{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T18:00:54Z","timestamp":1764784854009,"version":"build-2065373602"},"reference-count":68,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2022,4,29]],"date-time":"2022-04-29T00:00:00Z","timestamp":1651190400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Regional Development Fund (ERDF)","award":["23240\/IN0561","POCI-01-0145-FEDER-016390","CENTRO-01-0145-FEDER-000012","ENMed\/0005\/2015","UIDB\/04539\/2020","UIDP\/04539\/2020","LA\/P\/0058\/2020"],"award-info":[{"award-number":["23240\/IN0561","POCI-01-0145-FEDER-016390","CENTRO-01-0145-FEDER-000012","ENMed\/0005\/2015","UIDB\/04539\/2020","UIDP\/04539\/2020","LA\/P\/0058\/2020"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Notwithstanding the advances in the treatment of lung cancer with immune checkpoint inhibitors, the high percentage of non-responders supports the development of novel anticancer treatments. Herein, the expression of the onco-target nucleolin in patient-derived pulmonary carcinomas was characterized, along with the assessment of its potential as a therapeutic target. The clinical prognostic value of nucleolin for human pulmonary carcinomas was evaluated through data mining from the Cancer Genome Atlas project and immunohistochemical detection in human samples. Cell surface expression of nucleolin was evaluated by flow cytometry and subcellular fraction Western blotting in lung cancer cell lines. Nucleolin mRNA overexpression correlated with poor overall survival of lung adenocarcinoma cancer patients and further predicted the disease progression of both lung adenocarcinoma and squamous carcinoma. Furthermore, a third of the cases presented extra-nuclear expression, contrasting with the nucleolar pattern in non-malignant tissues. A two- to twelve-fold improvement in cytotoxicity, subsequent to internalization into the lung cancer cell lines of doxorubicin-loaded liposomes functionalized by the nucleolin-binding F3 peptide, was correlated with the nucleolin cell surface levels and the corresponding extent of cell binding. Overall, the results suggested nucleolin overexpression as a poor prognosis predictor and thus a target for therapeutic intervention in lung cancer.<\/jats:p>","DOI":"10.3390\/cancers14092217","type":"journal-article","created":{"date-parts":[[2022,4,28]],"date-time":"2022-04-28T23:52:30Z","timestamp":1651189950000},"page":"2217","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Nucleolin Overexpression Predicts Patient Prognosis While Providing a Framework for Targeted Therapeutic Intervention in Lung Cancer"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2196-4293","authenticated-orcid":false,"given":"\u00c2ngela","family":"Val\u00e9rio-Fernandes","sequence":"first","affiliation":[{"name":"CNC\u2014Center for Neurosciences and Cell Biology, Center for Innovative Biomedicine and Biotechnology (CIBB), Faculty of Medicine (Polo I), University of Coimbra, Rua Larga, 3004-504 Coimbra, Portugal"},{"name":"IIIUC, Institute for Interdisciplinary Research, University of Coimbra, 3030-789 Coimbra, Portugal"}]},{"given":"Nuno A.","family":"Fonseca","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neurosciences and Cell Biology, Center for Innovative Biomedicine and Biotechnology (CIBB), Faculty of Medicine (Polo I), University of Coimbra, Rua Larga, 3004-504 Coimbra, Portugal"},{"name":"TREAT U, SA-Parque Industrial de Taveiro, Lote 44, 3045-508 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0295-7143","authenticated-orcid":false,"given":"N\u00e9lio","family":"Gon\u00e7alves","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neurosciences and Cell Biology, Center for Innovative Biomedicine and Biotechnology (CIBB), Faculty of Medicine (Polo I), University of Coimbra, Rua Larga, 3004-504 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3404-5755","authenticated-orcid":false,"given":"Ana F.","family":"Cruz","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neurosciences and Cell Biology, Center for Innovative Biomedicine and Biotechnology (CIBB), Faculty of Medicine (Polo I), University of Coimbra, Rua Larga, 3004-504 Coimbra, Portugal"},{"name":"Univ Coimbra-University of Coimbra, CIBB, Faculty of Pharmacy, P\u00f3lo das Ci\u00eancias da Sa\u00fade, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal"}]},{"given":"Marta I.","family":"Pereira","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neurosciences and Cell Biology, Center for Innovative Biomedicine and Biotechnology (CIBB), Faculty