{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,24]],"date-time":"2025-12-24T12:15:52Z","timestamp":1766578552071,"version":"build-2065373602"},"reference-count":89,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2016,12,2]],"date-time":"2016-12-02T00:00:00Z","timestamp":1480636800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The role of microRNAs as oncogenes and tumor suppressor genes has emerged in several cancers, including hepatocellular carcinoma (HCC). The pivotal tumor suppressive role of p53-axis is indicated by the presence of inactivating mutations in TP53 gene in nearly all cancers. A close interaction between these two players, as well as the establishment of complex p53\/miRNAs loops demonstrated the strong contribution of p53-effector miRNAs in enhancing the p53-mediated tumor suppression program. On the other hand, the direct and indirect targeting of p53, as well as the regulation of its stability and activity by specific microRNAs, underlie the importance of the fine-tuning of p53 pathway, affecting the cell fate of damaged\/transformed cells. The promising results of miRNAs-based therapeutic approaches in preclinical studies and their entrance in clinical trials demonstrate the feasibility of this strategy in several diseases, including cancer. Molecularly targeted drugs approved so far for HCC treatment show intrinsic or acquired resistances with disease progression in many cases, therefore the identification of effective and non-toxic agents for the treatment of HCC is actually an unmet clinical need. The knowledge of p53\/miRNA inter-relations in HCC may provide useful elements for the identification of novel combined approaches in the context of the \u201cpersonalized-medicine\u201d era.<\/jats:p>","DOI":"10.3390\/ijms17122029","type":"journal-article","created":{"date-parts":[[2016,12,2]],"date-time":"2016-12-02T10:36:37Z","timestamp":1480674997000},"page":"2029","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["TP53\/MicroRNA Interplay in Hepatocellular Carcinoma"],"prefix":"10.3390","volume":"17","author":[{"given":"Daniela","family":"Pollutri","sequence":"first","affiliation":[{"name":"Center for Applied Biomedical Research, St. Orsola-Malpighi University Hospital, 40138 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Gramantieri","sequence":"additional","affiliation":[{"name":"Center for Applied Biomedical Research, St. Orsola-Malpighi University Hospital, 40138 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luigi","family":"Bolondi","sequence":"additional","affiliation":[{"name":"Center for Applied Biomedical Research, St. Orsola-Malpighi University Hospital, 40138 Bologna, Italy"},{"name":"Department of Medical and Surgical Sciences, Bologna University, 40138 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4302-4411","authenticated-orcid":false,"given":"Francesca","family":"Fornari","sequence":"additional","affiliation":[{"name":"Center for Applied Biomedical Research, St. Orsola-Malpighi University Hospital, 40138 Bologna, Italy"},{"name":"Department of Medical and Surgical Sciences, Bologna University, 40138 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2016,12,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"GBD 2013 Mortality and Causes of Death Collaborators (2015). Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990\u20132013: A systematic analysis for the global burden of disease study 2013. Lancet, 385, 117\u2013171.","DOI":"10.1016\/S0140-6736(14)61682-2"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1016\/S0140-6736(11)61347-0","article-title":"Hepatocellular carcinoma","volume":"379","author":"Forner","year":"2012","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1763","DOI":"10.1053\/gast.2001.24798","article-title":"Genetic alterations associated with hepatocellular carcinomas define distinct pathways of hepatocarcinogenesis","volume":"120","author":"Legoix","year":"2001","journal-title":"Gastroenterology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"16018","DOI":"10.1038\/nrdp.2016.18","article-title":"Hepatocellular carcinoma","volume":"2","author":"Llovet","year":"2016","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1038\/sj.cdd.4401910","article-title":"The p53 pathway: What questions remain to be explored?","volume":"13","author":"Levine","year":"2006","journal-title":"Cell Death Differ."