{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T04:37:23Z","timestamp":1784954243186,"version":"3.55.0"},"reference-count":41,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,2,12]],"date-time":"2021-02-12T00:00:00Z","timestamp":1613088000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Research Fund ex-60%\u201d, University of Turin","award":["BOSO_RILO_17_01"],"award-info":[{"award-number":["BOSO_RILO_17_01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Primary thrombopoietic mediator thrombopoietin (THPO) is mainly produced by the liver; it may act as a growth factor for hepatic progenitors. Principal angiogenesis inducer vascular endothelial growth factor-A (VEGF-A) is critical for the complex vascular network within the liver architecture. As a cross-regulatory loop between THPO and VEGF-A has been demonstrated in the hematopoietic system, the two growth factors were hypothesized to cooperatively contribute to the progression from liver cirrhosis (LC) to hepatocellular carcinoma (HCC). The mRNA and protein expression levels of THPO, VEGF-A, and their receptors were examined, compared, and correlated in paired cancerous and LC tissues from 26 cirrhosis-related HCC patients, using qRT-PCR and immunohistochemistry. THPO and VEGF-A were alternatively silenced by small interfering RNA (siRNA) in human liver cancer cell lines Huh7 and HepG2. THPO and VEGF-A expressions significantly increased in tumor versus LC tissues. HCC and paired LC cells expressed similar levels of THPO receptor (R), whereas vascular endothelial growth factor receptor (VEGFR) -1 and VEGFR-2 levels were higher in HCC than in corresponding LC tissue samples. A significant linear correlation emerged between THPO and VEGF-A transcripts in HCC and, at the protein level, THPO and THPOR were significantly correlated with VEGF-A in tumor tissues. Both HCC and LC expressed similar levels of gene and protein hypoxia inducible factor (HIF)-1\u03b1. Positive cross-regulation occurred with the alternative administration of siRNAs targeting THPO and those targeting VEGF-A in hypoxic liver cancer cell lines. These results suggest THPO and VEGF-A might act as interdependently regulated autocrine and\/or paracrine systems for cellular growth in HCC. This might be clinically interesting, since new classes of THPOR agonistic\/antagonistic drugs may provide novel therapeutic options to correct the frequent hemostatic abnormality seen in HCC patients.<\/jats:p>","DOI":"10.3390\/ijms22041818","type":"journal-article","created":{"date-parts":[[2021,2,12]],"date-time":"2021-02-12T18:45:00Z","timestamp":1613155500000},"page":"1818","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Cooperative Role of Thrombopoietin and Vascular Endothelial Growth Factor-A in the Progression of Liver Cirrhosis to Hepatocellular Carcinoma"],"prefix":"10.3390","volume":"22","author":[{"given":"Barbara","family":"Vizio","sequence":"first","affiliation":[{"name":"Department of Medical Sciences, University of Turin, Via Genova 3, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ornella","family":"Bosco","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, University of Turin, Via Genova 3, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ezio","family":"David","sequence":"additional","affiliation":[{"name":"Pathology Unit, AOU Citt\u00e0 della Salute e della Scienza di Torino, University of Turin, Via Santena 7, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0529-9481","authenticated-orcid":false,"given":"Gian Paolo","family":"Caviglia","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, University of Turin, Via Cavour 31, 10123 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7611-6099","authenticated-orcid":false,"given":"Maria Lorena","family":"Abate","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, University of Turin, Via Cavour 31, 10123 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2738-9119","authenticated-orcid":false,"given":"Martina","family":"Schiavello","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, University of Turin, Via Genova 3, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Pucci","sequence":"additional","affiliation":[{"name":"Department of Histopathology, Pisa University Hospital, Via Roma 57, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonina","family":"Smedile","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, University of Turin, Via Cavour 31, 10123 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianluca","family":"Paraluppi","sequence":"additional","affiliation":[{"name":"General Surgery 2U and Liver Transplantation Center, AOU Citt\u00e0 della Salute e della Scienza di Torino, University of Turin, Corso Bramante 88, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8340-8885","authenticated-orcid":false,"given":"Renato","family":"Romagnoli","sequence":"additional","affiliation":[{"name":"General Surgery 2U and Liver Transplantation Center, AOU Citt\u00e0 della Salute e della Scienza di Torino, University of Turin, Corso Bramante 88, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2719-1217","authenticated-orcid":false,"given":"Enrico","family":"Lupia","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, University of Turin, Via Genova 3, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graziella","family":"Bellone","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, University of Turin, Via Genova 3, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Montrucchio","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, University of Turin, Via Genova 3, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.1016\/S0140-6736(18)30010-2","article-title":"Hepatocellular carcinoma","volume":"391","author":"Forner","year":"2018","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"243","DOI":"10.21037\/jgo.2017.02.01","article-title":"Systemic therapy for advanced hepatocellular carcinoma: An update","volume":"8","author":"Desai","year":"2017","journal-title":"J. Gastrointest. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1038\/s41698-018-0048-z","article-title":"Role of nonresolving inflammation in hepatocellular carcinoma development and progression","volume":"2","author":"Yu","year":"2018","journal-title":"NPJ Precis. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2189","DOI":"10.1182\/blood.V92.6.2189","article-title":"Primary role of the liver in thrombopoietin production shown by tissue-specific knockout","volume":"92","author":"Qian","year":"1998","journal-title":"Blood"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1182\/blood.V86.2.419.bloodjournal862419","article-title":"Thrombopoietin: The primary regulator of platelet production","volume":"86","author":"Kaushansky","year":"1995","journal-title":"Blood"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2762","DOI":"10.1182\/blood.V87.7.2762.bloodjournal8772762","article-title":"Effects of recombinant human megakaryocyte growth and development factor on platelet activation","volume":"87","author":"Montrucchio","year":"1996","journal-title":"Blood"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1719","DOI":"10.1182\/blood.V85.7.1719.bloodjournal8571719","article-title":"Thrombopoietin (c-mpl ligand) acts synergistically with erythropoietin, stem cell factor, and interleukin-11 to enhance murine megakaryocyte colony growth and increases megakaryocyte ploidy in vitro","volume":"85","author":"Broudy","year":"1995","journal-title":"Blood"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4258","DOI":"10.1182\/blood-2004-07-2712","article-title":"Thrombopoietin enhances expression of vascular endothelial growth factor (VEGF) in primitive hematopoietic cells through induction of HIF-1alpha","volume":"105","author":"Kirito","year":"2005","journal-title":"Blood"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1186\/s12959-016-0095-z","article-title":"Thrombopoietin and its receptor in normal and neoplastic hematopoiesis","volume":"14","author":"Kaushansky","year":"2016","journal-title":"Thromb. J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1161\/01.RES.84.7.785","article-title":"Thrombopoietin stimulates endothelial cell motility and neoangiogenesis by a platelet-activating factor-dependent mechanism","volume":"84","author":"Brizzi","year":"1999","journal-title":"Circ. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1006\/mvre.1999.2161","article-title":"Effects of megakaryocyte growth and development factor (thrombopoietin) on liver endothelial cells in vitro","volume":"58","author":"Cardier","year":"1999","journal-title":"Microvasc. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1097\/MEG.0b013e3282f246e6","article-title":"Thrombopoietin is a growth factor for rat hepatic progenitors","volume":"20","author":"Schmelzer","year":"2008","journal-title":"Eur. J. Gastroenterol. Hepatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1952","DOI":"10.1182\/blood.V94.6.1952","article-title":"Production of thrombopoietin by human carcinomas and its novel isoforms","volume":"94","author":"Sasaki","year":"1999","journal-title":"Blood"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1016\/j.bbamcr.2015.07.008","article-title":"The role of platelets in the tumor microenvironment: From solid tumors to leukemia","volume":"1863","author":"Yan","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1038\/369571a0","article-title":"cMpl ligand is a humoral regulator of megakaryocytopoiesis","volume":"369","author":"Wendling","year":"1994","journal-title":"Nature"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"G120","DOI":"10.1152\/ajpgi.00350.2004","article-title":"Thrombopoietin stimulates migration and activates multiple signaling pathways in hepatoblastoma cells","volume":"290","author":"Romanelli","year":"2006","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1038\/nm0603-669","article-title":"The biology of VEGF and its receptors","volume":"9","author":"Ferrara","year":"2003","journal-title":"Nat. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.critrevonc.2004.11.006","article-title":"Molecular mechanisms of tumor vascularization","volume":"54","author":"Auguste","year":"2005","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1038\/nm0603-653","article-title":"Angiogenesis in health and disease","volume":"9","author":"Carmeliet","year":"2003","journal-title":"Nat. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1038\/nrc3627","article-title":"VEGF targets the tumour cell","volume":"13","author":"Goel","year":"2013","journal-title":"Nat. Rev. Cancer"},{"key":"ref_21","first-page":"3","article-title":"Hypoxia-inducible factors in hepatocellular carcinoma (Review)","volume":"43","author":"Guo","year":"2020","journal-title":"Oncol. Rep."},{"key":"ref_22","first-page":"3509","article-title":"Thrombopoietin receptor expression in human cancer cell lines and primary tissues","volume":"55","author":"Columbyova","year":"1995","journal-title":"Cancer Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/S0014-5793(98)00056-8","article-title":"Thrombopoietin stimulates VEGF release from c-Mpl-expressing cell lines and haematopoietic progenitors","volume":"423","author":"Bobik","year":"1998","journal-title":"FEBS Lett."