downregulated gene 9 (Nedd9)--which has been shown to promote melanoma metastasis. Nedd9 upregulation resulted in enhanced in vitro proliferation and invasion. Quantification of mRNA encoding CPE-ΔN in HCC patient samples predicted intrahepatic metastasis with high sensitivity and specificity, independent of cancer stage. Similarly, high CPE-ΔN mRNA copy numbers in resected pheochromocytomas/paragangliomas (PHEOs/PGLs), rare neuroendocrine tumors, accurately predicted future metastasis or recurrence. Thus, CPE-ΔN induces tumor metastasis and should be investigated as a potentially powerful biomarker for predicting future metastasis and recurrence in HCC and PHEO/PGL patients. |
doi_str_mv | 10.1172/jci40433 |
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However, the mechanisms governing the metastatic process remain elusive, and few accurate biomarkers exist for predicting whether metastasis will occur, something that would be invaluable for guiding therapy. We report here that the carboxypeptidase E gene (CPE) is alternatively spliced in human tumors to yield an N-terminal truncated protein (CPE-ΔN) that drives metastasis. mRNA encoding CPE-ΔN was found to be elevated in human metastatic colon, breast, and hepatocellular carcinoma (HCC) cell lines. In HCC cells, cytosolic CPE-ΔN was translocated to the nucleus and interacted with histone deacetylase 1/2 to upregulate expression of the gene encoding neural precursor cell expressed, developmentally downregulated gene 9 (Nedd9)--which has been shown to promote melanoma metastasis. Nedd9 upregulation resulted in enhanced in vitro proliferation and invasion. Quantification of mRNA encoding CPE-ΔN in HCC patient samples predicted intrahepatic metastasis with high sensitivity and specificity, independent of cancer stage. Similarly, high CPE-ΔN mRNA copy numbers in resected pheochromocytomas/paragangliomas (PHEOs/PGLs), rare neuroendocrine tumors, accurately predicted future metastasis or recurrence. Thus, CPE-ΔN induces tumor metastasis and should be investigated as a potentially powerful biomarker for predicting future metastasis and recurrence in HCC and PHEO/PGL patients.</description><identifier>ISSN: 0021-9738</identifier><identifier>EISSN: 1558-8238</identifier><identifier>DOI: 10.1172/jci40433</identifier><identifier>PMID: 21285511</identifier><language>eng</language><publisher>United States: American Society for Clinical Investigation</publisher><subject>Adaptor Proteins, Signal Transducing - metabolism ; Alternative Splicing ; Bioinformatics ; Biological markers ; Biomarkers ; Biomarkers, Tumor - metabolism ; Biomedical research ; Breast cancer ; Carboxypeptidase H - chemistry ; Carboxypeptidase H - genetics ; Cell Line, Tumor ; Cytosol - metabolism ; Female ; Gene expression ; Gene Expression Regulation, Neoplastic ; Genetic aspects ; Growth ; Health aspects ; Humans ; Liver cancer ; Male ; Metastasis ; Middle Aged ; Mortality ; Neoplasm Invasiveness ; Neoplasm Metastasis ; Neuropeptides ; Paraganglioma - metabolism ; Peptides ; Pheochromocytoma - metabolism ; Phosphoproteins - metabolism ; Physiological aspects ; Proteases ; Protein Isoforms ; Protein Structure, Tertiary ; Recurrence ; Tumorigenesis ; Tumors</subject><ispartof>The Journal of clinical investigation, 2011-03, Vol.121 (3), p.880-892</ispartof><rights>COPYRIGHT 2011 American Society for Clinical Investigation</rights><rights>COPYRIGHT 2019 American Society for Clinical Investigation</rights><rights>Copyright American Society for Clinical Investigation Mar 2011</rights><rights>Copyright © 2011, American Society for Clinical Investigation</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c841t-25eae8c61d2feacde2aa2d35f10264e5f9ebc8b830198824695c552b7317604d3</citedby><cites>FETCH-LOGICAL-c841t-25eae8c61d2feacde2aa2d35f10264e5f9ebc8b830198824695c552b7317604d3</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/PMC3049392/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3049392/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21285511$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lee, Terence K</creatorcontrib><creatorcontrib>Murthy, Saravana R K</creatorcontrib><creatorcontrib>Cawley, Niamh X</creatorcontrib><creatorcontrib>Dhanvantari, Savita</creatorcontrib><creatorcontrib>Hewitt, Stephen M</creatorcontrib><creatorcontrib>Lou, Hong</creatorcontrib><creatorcontrib>Lau, Tracy</creatorcontrib><creatorcontrib>Ma, Stephanie</creatorcontrib><creatorcontrib>Huynh, Thanh</creatorcontrib><creatorcontrib>Wesley, Robert