of Medicine (Polo I), University of Coimbra, Rua Larga, 3004-504 Coimbra, Portugal"},{"name":"CHUC\u2014Coimbra Hospital and University Center, Praceta Prof. Mota Pinto, 3000-075 Coimbra, Portugal"}]},{"given":"Ana C.","family":"Greg\u00f3rio","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neurosciences and Cell Biology, Center for Innovative Biomedicine and Biotechnology (CIBB), Faculty of Medicine (Polo I), University of Coimbra, Rua Larga, 3004-504 Coimbra, Portugal"},{"name":"TREAT U, SA-Parque Industrial de Taveiro, Lote 44, 3045-508 Coimbra, Portugal"}]},{"given":"Vera","family":"Moura","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neurosciences and Cell Biology, Center for Innovative Biomedicine and Biotechnology (CIBB), Faculty of Medicine (Polo I), University of Coimbra, Rua Larga, 3004-504 Coimbra, Portugal"},{"name":"TREAT U, SA-Parque Industrial de Taveiro, Lote 44, 3045-508 Coimbra, Portugal"}]},{"given":"Ana F.","family":"Ladeirinha","sequence":"additional","affiliation":[{"name":"IAP-PM, Institute of Anatomical and Molecular Pathology, Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"given":"Ana","family":"Alarc\u00e3o","sequence":"additional","affiliation":[{"name":"IAP-PM, Institute of Anatomical and Molecular Pathology, Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5854-8664","authenticated-orcid":false,"given":"Joana","family":"Gon\u00e7alves","sequence":"additional","affiliation":[{"name":"CIBIT\/ICNAS, Institute for Nuclear Sciences Applied to Health, University of Coimbra, 3000-548 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4145-854X","authenticated-orcid":false,"given":"Antero","family":"Abrunhosa","sequence":"additional","affiliation":[{"name":"CIBIT\/ICNAS, Institute for Nuclear Sciences Applied to Health, University of Coimbra, 3000-548 Coimbra, Portugal"}]},{"given":"Joana B.","family":"Melo","sequence":"additional","affiliation":[{"name":"CACC\u2014Clinical Academic Center of Coimbra, Faculty of Medicine, P\u00f3lo das Ci\u00eancias da Sa\u00fade, Azinhaga de Santa Comba, University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"iCBR\u2014Coimbra Institute for Clinical and Biomedical Research, CIBB, Center of Investigation on Environment Genetics and Oncobiology (CIMAGO), P\u00f3lo das Ci\u00eancias da Sa\u00fade, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal"}]},{"given":"Lina","family":"Carvalho","sequence":"additional","affiliation":[{"name":"IAP-PM, Institute of Anatomical and Molecular Pathology, Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"given":"S\u00e9rgio","family":"Sim\u00f5es","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neurosciences and Cell Biology, Center for Innovative Biomedicine and Biotechnology (CIBB), Faculty of Medicine (Polo I), University of Coimbra, Rua Larga, 3004-504 Coimbra, Portugal"},{"name":"Univ Coimbra-University of Coimbra, CIBB, Faculty of Pharmacy, P\u00f3lo das Ci\u00eancias da Sa\u00fade, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3449-0522","authenticated-orcid":false,"given":"Jo\u00e3o N.","family":"Moreira","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neurosciences and Cell Biology, Center for Innovative Biomedicine and Biotechnology (CIBB), Faculty of Medicine (Polo I), University of Coimbra, Rua Larga, 3004-504 Coimbra, Portugal"},{"name":"Univ Coimbra-University of Coimbra, CIBB, Faculty of Pharmacy, P\u00f3lo das Ci\u00eancias da Sa\u00fade, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"394","DOI":"10.3322\/caac.21492","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1056\/NEJMoa011954","article-title":"Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer","volume":"346","author":"Schiller","year":"2002","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1097\/JTO.0000000000000630","article-title":"The 2015 World Health Organization Classification of Lung Tumors: Impact of Genetic, Clinical and Radiologic Advances Since the 2004 Classification","volume":"10","author":"Travis","year":"2015","journal-title":"J. Thorac. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"iv192","DOI":"10.1093\/annonc\/mdy275","article-title":"Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up","volume":"29","author":"Planchard","year":"2018","journal-title":"Ann. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1600","DOI":"10.1001\/jama.2016.4059","article-title":"Association of Pembrolizumab With Tumor Response and Survival Among Patients With Advanced Melanoma","volume":"315","author":"Ribas","year":"2016","journal-title":"JAMA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1158\/2159-8290.CD-13-0199","article-title":"Antiangiogenic therapies: Going beyond their limits","volume":"4","author":"Moserle","year":"2014","journal-title":"Cancer Discov."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1172\/JCI42405","article-title":"Upregulated stromal EGFR and vascular remodeling in mouse xenograft models of angiogenesis inhibitor-resistant human lung adenocarcinoma","volume":"121","author":"Cascone","year":"2011","journal-title":"J. Clin. Investig."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1038\/ncponc0403","article-title":"Lessons from phase III clinical trials on anti-VEGF therapy for cancer","volume":"3","author":"Jain","year":"2006","journal-title":"Nat. Clin. Pract. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"799","DOI":"10.4161\/rna.19718","article-title":"RNA-binding protein nucleolin in disease","volume":"9","author":"Abdelmohsen","year":"2012","journal-title":"RNA Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"43370","DOI":"10.1074\/jbc.M111.225185","article-title":"Nucleolin maintains embryonic stem cell self-renewal by suppression of p53 protein-dependent pathway","volume":"286","author":"Yang","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2220","DOI":"10.18632\/oncotarget.23346","article-title":"Cell surface expression of nucleolin mediates the antiangiogenic and antitumor activities of kallistatin","volume":"9","author":"Huang","year":"2018","journal-title":"Oncotarget"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.2174\/1567201815666180724104451","article-title":"Cell Surface Nucleolin as a Promising Receptor for Effective AS1411 Aptamer-Mediated Targeted Drug Delivery into Cancer Cells","volume":"15","author":"Mosafer","year":"2018","journal-title":"Curr. Drug Deliv."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1016\/j.ejpb.2013.04.007","article-title":"Impact of anti-PLK1 siRNA-containing F3-targeted liposomes on the viability of both cancer and endothelial cells","volume":"85","author":"Ramalho","year":"2013","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1083\/jcb.200304132","article-title":"Nucleolin expressed at the cell surface is a marker of endothelial cells in angiogenic blood vessels","volume":"163","author":"Christian","year":"2003","journal-title":"J. Cell Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.jconrel.2014.09.024","article-title":"Simultaneous active intracellular delivery of doxorubicin and C6-ceramide shifts the additive\/antagonistic drug interaction of non-encapsulated combination","volume":"196","author":"Fonseca","year":"2014","journal-title":"J. Control. Release"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.biomaterials.2015.08.007","article-title":"Nucleolin overexpression in breast cancer cell sub-populations with different stem-like phenotype enables targeted intracellular delivery of synergistic drug combination","volume":"69","author":"Fonseca","year":"2015","journal-title":"Biomaterials"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.ijpharm.2012.05.018","article-title":"Towards a siRNA-containing nanoparticle targeted to breast cancer cells and the tumor microenvironment","volume":"434","author":"Santos","year":"2012","journal-title":"Int. J. Pharm."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1007\/s10549-011-1688-7","article-title":"Targeted and intracellular triggered delivery of therapeutics to cancer cells and the tumor microenvironment: Impact on the treatment of breast cancer","volume":"133","author":"Moura","year":"2012","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"101095","DOI":"10.1016\/j.nantod.2021.101095","article-title":"GMP-grade nanoparticle targeted to nucleolin downregulates tumor molecular signature, blocking growth and invasion, at low systemic exposure","volume":"37","author":"Fonseca","year":"2021","journal-title":"Nano Today"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"7444","DOI":"10.1073\/pnas.062189599","article-title":"A fragment of the HMGN2 protein homes to the nuclei of tumor cells and tumor endothelial cells in vivo","volume":"99","author":"Porkka","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/S0167-9473(02)00225-6","article-title":"On the exact distribution of maximally selected rank statistics","volume":"43","author":"Hothorn","year":"2003","journal-title":"Comput. Stat. Data Anal."