Mitogenic Insulin Receptor-A Is Overexpressed in Human Hepatocellular Carcinoma due to EGFR-Mediated Dysregulation of RNA Splicing Factors
Insulin receptor (IR) exists as two isoforms resulting from the alternative splicing of IR pre-mRNA. IR-B promotes the metabolic effects of insulin, whereas IR-A rather signals proliferative effects. IR-B is predominantly expressed in the adult liver. Here, we show that the alternative splicing of I...
Gespeichert in:
| Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 2013-07, Vol.73 (13), p.3974-3986 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 3986 |
|---|---|
| container_issue | 13 |
| container_start_page | 3974 |
| container_title | Cancer research (Chicago, Ill.) |
| container_volume | 73 |
| creator | CHETTOUH, Hamza FARTOUX, Laetitia PRAZ, Françoise HOUSSET, Chantal ROSMORDUC, Olivier DESBOIS-MOUTHON, Christèle AOUDJEHANE, Lynda WENDUM, Dominique CLAPERON, Audrey CHRÉTIEN, Yves REY, Colette SCATTON, Olivier SOUBRANE, Olivier CONTI, Filomena |
| description | Insulin receptor (IR) exists as two isoforms resulting from the alternative splicing of IR pre-mRNA. IR-B promotes the metabolic effects of insulin, whereas IR-A rather signals proliferative effects. IR-B is predominantly expressed in the adult liver. Here, we show that the alternative splicing of IR pre-mRNA is dysregulated in a panel of 85 human hepatocellular carcinoma (HCC) while being normal in adjacent nontumor liver tissue. An IR-B to IR-A switch is frequently observed in HCC tumors regardless of tumor etiology. Using pharmacologic and siRNA approaches, we show that the autocrine or paracrine activation of the EGF receptor (EGFR)/mitogen-activated protein/extracellular signal-regulated kinase pathway increases the IR-A:IR-B ratio in HCC cell lines, but not in normal hepatocytes, by upregulating the expression of the splicing factors CUGBP1, hnRNPH, hnRNPA1, hnRNPA2B1, and SF2/ASF. In HCC tumors, there is a significant correlation between the expression of IR-A and that of splicing factors. Dysregulation of IR pre-mRNA splicing was confirmed in a chemically induced model of HCC in rat but not in regenerating livers after partial hepatectomy. This study identifies a mechanism responsible for the generation of mitogenic IR-A and provides a novel interplay between IR and EGFR pathways in HCC. Increased expression of IR-A during neoplastic transformation of hepatocytes could mediate some of the adverse effects of hyperinsulinemia on HCC. |
| doi_str_mv | 10.1158/0008-5472.can-12-3824 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_hal_p</sourceid><recordid>TN_cdi_hal_primary_oai_HAL_hal_03979220v1</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1551623675</sourcerecordid><originalsourceid>FETCH-LOGICAL-c472t-74e6605ac98f1ea28bc65d1525250c0b63bacbd35b0429bbbec49dc7a09e5b9c3</originalsourceid><addsrcrecordid>eNqFkV1v0zAUhi3ExMrgJ4B8gwQXGf6I83FZlXWt1G1SgWvrxDkpRkkc7GRif4FfjaOW7hJZsmX7eX38npeQd5xdc66Kz4yxIlFpLq4N9AkXiSxE-oIsuJJFkqepekkWZ-aSvA7hZ9wqztQrcilkJmVasAX5c2dHd8DeGrrtw9Tanu7R4DA6nyzpNtCHR_T4e_AYAtY0Xm-mDuKMA4zOYNtOLXi6Am9s7zqg9YR0dPTmdr1P7rC2MEbZl6fg8RDJ0bqeuobu75f069DaKDrQNZhYLrwhFw20Ad-e1ivyfX3zbbVJdg-329Vyl5joZIzeMMuYAlMWDUcQRWUyVXMl4mCGVZmswFS1VBVLRVlVFZq0rE0OrERVlUZekU_Hd39AqwdvO_BP2oHVm-VOz2dMlnkpBHvkkf14ZAfvfk0YRt3ZMLuGHt0UNFeKZ7Gbufo_KssiFaIQeUTVETXehdiZ5vwNzvScrp6T03NyerW811zoOd2oe38qMVUd1mfVvzgj8OEEQDDQNh56Y8MzlysmGC_lX_kOrWk</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1398422827</pqid></control><display><type>article</type><title>Mitogenic Insulin Receptor-A Is Overexpressed in Human Hepatocellular Carcinoma due to EGFR-Mediated Dysregulation of RNA Splicing