A</creatorcontrib><creatorcontrib>Ng, Irene O</creatorcontrib><creatorcontrib>Pacak, Karel</creatorcontrib><creatorcontrib>Poon, Ronnie T</creatorcontrib><creatorcontrib>Loh, Y Peng</creatorcontrib><title>An N-terminal truncated carboxypeptidase E splice isoform induces tumor growth and is a biomarker for predicting future metastasis in human cancers</title><title>The Journal of clinical investigation</title><addtitle>J Clin Invest</addtitle><description>Metastasis is a major cause of mortality in cancer patients. However, the mechanisms governing the metastatic process remain elusive, and few accurate biomarkers exist for predicting whether metastasis will occur, something that would be invaluable for guiding therapy. We report here that the carboxypeptidase E gene (CPE) is alternatively spliced in human tumors to yield an N-terminal truncated protein (CPE-ΔN) that drives metastasis. mRNA encoding CPE-ΔN was found to be elevated in human metastatic colon, breast, and hepatocellular carcinoma (HCC) cell lines. In HCC cells, cytosolic CPE-ΔN was translocated to the nucleus and interacted with histone deacetylase 1/2 to upregulate expression of the gene encoding neural precursor cell expressed, developmentally downregulated gene 9 (Nedd9)--which has been shown to promote melanoma metastasis. Nedd9 upregulation resulted in enhanced in vitro proliferation and invasion. Quantification of mRNA encoding CPE-ΔN in HCC patient samples predicted intrahepatic metastasis with high sensitivity and specificity, independent of cancer stage. Similarly, high CPE-ΔN mRNA copy numbers in resected pheochromocytomas/paragangliomas (PHEOs/PGLs), rare neuroendocrine tumors, accurately predicted future metastasis or recurrence. Thus, CPE-ΔN induces tumor metastasis and should be investigated as a potentially powerful biomarker for predicting future metastasis and recurrence in HCC and PHEO/PGL patients.</description><subject>Adaptor Proteins, Signal Transducing - metabolism</subject><subject>Alternative Splicing</subject><subject>Bioinformatics</subject><subject>Biological markers</subject><subject>Biomarkers</subject><subject>Biomarkers, Tumor - metabolism</subject><subject>Biomedical research</subject><subject>Breast cancer</subject><subject>Carboxypeptidase H - chemistry</subject><subject>Carboxypeptidase H - genetics</subject><subject>Cell Line, Tumor</subject><subject>Cytosol - metabolism</subject><subject>Female</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Genetic aspects</subject><subject>Growth</subject><subject>Health aspects</subject><subject>Humans</subject><subject>Liver cancer</subject><subject>Male</subject><subject>Metastasis</subject><subject>Middle Aged</subject><subject>Mortality</subject><subject>Neoplasm Invasiveness</subject><subject>Neoplasm Metastasis</subject><subject>Neuropeptides</subject><subject>Paraganglioma - metabolism</subject><subject>Peptides</subject><subject>Pheochromocytoma - metabolism</subject><subject>Phosphoproteins - metabolism</subject><subject>Physiological aspects</subject><subject>Proteases</subject><subject>Protein Isoforms</subject><subject>Protein Structure, Tertiary</subject><subject>Recurrence</subject><subject>Tumorigenesis</subject><subject>Tumors</subject><issn>0021-9738</issn><issn>1558-8238</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNqN01uL1DAUB_Aiiruugp9AgoKXh65JmrTpizAMq44sLnh7LWl62snYJjVJdfdz-IXNOOsyI4MODRSSX_6nl5wkeUjwKSEFfblSmmGWZbeSY8K5SAXNxO3kGGNK0rLIxFFyz_sVxoQxzu4mR5RQwTkhx8nPmUHv0wBu0Eb2KLjJKBmgQUq62l5ejTAG3UgP6Az5sdcKkPa2tW5A2jSTAo_CNFiHOmd_hCWSpokASVRrO0j3FRyKGI0OGq2CNh1qpzA5QAME6eOIWBu0nAZpYk2jwPn7yZ1W9h4eXN9Pks-vzz7N36bnF28W89l5qgQjIaUcJAiVk4a2IFUDVEraZLwlmOYMeFtCrUQtMkxKISjLS644p3WRkSLHrMlOkleb3HGqB2gUmOBkX41Oxye_qqzU1e6K0cuqs9-rDLMyK2kMeHYd4Oy3CXyoBu0V9L00YCdfiZxQnBcFi_LxX3JlJxe_eEQ8Z5TmBY_oyQZ1sodKm9bGqmodWc24oBRnhJF_Khr_ackKsi6Y7lEdGIgvYg20Ok7vpB7it_NP9_h4NTBotbfAQRu2K7zY2RBNgMvQycn7avHxw274_-yhuRdfDs9d2-3cp1t2CbIPS2_7KWhr_C58voHKWe8dtDcnjuBq3c7Vu_nidztH-mj7hN7AP_2b_QIUeT97</recordid><startdate>20110301</startdate><enddate>20110301</enddate><creator>Lee, Terence K</creator><creator>Murthy, Saravana R K</creator><creator>Cawley, Niamh X</creator><creator>Dhanvantari, Savita</creator><creator>Hewitt, Stephen M</creator><creator>Lou, Hong</creator><creator>Lau, Tracy</creator><creator>Ma, Stephanie</creator><creator>Huynh, Thanh</creator><creator>Wesley, Robert A</creator><creator>Ng, Irene O</creator><creator>Pacak, Karel</creator><creator>Poon, Ronnie