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1177\/1947601911423031","article-title":"Vascular Endothelial Growth Factor (VEGF) and Its Receptor (VEGFR) Signaling in Angiogenesis: A Crucial Target for Anti- and Pro-Angiogenic Therapies","volume":"2","author":"Shibuya","year":"2011","journal-title":"Genes Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1182\/blood.V91.3.923","article-title":"Thrombopoietin and its receptor, c-mpl, are constitutively expressed by mouse liver endothelial cells: Evidence of thrombopoietin as a growth factor for liver endothelial cells","volume":"91","author":"Cardier","year":"1998","journal-title":"Blood"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1111\/j.1440-1746.2010.06539.x","article-title":"New concepts in liver regeneration","volume":"26","author":"Riehle","year":"2011","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.dld.2015.09.019","article-title":"Different expression of VEGF and EGFL7 in human hepatocellular carcinoma","volume":"48","author":"Campagnolo","year":"2016","journal-title":"Dig. Liver Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/S1665-2681(19)31924-6","article-title":"Angiogenesis in chronic liver disease","volume":"6","author":"Amarapurkar","year":"2007","journal-title":"Ann. Hepatol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1016\/j.cell.2009.12.046","article-title":"Autocrine VEGF signaling synergizes with EGFR in tumor cells to promote epithelial cancer development","volume":"140","author":"Lichtenberger","year":"2010","journal-title":"Cell"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1136\/jclinpath-2012-200721","article-title":"Expression and prognostic significance of vascular endothelial growth factor receptor 1 in hepatocellular carcinoma","volume":"65","author":"Li","year":"2012","journal-title":"J. Clin. Pathol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1002\/cncr.24789","article-title":"Vascular endothelial growth factor receptor-1 in human cancer: Concise review and rationale for development of IMC-18F1 (Human antibody targeting vascular endothelial growth factor receptor-1)","volume":"116","author":"Schwartz","year":"2010","journal-title":"Cancer"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.1002\/hep.27236","article-title":"Autocrine vascular endothelial growth factor signaling promotes cell proliferation and modulates sorafenib treatment efficacy in hepatocellular carcinoma","volume":"60","author":"Peng","year":"2014","journal-title":"Hepatology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1007\/s12185-008-0091-6","article-title":"Thrombopoietin (TPO) regulates HIF-1alpha levels through generation of mitochondrial reactive oxygen species","volume":"88","author":"Yoshida","year":"2008","journal-title":"Int. J. Hematol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"549412","DOI":"10.1155\/2015\/549412","article-title":"Hypoxia-Inducible Factor-1 in Physiological and Pathophysiological Angiogenesis: Applications and Therapies","volume":"2015","author":"Zimna","year":"2015","journal-title":"Biomed. Res. Int."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2301","DOI":"10.1182\/blood.V94.7.2301.419k24_2301_2309","article-title":"Neuropilin-1 is expressed on bone marrow stromal cells: A novel interaction with hematopoietic cells?","volume":"94","author":"Tordjman","year":"1999","journal-title":"Blood"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1159\/000343852","article-title":"From cirrhosis to hepatocellular carcinoma: New molecular insights on inflammation and cellular senescence","volume":"2","author":"Ramakrishna","year":"2013","journal-title":"Liver Cancer"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Mossenta, M., Busato, D., Baboci, L., Cintio, F.D., Toffoli, G., and Bo, M.D. (2019). New Insight into Therapies Targeting Angiogenesis in Hepatocellular Carcinoma. Cancers, 11.","DOI":"10.3390\/cancers11081086"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1634\/theoncologist.6-suppl_5-15","article-title":"Targeted approaches for the treatment of thrombocytopenia","volume":"6","author":"Demetri","year":"2001","journal-title":"Oncologist"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1802932","DOI":"10.1155\/2016\/1802932","article-title":"The Use of Thrombopoietin Receptor Agonists for Correction of Thrombocytopenia prior to Elective Procedures in Chronic Liver Diseases: Review of Current Evidence","volume":"2016","author":"Qureshi","year":"2016","journal-title":"Int. J. Hepatol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3398","DOI":"10.1182\/blood-2015-10-674465","article-title":"A thrombopoietin receptor antagonist is capable of depleting myelofibrosis hematopoietic stem and progenitor cells","volume":"127","author":"Wang","year":"2016","journal-title":"Blood"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/gb-2002-3-7-research0034","article-title":"Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes","volume":"3","author":"Vandesompele","year":"2002","journal-title":"Genome Biol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/4\/1818\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:23:11Z","timestamp":1760160191000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/4\/1818"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,12]]},"references-count":41,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,2]]}},"alternative-id":["ijms22041818"],"URL":"https:\/\/doi.org\/10.3390\/ijms22041818","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,12]]}}}