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.1101\/gr.092759.109","article-title":"Circos: An information aesthetic for comparative genomics","volume":"19","author":"Krzywinski","year":"2009","journal-title":"Genome Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/0005-2736(93)90105-9","article-title":"Transmembrane ammonium sulfate gradients in liposomes produce efficient and stable entrapment of amphipathic weak bases","volume":"1151","author":"Haran","year":"1993","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1023\/A:1014434732752","article-title":"Use of the post-insertion technique to insert peptide ligands into pre-formed stealth liposomes with retention of binding activity and cytotoxicity","volume":"19","author":"Moreira","year":"2002","journal-title":"Pharm. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1016\/0883-2897(92)90149-S","article-title":"A simple method for producing a technetium-99m-labeled liposome which is stable in vivo","volume":"19","author":"Phillips","year":"1992","journal-title":"Int. J. Radiat. Appl. Instrumentation. Part B Nucl. Med. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1016\/0306-4522(95)00066-R","article-title":"Dose-dependent lesions of the dopaminergic nigrostriatal pathway induced by instrastriatal injection of 6-hydroxydopamine","volume":"67","author":"Przedbroski","year":"1995","journal-title":"Neuroscience"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3709","DOI":"10.1038\/onc.2011.529","article-title":"Tumor suppressor Alpha B-crystallin (CRYAB) associates with the cadherin\/catenin adherens junction and impairs NPC progression-associa.ated properties","volume":"31","author":"Huang","year":"2012","journal-title":"Oncogene"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Hovanessian, A.G., Soundaramourty, C., Khoury, D.E., Nondier, I., Svab, J., and Krust, B. (2010). Surface expressed nucleolin is constantly induced in tumor cells to mediate calcium-dependent ligand internalization. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0015787"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1016\/j.cell.2018.02.052","article-title":"An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics","volume":"173","author":"Liu","year":"2018","journal-title":"Cell"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1186\/s13000-014-0175-y","article-title":"Increased level of nucleolin confers to aggressive tumor progression and poor prognosis in patients with hepatocellular carcinoma after hepatectomy","volume":"9","author":"Guo","year":"2014","journal-title":"Diagn Pathol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3734","DOI":"10.1158\/1078-0432.CCR-09-3411","article-title":"High levels of nucleolar expression of nucleolin are associated with better prognosis in patients with stage II pancreatic ductal adenocarcinoma","volume":"16","author":"Peng","year":"2010","journal-title":"Clin. Cancer Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1111\/apm.12131","article-title":"Overexpression of nucleolin and different expression sites both related to the prognosis of gastric cancer","volume":"121","author":"Qiu","year":"2013","journal-title":"APMIS Acta Pathol. Microbiol. Immunol. Scand."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1164\/rccm.200607-984PP","article-title":"Lung cancer and lung stem cells: Strange bedfellows?","volume":"175","author":"Giangreco","year":"2007","journal-title":"Am. J. Respir Crit Care Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1007\/s40610-017-0073-7","article-title":"Tumor microenvironment heterogeneity: Challenges and opportunities","volume":"3","author":"Runa","year":"2017","journal-title":"Curr Mol. Biol Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"7450","DOI":"10.1038\/s41598-018-25816-8","article-title":"Anticancer activity and antibody-dependent cell-mediated cytotoxicity of novel anti-nucleolin antibodies","volume":"8","author":"Romano","year":"2018","journal-title":"Sci Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1016\/j.addr.2003.10.038","article-title":"On the formulation of pH-sensitive liposomes with long circulation times","volume":"56","author":"Simoes","year":"2004","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1002\/1097-0142(197308)32:2<302::AID-CNCR2820320205>3.0.CO;2-2","article-title":"A clinicopathologic analysis of adriamycin cardiotoxicity","volume":"32","author":"Lefrak","year":"1973","journal-title":"Cancer"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Zhao, H., Huang, Y., Xue, C., Chen, Y., Hou, X., Guo, Y., Zhao, L., Hu, Z., Huang, Y., and Luo, Y. (2013). Prognostic significance of the combined score of endothelial expression of nucleolin and CD31 in surgically resected non-small cell lung cancer. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0054674"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: The next generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Chen, Y., Huang, Y., Huang, Y., Chen, J., Wang, S., and Zhou, J. (2013). The prognostic value of SOX2 expression in non-small cell lung cancer: A meta-analysis. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0071140"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1007\/s10238-016-0421-6","article-title":"Clinicopathological and prognostic significance of Nestin expression in patients with non-small cell lung cancer: A systematic review and meta-analysis","volume":"17","author":"Li","year":"2017","journal-title":"Clin. Exp. Med."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Ye, Z., Zhang, X., Luo, Y., Li, S., Huang, L., Li, Z., Li, P., and Chen, G. (2016). Prognostic Values of Vimentin Expression and Its Clinicopathological Significance in Non-Small Cell Lung Cancer: A Meta-Analysis of Observational Studies with 4118 Cases. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0163162"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"10349","DOI":"10.1007\/s13277-016-4920-6","article-title":"Prognostic significance of nuclear or cytoplasmic nucleolin expression in human non-small cell lung cancer and its relationship with DNA-PKcs","volume":"37","author":"Xu","year":"2016","journal-title":"Tumour Biol. J. Int. Soc. Oncodevelopmental Biol. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1007\/s10555-015-9558-0","article-title":"Global analysis of chromosome 1 genes among patients with lung adenocarcinoma, squamous carcinoma, large-cell carcinoma, small-cell carcinoma, or non-cancer","volume":"34","author":"Zhang","year":"2015","journal-title":"Cancer Metastasis Rev."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1083\/jcb.200506057","article-title":"Myc regulates keratinocyte adhesion and differentiation via complex formation with Miz1","volume":"172","author":"Gebhardt","year":"2006","journal-title":"J. Cell Biol."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Nguyen Van Long, F., Lardy-Cleaud, A., Bray, S., Chabaud, S., Dubois, T., Diot, A., Thompson, A.M., Bourdon, J.C., Perol, D., and Bouvet, P. (2018). Druggable Nucleolin Identifies Breast Tumours Associated with Poor Prognosis That Exhibit Different Biological Processes. Cancers, 10.","DOI":"10.3390\/cancers10100390"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3337","DOI":"10.1080\/15384101.2016.1237170","article-title":"Nucleus or cytoplasm? The mysterious case of SIRT1\u2019s subcellular localization","volume":"15","author":"Bai","year":"2016","journal-title":"Cell Cycle"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Hida, K., Maishi, N., Annan, D.A., and Hida, Y. (2018). Contribution of Tumor Endothelial Cells in Cancer Progression. Int. J. Mol. Sci, 19.","DOI":"10.3390\/ijms19051272"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.semcancer.2014.02.006","article-title":"Prognostic relevance of cancer-associated fibroblasts in human cancer","volume":"25","author":"Paulsson","year":"2014","journal-title":"Semin. Cancer Biol."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Kilvaer, T.K., Khanehkenari, M.R., Hellevik, T., Al-Saad, S., Paulsen, E.E., Bremnes, R.M., Busund, L.T., Donnem, T., and Martinez, I.Z. (2015). Cancer Associated Fibroblasts in Stage I-IIIA NSCLC: Prognostic Impact and Their Correlations with Tumor Molecular Markers. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0134965"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"7160","DOI":"10.1073\/pnas.1014506108","article-title":"Prognostic gene-expression signature of carcinoma-associated fibroblasts in non-small cell lung cancer","volume":"108","author":"Navab","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1016\/j.cell.2018.01.009","article-title":"CD10(+)GPR77(+) Cancer-Associated Fibroblasts Promote Cancer Formation and Chemoresistance by Sustaining Cancer Stemness","volume":"172","author":"Su","year":"2018","journal-title":"Cell"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"7227","DOI":"10.18632\/oncotarget.6979","article-title":"Prognostic value of tumor-infiltrating lymphocytes for patients with completely resected stage IIIA(N2) non-small cell lung cancer","volume":"7","author":"Feng","year":"2016","journal-title":"Oncotarget"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jss.2011.03.068","article-title":"Increased