Factors</title><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>American Association for Cancer Research</source><creator>CHETTOUH, Hamza ; FARTOUX, Laetitia ; PRAZ, Françoise ; HOUSSET, Chantal ; ROSMORDUC, Olivier ; DESBOIS-MOUTHON, Christèle ; AOUDJEHANE, Lynda ; WENDUM, Dominique ; CLAPERON, Audrey ; CHRÉTIEN, Yves ; REY, Colette ; SCATTON, Olivier ; SOUBRANE, Olivier ; CONTI, Filomena</creator><creatorcontrib>CHETTOUH, Hamza ; FARTOUX, Laetitia ; PRAZ, Françoise ; HOUSSET, Chantal ; ROSMORDUC, Olivier ; DESBOIS-MOUTHON, Christèle ; AOUDJEHANE, Lynda ; WENDUM, Dominique ; CLAPERON, Audrey ; CHRÉTIEN, Yves ; REY, Colette ; SCATTON, Olivier ; SOUBRANE, Olivier ; CONTI, Filomena</creatorcontrib><description>Insulin receptor (IR) exists as two isoforms resulting from the alternative splicing of IR pre-mRNA. IR-B promotes the metabolic effects of insulin, whereas IR-A rather signals proliferative effects. IR-B is predominantly expressed in the adult liver. Here, we show that the alternative splicing of IR pre-mRNA is dysregulated in a panel of 85 human hepatocellular carcinoma (HCC) while being normal in adjacent nontumor liver tissue. An IR-B to IR-A switch is frequently observed in HCC tumors regardless of tumor etiology. Using pharmacologic and siRNA approaches, we show that the autocrine or paracrine activation of the EGF receptor (EGFR)/mitogen-activated protein/extracellular signal-regulated kinase pathway increases the IR-A:IR-B ratio in HCC cell lines, but not in normal hepatocytes, by upregulating the expression of the splicing factors CUGBP1, hnRNPH, hnRNPA1, hnRNPA2B1, and SF2/ASF. In HCC tumors, there is a significant correlation between the expression of IR-A and that of splicing factors. Dysregulation of IR pre-mRNA splicing was confirmed in a chemically induced model of HCC in rat but not in regenerating livers after partial hepatectomy. This study identifies a mechanism responsible for the generation of mitogenic IR-A and provides a novel interplay between IR and EGFR pathways in HCC. Increased expression of IR-A during neoplastic transformation of hepatocytes could mediate some of the adverse effects of hyperinsulinemia on HCC.</description><identifier>ISSN: 0008-5472</identifier><identifier>EISSN: 1538-7445</identifier><identifier>DOI: 10.1158/0008-5472.can-12-3824</identifier><identifier>PMID: 23633480</identifier><identifier>CODEN: CNREA8</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>Animals ; Antigens, CD - genetics ; Antigens, CD - metabolism ; Antineoplastic agents ; Biological and medical sciences ; Carcinoma, Hepatocellular - metabolism ; CELF1 Protein ; Cell Transformation, Neoplastic - metabolism ; ErbB Receptors - metabolism ; Gastroenterology. Liver. Pancreas. Abdomen ; Gene Expression ; Gene Expression Regulation, Neoplastic ; Hep G2 Cells ; Hepatocytes - metabolism ; Heterogeneous Nuclear Ribonucleoprotein A1 ; Heterogeneous-Nuclear Ribonucleoprotein Group A-B - genetics ; Heterogeneous-Nuclear Ribonucleoprotein Group A-B - metabolism ; Humans ; Insulin - physiology ; Insulin-Like Growth Factor II - physiology ; Life Sciences ; Liver Neoplasms, Experimental - metabolism ; Liver Regeneration ; Liver. Biliary tract. Portal circulation. Exocrine pancreas ; MAP Kinase Signaling System ; Medical sciences ; Multiple tumors. Solid tumors. Tumors in childhood (general aspects) ; Nuclear Proteins - genetics ; Nuclear Proteins - metabolism ; Pharmacology. Drug treatments ; Protein Isoforms - genetics ; Protein Isoforms - metabolism ; Rats ; Receptor, Insulin - genetics ; Receptor, Insulin - metabolism ; RNA Splicing ; RNA, Messenger - genetics ; RNA, Messenger - metabolism ; RNA-Binding Proteins - genetics ; RNA-Binding Proteins - metabolism ; Serine-Arginine Splicing Factors ; Tumors</subject><ispartof>Cancer research (Chicago, Ill.), 2013-07, Vol.73 (13), p.3974-3986</ispartof><rights>2014 INIST-CNRS</rights><rights>2013 AACR.