T</creator><creator>Loh, Y Peng</creator><general>American Society for Clinical Investigation</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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</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>BEC</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>S0X</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20110301</creationdate><title>An N-terminal truncated carboxypeptidase E splice isoform induces tumor growth and is a biomarker for predicting future metastasis in human cancers</title><author>Lee, Terence K ; Murthy, Saravana R K ; Cawley, Niamh X ; Dhanvantari, Savita ; Hewitt, Stephen M ; Lou, Hong ; Lau, Tracy ; Ma, Stephanie ; Huynh, Thanh ; Wesley, Robert A ; Ng, Irene O ; Pacak, Karel ; Poon, Ronnie T ; Loh, Y Peng</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c841t-25eae8c61d2feacde2aa2d35f10264e5f9ebc8b830198824695c552b7317604d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Adaptor Proteins, Signal Transducing - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of clinical investigation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lee, Terence K</au><au>Murthy, Saravana R K</au><au>Cawley, Niamh X</au><au>Dhanvantari, Savita</au><au>Hewitt, Stephen M</au><au>Lou, Hong</au><au>Lau, Tracy</au><au>Ma, Stephanie</au><au>Huynh, Thanh</au><au>Wesley, Robert A</au><au>Ng, Irene O</au><au>Pacak, Karel</au><au>Poon, Ronnie T</au><au>Loh, Y Peng</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>An N-terminal truncated carboxypeptidase E splice isoform induces tumor growth and is a biomarker for predicting future metastasis in human cancers</atitle><jtitle>The Journal of clinical investigation</jtitle><addtitle>J Clin Invest</addtitle><date>2011-03-01</date><risdate>2011</risdate><volume>121</volume><issue>3</issue><spage>880</spage><epage>892</epage><pages>880-892</pages><issn>0021-9738</issn><eissn>1558-8238</eissn><abstract>Metastasis is a major cause of mortality in cancer patients. However, the mechanisms governing the metastatic process remain elusive, and few accurate biomarkers exist for predicting whether metastasis will occur, something that would be invaluable for guiding therapy. We report here that the carboxypeptidase E gene (CPE) is alternatively spliced in human tumors to yield an N-terminal truncated protein (CPE-ΔN) that drives metastasis. mRNA encoding CPE-ΔN was found to be elevated in human metastatic colon, breast, and hepatocellular carcinoma (HCC) cell lines. In HCC cells, cytosolic CPE-ΔN was translocated to the nucleus and interacted with histone deacetylase 1/2 to upregulate expression of the gene encoding neural precursor cell expressed, developmentally downregulated gene 9 (Nedd9)--which has been shown to promote melanoma metastasis. Nedd9 upregulation resulted in enhanced in vitro proliferation and invasion. Quantification of mRNA encoding CPE-ΔN in HCC patient samples predicted intrahepatic metastasis with high sensitivity and specificity, independent of cancer stage. Similarly, high CPE-ΔN mRNA copy numbers in resected pheochromocytomas/paragangliomas (PHEOs/PGLs), rare neuroendocrine tumors, accurately predicted future metastasis or recurrence. Thus, CPE-ΔN induces tumor metastasis and should be investigated as a potentially powerful biomarker for predicting future metastasis and recurrence in HCC and PHEO/PGL patients.</abstract><cop>United States</cop><pub>American Society for Clinical Investigation</pub><pmid>21285511</pmid><doi>10.1172/jci40433</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Adaptor Proteins, Signal Transducing - metabolism Alternative Splicing Bioinformatics Biological markers Biomarkers Biomarkers, Tumor - metabolism Biomedical research Breast cancer Carboxypeptidase H - chemistry Carboxypeptidase H - genetics Cell Line, Tumor Cytosol - metabolism Female Gene expression Gene Expression Regulation, Neoplastic Genetic aspects Growth Health aspects Humans Liver cancer Male Metastasis Middle Aged Mortality Neoplasm Invasiveness Neoplasm Metastasis Neuropeptides Paraganglioma - metabolism Peptides Pheochromocytoma - metabolism Phosphoproteins - metabolism Physiological aspects Proteases Protein Isoforms Protein Structure, Tertiary Recurrence Tumorigenesis Tumors |
title | An N-terminal truncated carboxypeptidase E splice isoform induces tumor growth and is a biomarker for predicting future metastasis in human cancers |
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