Emerging role of IGF1R and IR expression and localisation in adrenocortical carcinomas
Abstract Background The insulin-like growth factor 2 (IGF2) is overexpressed in 90% of adrenocortical carcinomas (ACC) and promotes cell proliferation via IGF1R and isoform A of insulin receptor (IRA). However, IGF2 role in ACC tumourigenesis has not been completely understood yet, and the contribut...
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2025-03-01
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| author | Rosa Catalano Emma Nozza Barbara Altieri Emanuela Esposito Giorgio A. Croci Anna Maria Barbieri Donatella Treppiedi Sonia Di Bari Otilia Kimpel Mario Detomas Mariangela Tamburello Marc P. Schauer Sabine Herterich Anna Angelousi Michaela Luconi Letizia Canu Gabriella Nesi Constanze Hantel Sandra Sigala Laura-Sophie Landwehr Guido Di Dalmazi Elisa Cassinotti Ludovica Baldari Serena Palmieri Alessandra Mangone Emanuele Ferrante Cristina L. Ronchi Giovanna Mantovani Erika Peverelli |
| author_facet | Rosa Catalano Emma Nozza Barbara Altieri Emanuela Esposito Giorgio A. Croci Anna Maria Barbieri Donatella Treppiedi Sonia Di Bari Otilia Kimpel Mario Detomas Mariangela Tamburello Marc P. Schauer Sabine Herterich Anna Angelousi Michaela Luconi Letizia Canu Gabriella Nesi Constanze Hantel Sandra Sigala Laura-Sophie Landwehr Guido Di Dalmazi Elisa Cassinotti Ludovica Baldari Serena Palmieri Alessandra Mangone Emanuele Ferrante Cristina L. Ronchi Giovanna Mantovani Erika Peverelli |
| author_sort | Rosa Catalano |
| collection | DOAJ |
| description | Abstract Background The insulin-like growth factor 2 (IGF2) is overexpressed in 90% of adrenocortical carcinomas (ACC) and promotes cell proliferation via IGF1R and isoform A of insulin receptor (IRA). However, IGF2 role in ACC tumourigenesis has not been completely understood yet, and the contribution of IGF1R and IRA in mediating ACC cell growth has been poorly explored. This study aimed to investigate IGF1R and IR expression and localisation, including the expression of IR isoforms, in ACC and adrenocortical adenomas (ACA), and their role in IGF2-driven proliferation. Methods Immunohistochemistry staining of IGF1R and IR was performed on 118 ACC and 22 ACA to evaluate their expression and cellular localisation and statistical analyses were carried out to assess correlations with clinicopathological data. The expression of IRA and IRB in ACC and ACA tissues, ACC cell lines and ACC and ACA primary cultures was determined by RT-qPCR. To appraise the specific role of IGF1R and IR in mediating IGF2 mitogenic pathway, single and double silencing of receptors and their inhibition in 2 ACC cell lines derived from primary tumours (H295R and JIL-2266) and 2 derived from metastatic tumours (MUC-1 and TVBF-7) as well as in ACC and ACA primary cultures were performed. Results We found a higher IGF1R plasma membrane localisation in ACC compared to ACA. In ACC this localisation was associated with higher Ki67 and Weiss score. IR was expressed in about half of ACC and in all ACA but, in ACC, it was associated with higher Ki67 and Weiss score. RT-qPCR revealed that the prevalent isoform of IR was IRA in ACC and ACA, but not in normal adrenals. In ACC cell lines, double IGF1R + IR silencing reduced cell proliferation in JIL-2266, MUC-1 and TVBF-7 but not in H295R. In ACC, but not ACA, primary cultures, cell proliferation was reduced after IR but not IGF1R knockdown. Conclusions Overall, these data suggest that IGF1R localisation and IR expression represent new biomarkers predicting tumour aggressiveness, as well as possible molecular markers useful to patients’ stratification for more individualized IGF1R-IR targeted therapies or for novel pharmacological approaches specifically targeting IRA isoform. |
| format | Article |
| id | doaj-art-6fcd942ce65e46ffbe8e7141748f29e6 |
| institution | DOAJ |
| issn | 1478-811X |
| language | English |
| publishDate | 2025-03-01 |
| publisher | BMC |
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| series | Cell Communication and Signaling |
| spelling | doaj-art-6fcd942ce65e46ffbe8e7141748f29e62025-08-20T03:05:49ZengBMCCell Communication and Signaling1478-811X2025-03-0123111610.1186/s12964-025-02115-0Emerging role of IGF1R and IR expression and localisation in adrenocortical carcinomasRosa Catalano0Emma Nozza1Barbara Altieri2Emanuela Esposito3Giorgio A. Croci4Anna Maria Barbieri5Donatella Treppiedi6Sonia Di Bari7Otilia Kimpel8Mario Detomas9Mariangela Tamburello10Marc P. Schauer11Sabine Herterich12Anna Angelousi13Michaela Luconi14Letizia Canu15Gabriella Nesi16Constanze Hantel17Sandra Sigala18Laura-Sophie Landwehr19Guido Di Dalmazi20Elisa Cassinotti21Ludovica Baldari22Serena Palmieri23Alessandra Mangone24Emanuele Ferrante25Cristina L. Ronchi26Giovanna Mantovani27Erika Peverelli28Department of Clinical Sciences and Community Health, University of MilanDepartment of Clinical Sciences and Community Health, University of MilanDivision of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital, University of WürzburgDepartment of Clinical Sciences and Community Health, University of MilanPathology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore PoliclinicoDepartment of Clinical Sciences and Community Health, University of MilanEndocrinology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore PoliclinicoDepartment of Clinical Sciences and Community Health, University of MilanDivision of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital, University of WürzburgDivision