levels of tumor-infiltrating lymphocytes are associated with improved recurrence-free survival in stage 1A non-small-cell lung cancer","volume":"171","author":"Horne","year":"2011","journal-title":"J. Surg Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2959","DOI":"10.1200\/JCO.2013.55.0491","article-title":"Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199","volume":"32","author":"Adams","year":"2014","journal-title":"J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1001\/archsurg.2012.35","article-title":"Prognostic significance of tumor-infiltrating lymphocytes for patients with colorectal cancer","volume":"147","author":"Huh","year":"2012","journal-title":"Arch. Surg"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1111\/j.1477-2574.2010.00231.x","article-title":"T cell infiltrate and outcome following resection of intermediate-grade primary neuroendocrine tumours and liver metastases","volume":"12","author":"Katz","year":"2010","journal-title":"HPB"},{"key":"ref_58","first-page":"2045","article-title":"Prognostic value of ALDH1 expression in lung cancer: A meta-analysis","volume":"8","author":"Huo","year":"2015","journal-title":"Int. J. Clin. Exp. Med."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"111","DOI":"10.3892\/mco.2013.195","article-title":"Clinicopathological significance of CD133 in lung cancer: A meta-analysis","volume":"2","author":"Tan","year":"2014","journal-title":"Mol. Clin. Oncol"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"5416923","DOI":"10.1155\/2018\/5416923","article-title":"Cancer Stem Cells (CSCs) in Drug Resistance and their Therapeutic Implications in Cancer Treatment","volume":"2018","author":"Phi","year":"2018","journal-title":"Stem Cells Int"},{"key":"ref_61","first-page":"145","article-title":"Cancer stem cells and chemoresistance: The smartest survives the raid","volume":"160","author":"Zhao","year":"2016","journal-title":"Pharmthera"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.2217\/nnm.12.174","article-title":"Efficient intracellular delivery of siRNA with a safe multitargeted lipid-based nanoplatform","volume":"8","author":"Fernandez","year":"2013","journal-title":"Nanomedicine"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2905","DOI":"10.1016\/j.biomaterials.2013.12.054","article-title":"Synergistic inhibition of lung cancer cell invasion, tumor growth and angiogenesis using aptamer-siRNA chimeras","volume":"35","author":"Lai","year":"2014","journal-title":"Biomaterials"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1360","DOI":"10.7150\/thno.16532","article-title":"Nucleolin-targeted Extracellular Vesicles as a Versatile Platform for Biologics Delivery to Breast Cancer","volume":"7","author":"Wang","year":"2017","journal-title":"Theranostics"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Trinh, T.L., Zhu, G., Xiao, X., Puszyk, W., Sefah, K., Wu, Q., Tan, W., and Liu, C. (2015). A Synthetic Aptamer-Drug Adduct for Targeted Liver Cancer Therapy. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0136673"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"3613","DOI":"10.1021\/jacs.8b12872","article-title":"Nucleolin Is a Functional Binding Protein for Salinomycin in Neuroblastoma Stem Cells","volume":"141","author":"Wang","year":"2019","journal-title":"J. Am. Chem Soc."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1248\/bpb.33.796","article-title":"Nucleolin on the cell surface as a new molecular target for gastric cancer treatment","volume":"33","author":"Watanabe","year":"2010","journal-title":"Biol. Pharm. Bull."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1921","DOI":"10.1016\/j.febslet.2014.03.047","article-title":"Phosphorylation and changes in the distribution of nucleolin promote tumor metastasis via the PI3K\/Akt pathway in colorectal carcinoma","volume":"588","author":"Wu","year":"2014","journal-title":"FEBS Lett."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/9\/2217\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:03:45Z","timestamp":1760137425000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/9\/2217"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,29]]},"references-count":68,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["cancers14092217"],"URL":"https:\/\/doi.org\/10.3390\/cancers14092217","relation":{},"ISSN":["2072-6694"],"issn-type":[{"type":"electronic","value":"2072-6694"}],"subject":[],"published":{"date-parts":[[2022,4,29]]}}}