</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c472t-74e6605ac98f1ea28bc65d1525250c0b63bacbd35b0429bbbec49dc7a09e5b9c3</citedby><cites>FETCH-LOGICAL-c472t-74e6605ac98f1ea28bc65d1525250c0b63bacbd35b0429bbbec49dc7a09e5b9c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,781,785,886,3357,27929,27930</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=27502019$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23633480$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.sorbonne-universite.fr/hal-03979220$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>CHETTOUH, Hamza</creatorcontrib><creatorcontrib>FARTOUX, Laetitia</creatorcontrib><creatorcontrib>PRAZ, Françoise</creatorcontrib><creatorcontrib>HOUSSET, Chantal</creatorcontrib><creatorcontrib>ROSMORDUC, Olivier</creatorcontrib><creatorcontrib>DESBOIS-MOUTHON, Christèle</creatorcontrib><creatorcontrib>AOUDJEHANE, Lynda</creatorcontrib><creatorcontrib>WENDUM, Dominique</creatorcontrib><creatorcontrib>CLAPERON, Audrey</creatorcontrib><creatorcontrib>CHRÉTIEN, Yves</creatorcontrib><creatorcontrib>REY, Colette</creatorcontrib><creatorcontrib>SCATTON, Olivier</creatorcontrib><creatorcontrib>SOUBRANE, Olivier</creatorcontrib><creatorcontrib>CONTI, Filomena</creatorcontrib><title>Mitogenic Insulin Receptor-A Is Overexpressed in Human Hepatocellular Carcinoma due to EGFR-Mediated Dysregulation of RNA Splicing Factors</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>Insulin receptor (IR) exists as two isoforms resulting from the alternative splicing of IR pre-mRNA. IR-B promotes the metabolic effects of insulin, whereas IR-A rather signals proliferative effects. IR-B is predominantly expressed in the adult liver. Here, we show that the alternative splicing of IR pre-mRNA is dysregulated in a panel of 85 human hepatocellular carcinoma (HCC) while being normal in adjacent nontumor liver tissue. An IR-B to IR-A switch is frequently observed in HCC tumors regardless of tumor etiology. Using pharmacologic and siRNA approaches, we show that the autocrine or paracrine activation of the EGF receptor (EGFR)/mitogen-activated protein/extracellular signal-regulated kinase pathway increases the IR-A:IR-B ratio in HCC cell lines, but not in normal hepatocytes, by upregulating the expression of the splicing factors CUGBP1, hnRNPH, hnRNPA1, hnRNPA2B1, and SF2/ASF. In HCC tumors, there is a significant correlation between the expression of IR-A and that of splicing factors. Dysregulation of IR pre-mRNA splicing was confirmed in a chemically induced model of HCC in rat but not in regenerating livers after partial hepatectomy. This study identifies a mechanism responsible for the generation of mitogenic IR-A and provides a novel interplay between IR and EGFR pathways in HCC. Increased expression of IR-A during neoplastic transformation of hepatocytes could mediate some of the adverse effects of hyperinsulinemia on HCC.</description><subject>Animals</subject><subject>Antigens, CD - genetics</subject><subject>Antigens, CD - metabolism</subject><subject>Antineoplastic agents</subject><subject>Biological and medical sciences</subject><subject>Carcinoma, Hepatocellular - metabolism</subject><subject>CELF1 Protein</subject><subject>Cell Transformation, Neoplastic - metabolism</subject><subject>ErbB Receptors - metabolism</subject><subject>Gastroenterology. Liver. Pancreas. Abdomen</subject><subject>Gene Expression</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Hep G2 Cells</subject><subject>Hepatocytes - metabolism</subject><subject>Heterogeneous Nuclear Ribonucleoprotein A1</subject><subject>Heterogeneous-Nuclear Ribonucleoprotein Group A-B - genetics</subject><subject>Heterogeneous-Nuclear Ribonucleoprotein Group A-B - metabolism</subject><subject>Humans</subject><subject>Insulin - physiology</subject><subject>Insulin-Like Growth Factor II - physiology</subject><subject>Life Sciences</subject><subject>Liver Neoplasms, Experimental - metabolism</subject><subject>Liver Regeneration</subject><subject>Liver. Biliary tract. Portal circulation. Exocrine pancreas</subject><subject>MAP Kinase Signaling System</subject><subject>Medical sciences</subject><subject>Multiple tumors. Solid tumors. Tumors in childhood (general aspects)</subject><subject>Nuclear Proteins - genetics</subject><subject>Nuclear Proteins - metabolism</subject><subject>Pharmacology. Drug treatments</subject><subject>Protein Isoforms - genetics</subject><subject>Protein Isoforms - metabolism</subject><subject>Rats</subject><subject>Receptor, Insulin - genetics</subject><subject>Receptor, Insulin - metabolism</subject><subject>RNA Splicing</subject><subject>RNA, Messenger - genetics</subject><subject>RNA, Messenger - metabolism</subject><subject>RNA-Binding Proteins - genetics</subject><subject>RNA-Binding Proteins - metabolism</subject><subject>Serine-Arginine Splicing Factors</subject><subject>Tumors</subject><issn>0008-5472</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkV1v0zAUhi3ExMrgJ4B8gwQXGf6I83FZlXWt1G1SgWvrxDkpRkkc7GRif4FfjaOW7hJZsmX7eX38npeQd5xdc66Kz4yxIlFpLq4N9AkXiSxE-oIsuJJFkqepekkWZ-aSvA7hZ9wqztQrcilkJmVasAX5c2dHd8DeGrrtw9Tanu7R4DA6nyzpNtCHR_T4e_AYAtY0Xm-mDuKMA4zOYNtOLXi6Am9s7zqg9YR0dPTmdr1P7rC2MEbZl6fg8RDJ0bqeuobu75f069DaKDrQNZhYLrwhFw20Ad-e1ivyfX3zbbVJdg-329Vyl5joZIzeMMuYAlMWDUcQRWUyVXMl4mCGVZmswFS1VBVLRVlVFZq0rE0OrERVlUZekU_Hd39AqwdvO_BP2oHVm-VOz2dMlnkpBHvkkf14ZAfvfk0YRt3ZMLuGHt0UNFeKZ7Gbufo_KssiFaIQeUTVETXehdiZ5vwNzvScrp6T03NyerW811zoOd2oe38qMVUd1mfVvzgj8OEEQDDQNh56Y8MzlysmGC_lX_kOrWk</recordid><startdate>20130701</startdate><enddate>20130701</enddate><creator>CHETTOUH, Hamza</creator><creator>FARTOUX, Laetitia</creator><creator>PRAZ, Françoise</creator><creator>HOUSSET, Chantal</creator><creator>ROSMORDUC, Olivier</creator><creator>DESBOIS-MOUTHON, Christèle</creator><creator>AOUDJEHANE, Lynda</creator><creator>WENDUM, Dominique</creator><creator>CLAPERON, Audrey</creator><creator>CHRÉTIEN, Yves</creator><creator>REY, Colette</creator><creator>SCATTON, Olivier</creator><creator>SOUBRANE, Olivier</creator><creator>CONTI, Filomena</creator><general>American Association for Cancer Research</general><scope>IQODW</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>7TM</scope><scope>1XC</scope></search><sort><creationdate>20130701</creationdate><title>Mitogenic Insulin Receptor-A Is Overexpressed in Human Hepatocellular Carcinoma due to EGFR-Mediated Dysregulation of RNA Splicing Factors</title><author>CHETTOUH, Hamza ; FARTOUX, Laetitia ; PRAZ, Françoise ; HOUSSET, Chantal ; ROSMORDUC, Olivier ; DESBOIS-MOUTHON, Christèle ; AOUDJEHANE, Lynda ; WENDUM, Dominique ; CLAPERON, Audrey ; CHRÉTIEN, Yves ; REY, Colette ; SCATTON, Olivier ; SOUBRANE, Olivier ; CONTI, Filomena</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c472t-74e6605ac98f1ea28bc65d1525250c0b63bacbd35b0429bbbec49dc7a09e5b9c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Animals</topic><topic>Antigens, CD - genetics</topic><topic>Antigens, CD - metabolism</topic><topic>Antineoplastic agents</topic><topic>Biological and medical sciences</topic><topic>Carcinoma, Hepatocellular - metabolism</topic><topic>CELF1 Protein</topic><topic>Cell Transformation, Neoplastic - metabolism</topic><topic>ErbB