of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital, University of WürzburgDivision of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital, University of WürzburgDivision of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital, University of WürzburgCentral Laboratory, University Hospital of WürzburgFirst Department of Internal Medicine, Laikon General Hospital, Medical School, National and Kapodistrian University of AthensEndocrinology Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of FlorenceEndocrinology Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of FlorenceEndocrinology Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of FlorenceDepartment of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ) and University of Zurich (UZH)Section of Pharmacology, Department of Molecular and Translational Medicine, University of BresciaDivision of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital, University of WürzburgDivision of Endocrinology and Diabetes Prevention and Care, IRCCS Azienda Ospedaliero-Universitaria di BolognaDepartment of Surgery, Fondazione IRCCS Ca’ Granda Ospedale Maggiore PoliclinicoDepartment of Surgery, Fondazione IRCCS Ca’ Granda Ospedale Maggiore PoliclinicoEndocrinology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore PoliclinicoEndocrinology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore PoliclinicoEndocrinology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore PoliclinicoDivision of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital, University of WürzburgDepartment of Clinical Sciences and Community Health, University of MilanDepartment of Clinical Sciences and Community Health, University of MilanAbstract Background The insulin-like growth factor 2 (IGF2) is overexpressed in 90% of adrenocortical carcinomas (ACC) and promotes cell proliferation via IGF1R and isoform A of insulin receptor (IRA). However, IGF2 role in ACC tumourigenesis has not been completely understood yet, and the contribution of IGF1R and IRA in mediating ACC cell growth has been poorly explored. This study aimed to investigate IGF1R and IR expression and localisation, including the expression of IR isoforms, in ACC and adrenocortical adenomas (ACA), and their role in IGF2-driven proliferation. Methods Immunohistochemistry staining of IGF1R and IR was performed on 118 ACC and 22 ACA to evaluate their expression and cellular localisation and statistical analyses were carried out to assess correlations with clinicopathological data. The expression of IRA and IRB in ACC and ACA tissues, ACC cell lines and ACC and ACA primary cultures was determined by RT-qPCR. To appraise the specific role of IGF1R and IR in mediating IGF2 mitogenic pathway, single and double silencing of receptors and their inhibition in 2 ACC cell lines derived from primary tumours (H295R and JIL-2266) and 2 derived from metastatic tumours (MUC-1 and TVBF-7) as well as in ACC and ACA primary cultures were performed. Results We found a higher IGF1R plasma membrane localisation in ACC compared to ACA. In ACC this localisation was associated with higher Ki67 and Weiss score. IR was expressed in about half of ACC and in all ACA but, in ACC, it was associated with higher Ki67 and Weiss score. RT-qPCR revealed that the prevalent isoform of IR was IRA in ACC and ACA, but not in normal adrenals. In ACC cell lines, double IGF1R + IR silencing reduced cell proliferation in JIL-2266, MUC-1 and TVBF-7 but not in H295R. In ACC, but not ACA, primary cultures, cell proliferation was reduced after IR but not IGF1R knockdown. Conclusions Overall, these data suggest that IGF1R localisation and IR expression represent new biomarkers predicting tumour aggressiveness, as well as possible molecular markers useful to patients’ stratification for more individualized IGF1R-IR targeted therapies or for novel pharmacological approaches specifically targeting IRA isoform.https://doi.org/10.1186/s12964-025-02115-0Adrenocortical carcinomaIGF1RInsulin receptorBiomarkerCellular localisation |
| spellingShingle | Rosa Catalano Emma Nozza Barbara Altieri Emanuela Esposito Giorgio A. Croci Anna Maria Barbieri Donatella Treppiedi Sonia Di Bari Otilia Kimpel Mario Detomas Mariangela Tamburello Marc P. Schauer Sabine Herterich Anna Angelousi Michaela Luconi Letizia Canu Gabriella Nesi Constanze Hantel Sandra Sigala Laura-Sophie Landwehr Guido Di Dalmazi Elisa Cassinotti Ludovica Baldari Serena Palmieri Alessandra Mangone Emanuele Ferrante Cristina L. Ronchi Giovanna Mantovani Erika Peverelli Emerging role of IGF1R and IR expression and localisation in adrenocortical carcinomas Cell Communication and Signaling Adrenocortical carcinoma IGF1R Insulin receptor Biomarker Cellular localisation |
| title | Emerging role of IGF1R and IR expression and localisation in adrenocortical carcinomas |
| title_full | Emerging role of IGF1R and IR expression and localisation in adrenocortical carcinomas |
| title_fullStr | Emerging role of IGF1R and IR expression and localisation in adrenocortical carcinomas |
| title_full_unstemmed | Emerging role of IGF1R and IR expression and localisation in adrenocortical carcinomas |
| title_short | Emerging role of IGF1R and IR expression and localisation in adrenocortical carcinomas |
| title_sort | emerging role of igf1r and ir expression and localisation in adrenocortical carcinomas |
| topic | Adrenocortical carcinoma IGF1R Insulin receptor Biomarker Cellular localisation |
| url | https://doi.org/10.1186/s12964-025-02115-0 |
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