Receptors - metabolism</topic><topic>Gastroenterology. Liver. Pancreas. Abdomen</topic><topic>Gene Expression</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Hep G2 Cells</topic><topic>Hepatocytes - metabolism</topic><topic>Heterogeneous Nuclear Ribonucleoprotein A1</topic><topic>Heterogeneous-Nuclear Ribonucleoprotein Group A-B - genetics</topic><topic>Heterogeneous-Nuclear Ribonucleoprotein Group A-B - metabolism</topic><topic>Humans</topic><topic>Insulin - physiology</topic><topic>Insulin-Like Growth Factor II - physiology</topic><topic>Life Sciences</topic><topic>Liver Neoplasms, Experimental - metabolism</topic><topic>Liver Regeneration</topic><topic>Liver. Biliary tract. Portal circulation. Exocrine pancreas</topic><topic>MAP Kinase Signaling System</topic><topic>Medical sciences</topic><topic>Multiple tumors. Solid tumors. Tumors in childhood (general aspects)</topic><topic>Nuclear Proteins - genetics</topic><topic>Nuclear Proteins - metabolism</topic><topic>Pharmacology. Drug treatments</topic><topic>Protein Isoforms - genetics</topic><topic>Protein Isoforms - metabolism</topic><topic>Rats</topic><topic>Receptor, Insulin - genetics</topic><topic>Receptor, Insulin - metabolism</topic><topic>RNA Splicing</topic><topic>RNA, Messenger - genetics</topic><topic>RNA, Messenger - metabolism</topic><topic>RNA-Binding Proteins - genetics</topic><topic>RNA-Binding Proteins - metabolism</topic><topic>Serine-Arginine Splicing Factors</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>CHETTOUH, Hamza</creatorcontrib><creatorcontrib>FARTOUX, Laetitia</creatorcontrib><creatorcontrib>PRAZ, Françoise</creatorcontrib><creatorcontrib>HOUSSET, Chantal</creatorcontrib><creatorcontrib>ROSMORDUC, Olivier</creatorcontrib><creatorcontrib>DESBOIS-MOUTHON, Christèle</creatorcontrib><creatorcontrib>AOUDJEHANE, Lynda</creatorcontrib><creatorcontrib>WENDUM, Dominique</creatorcontrib><creatorcontrib>CLAPERON, Audrey</creatorcontrib><creatorcontrib>CHRÉTIEN, Yves</creatorcontrib><creatorcontrib>REY, Colette</creatorcontrib><creatorcontrib>SCATTON, Olivier</creatorcontrib><creatorcontrib>SOUBRANE, Olivier</creatorcontrib><creatorcontrib>CONTI, Filomena</creatorcontrib><collection>Pascal-Francis</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>Nucleic Acids Abstracts</collection><collection>Hyper Article en Ligne (HAL)</collection><jtitle>Cancer research (Chicago, Ill.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>CHETTOUH, Hamza</au><au>FARTOUX, Laetitia</au><au>PRAZ, Françoise</au><au>HOUSSET, Chantal</au><au>ROSMORDUC, Olivier</au><au>DESBOIS-MOUTHON, Christèle</au><au>AOUDJEHANE, Lynda</au><au>WENDUM, Dominique</au><au>CLAPERON, Audrey</au><au>CHRÉTIEN, Yves</au><au>REY, Colette</au><au>SCATTON, Olivier</au><au>SOUBRANE, Olivier</au><au>CONTI, Filomena</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mitogenic Insulin Receptor-A Is Overexpressed in Human Hepatocellular Carcinoma due to EGFR-Mediated Dysregulation of RNA Splicing Factors</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>2013-07-01</date><risdate>2013</risdate><volume>73</volume><issue>13</issue><spage>3974</spage><epage>3986</epage><pages>3974-3986</pages><issn>0008-5472</issn><eissn>1538-7445</eissn><coden>CNREA8</coden><abstract>Insulin receptor (IR) exists as two isoforms resulting from the alternative splicing of IR pre-mRNA. IR-B promotes the metabolic effects of insulin, whereas IR-A rather signals proliferative effects. IR-B is predominantly expressed in the adult liver. Here, we show that the alternative splicing of IR pre-mRNA is dysregulated in a panel of 85 human hepatocellular carcinoma (HCC) while being normal in adjacent nontumor liver tissue. An IR-B to IR-A switch is frequently observed in HCC tumors regardless of tumor etiology. Using pharmacologic and siRNA approaches, we show that the autocrine or paracrine activation of the EGF receptor (EGFR)/mitogen-activated protein/extracellular signal-regulated kinase pathway increases the IR-A:IR-B ratio in HCC cell lines, but not in normal hepatocytes, by upregulating the expression of the splicing factors CUGBP1, hnRNPH, hnRNPA1, hnRNPA2B1, and SF2/ASF. In HCC tumors, there is a significant correlation between the expression of IR-A and that of splicing factors. Dysregulation of IR pre-mRNA splicing was confirmed in a chemically induced model of HCC in rat but not in regenerating livers after partial hepatectomy. This study identifies a mechanism responsible for the generation of mitogenic IR-A and provides a novel interplay between IR and EGFR pathways in HCC. Increased expression of IR-A during neoplastic transformation of hepatocytes could mediate some of the adverse effects of hyperinsulinemia on HCC.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>23633480</pmid><doi>10.1158/0008-5472.can-12-3824</doi><tpages>13</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0008-5472 |
| ispartof | Cancer research (Chicago, Ill.), 2013-07, Vol.73 (13), p.3974-3986 |
| issn | 0008-5472 1538-7445 |
| language | eng |
| recordid | cdi_hal_primary_oai_HAL_hal_03979220v1 |
| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; American Association for Cancer Research |
| subjects | Animals Antigens, CD - genetics Antigens, CD - metabolism Antineoplastic agents Biological and medical sciences Carcinoma, Hepatocellular - metabolism CELF1 Protein Cell Transformation, Neoplastic - metabolism ErbB Receptors - metabolism Gastroenterology. Liver. Pancreas. Abdomen Gene Expression Gene Expression Regulation, Neoplastic Hep G2 Cells Hepatocytes - metabolism Heterogeneous Nuclear Ribonucleoprotein A1 Heterogeneous-Nuclear Ribonucleoprotein Group A-B - genetics Heterogeneous-Nuclear Ribonucleoprotein Group A-B - metabolism Humans Insulin - physiology Insulin-Like Growth Factor II - physiology Life Sciences Liver Neoplasms, Experimental - metabolism Liver Regeneration Liver. Biliary tract. Portal circulation. Exocrine pancreas MAP Kinase Signaling System Medical sciences Multiple tumors. Solid tumors. Tumors in childhood (general aspects) Nuclear Proteins - genetics Nuclear Proteins - metabolism Pharmacology. Drug treatments Protein Isoforms - genetics Protein Isoforms - metabolism Rats Receptor, Insulin - genetics Receptor, Insulin - metabolism RNA Splicing RNA, Messenger - genetics RNA, Messenger - metabolism RNA-Binding Proteins - genetics RNA-Binding Proteins - metabolism Serine-Arginine Splicing Factors Tumors |
| title | Mitogenic Insulin Receptor-A Is Overexpressed in Human Hepatocellular Carcinoma due to EGFR-Mediated Dysregulation of RNA Splicing Factors |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-15T18%3A21%3A30IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_hal_p&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Mitogenic%20Insulin%20Receptor-A%20Is%20Overexpressed%20in%20Human%20Hepatocellular%20Carcinoma%20due%20to%20EGFR-Mediated%20Dysregulation%20of%20RNA%20Splicing%20Factors&rft.jtitle=Cancer%20research%20(Chicago,%20Ill.)&rft.au=CHETTOUH,%20Hamza&rft.date=2013-07-01&rft.volume=73&rft.issue=13&rft.spage=3974&rft.epage=3986&rft.pages=3974-3986&rft.issn=0008-5472&rft.eissn=1538-7445&rft.coden=CNREA8&rft_id=info:doi/10.1158/0008-5472.can-12-3824&rft_dat=%3Cproquest_hal_p%3E1551623675%3C/proquest_hal_p%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1398422827&rft_id=info:pmid/23633480&rfr_iscdi=true |