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4663","DOI":"10.1093\/emboj\/cdf476","article-title":"MicroRNA maturation: Stepwise processing and subcellular localization","volume":"21","author":"Lee","year":"2002","journal-title":"EMBO J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2257","DOI":"10.1073\/pnas.0510565103","article-title":"A microRNA expression signature of human solid tumors defines cancer gene targets","volume":"103","author":"Volinia","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"7390","DOI":"10.1158\/0008-5472.CAN-06-0800","article-title":"MicroRNA-Cancer connection: The beginning of a new tale","volume":"66","author":"Calin","year":"2006","journal-title":"Cancer Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1038\/nrc3318","article-title":"MicroRNAs in the p53 network: Micromanagement of tumour suppression","volume":"12","author":"Hermeking","year":"2012","journal-title":"Nat. Rev. Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1038\/cdd.2014.136","article-title":"MicroRNAs in liver cancer: A model for investigating pathogenesis and novel therapeutic approaches","volume":"22","author":"Callegari","year":"2015","journal-title":"Cell Death Differ."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1038\/nature08199","article-title":"Modulation of microRNA processing by p53","volume":"460","author":"Suzuki","year":"2009","journal-title":"Nature"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.cell.2004.12.035","article-title":"Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets","volume":"120","author":"Lewis","year":"2005","journal-title":"Cell"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Yang, Y., Liu, W., Ding, R., Xiong, L., Dou, R., Zhang, Y., and Guo, Z. (2016). Comprehensive expression profiling and functional network analysis of p53-regulated microRNAs in HEPG2 cells treated with doxorubicin. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0149227"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1130","DOI":"10.1038\/nature05939","article-title":"A microRNA component of the p53 tumour suppressor network","volume":"447","author":"He","year":"2007","journal-title":"Nature"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1016\/j.molcel.2007.05.017","article-title":"Transcriptional activation of miR-34a contributes to p53-mediated apoptosis","volume":"26","author":"Marciano","year":"2007","journal-title":"Mol. Cell"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.gene.2013.04.042","article-title":"Promoter polymorphisms of pri-miR-34b\/c are associated with hepatocellular carcinoma","volume":"524","author":"Son","year":"2013","journal-title":"Gene"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.canlet.2008.09.035","article-title":"miR-34a inhibits migration and invasion by down-regulation of C-met expression in human hepatocellular carcinoma cells","volume":"275","author":"Li","year":"2009","journal-title":"Cancer Lett."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1002\/mc.20484","article-title":"Down-regulation of the microRNAs miR-34a, miR-127, and miR-200b in rat liver during hepatocarcinogenesis induced by a methyl-deficient diet","volume":"48","author":"Tryndyak","year":"2009","journal-title":"Mol. Carcinog."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1073\/pnas.0907904107","article-title":"miR-221 overexpression contributes to liver tumorigenesis","volume":"107","author":"Pineau","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1136\/gutjnl-2014-308969","article-title":"Antitumour activity of an inhibitor of miR-34a in liver cancer with beta-catenin-mutations","volume":"65","author":"Gougelet","year":"2016","journal-title":"Gut"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"14240","DOI":"10.1073\/pnas.1017536108","article-title":"Wild-Type p53 controls cell motility and invasion by dual regulation of met expression","volume":"108","author":"Hwang","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Dang, Y., Luo, D., Rong, M., and Chen, G. (2013). Underexpression of miR-34a in hepatocellular carcinoma and its contribution towards enhancement of proliferating inhibitory effects of agents targeting C-met. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0061054"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.ccr.2012.07.023","article-title":"TGF-\u03b2-miR-34a-CCL22 signaling-induced Treg cell recruitment promotes venous metastases of hbv-positive hepatocellular carcinoma","volume":"22","author":"Yang","year":"2012","journal-title":"Cancer Cell"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3085","DOI":"10.1038\/onc.2014.254","article-title":"MicroRNA regulons in tumor microenvironment","volume":"34","author":"Suzuki","year":"2015","journal-title":"Oncogene"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Bi, Q., Tang, S., Xia, L., Du, R., Fan, R., Gao, L., Jin, J., Liang, S., Chen, Z., and Xu, G. (2012). Ectopic expression of miR-125a inhibits the proliferation and metastasis of hepatocellular carcinoma by targeting mmp11 and VEGF. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0040169"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1101\/gad.1767609","article-title":"MicroRNA-125b is a novel negative regulator of p53","volume":"23","author":"Le","year":"2009","journal-title":"Genes Dev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1002\/hep.26101","article-title":"Sirtuin7 oncogenic potential in human hepatocellular carcinoma and its regulation by the tumor suppressors miR-125a-5p and miR-125b","volume":"57","author":"Kim","year":"2013","journal-title":"Hepatology"},{"key":"ref_28","unstructured":"Pollutri, D., Gramantieri, L., Bolondi, L., and Fornari, F. (2017). miR-30e\/p53 positive feedback loop in hepatocellular carcinoma. MCR, in preparation."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1084\/jem.20110235","article-title":"P53 regulates epithelial-mesenchymal transition through microRNAs targeting ZEB1 and ZEB2","volume":"208","author":"Kim","year":"2011","journal-title":"J. Exp. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2910","DOI":"10.1038\/onc.2014.218","article-title":"G\u03b112 GEP oncogene deregulation of p53-responsive microRNAs promotes epithelial-mesenchymal transition of hepatocellular carcinoma","volume":"34","author":"Yang","year":"2015","journal-title":"Oncogene"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5761","DOI":"10.1158\/0008-5472.CAN-08-4797","article-title":"miR-122\/cyclin G1 interaction modulates p53 activity and affects doxorubicin sensitivity of human hepatocarcinoma cells","volume":"69","author":"Fornari","year":"2009","journal-title":"Cancer Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"S5","DOI":"10.1053\/j.gastro.2004.09.011","article-title":"Primary liver cancer: Worldwide incidence and trends","volume":"127","author":"Bosch","year":"2004","journal-title":"Gastroenterology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1126\/science.1140485","article-title":"Gender disparity in liver cancer due to sex differences in MYD88-dependent IL-6 production","volume":"317","author":"Naugler","year":"2007","journal-title":"Science"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.1056\/NEJMoa0901282","article-title":"MicroRNA expression, survival, and response to interferon in liver cancer","volume":"361","author":"Ji","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1016\/j.cell.2009.04.021","article-title":"Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model","volume":"137","author":"Kota","year":"2009","journal-title":"Cell"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.1038\/mt.2011.64","article-title":"Tumor-Specific expression of microRNA-26a suppresses human hepatocellular carcinoma growth via cyclin-dependent and -independent pathways","volume":"19","author":"Chen","year":"2011","journal-title":"Mol. Ther. J. Am. Soc. Gene Ther."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1002\/ijc.29052","article-title":"Elevated p53 promotes the processing of miR-18a to decrease estrogen receptor-\u03b1 in female hepatocellular carcinoma","volume":"136","author":"Li","year":"2015","journal-title":"Int. J. Cancer"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"34941","DOI":"10.18632\/oncotarget.5472","article-title":"Estradiol induces apoptosis via activation of miRNA-23a and p53: Implication for gender difference in liver cancer development","volume":"6","author":"Huang","year":"2015","journal-title":"Oncotarget"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"6092","DOI":"10.1158\/0008-5472.CAN-06-4607","article-title":"Cyclin G1 is a target of miR-122a, a microRNA frequently down-regulated in human hepatocellular carcinoma","volume":"67","author":"Gramantieri","year":"2007","journal-title":"Cancer Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2537","DOI":"10.1038\/sj.onc.1209283","article-title":"Comprehensive analysis of microRNA expression patterns in hepatocellular carcinoma and non-tumorous tissues","volume":"25","author":"Murakami","year":"2006","journal-title":"Oncogene"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1002\/hep.26616","article-title":"MicroRNA\/gene profiling unveils early molecular changes and nuclear factor erythroid related factor 2 (Nrf2) activation in a rat model recapitulating human hepatocellular carcinoma (HCC)","volume":"59","author":"Petrelli","year":"2014","journal-title":"Hepatology"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1002\/jcb.20982","article-title":"Downregulation of miR-122 in the rodent and human hepatocellular carcinomas","volume":"99","author":"Kutay","year":"2006","journal-title":"J. Cell. Biochem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1002\/hep.22160","article-title":"Identification of metastasis-related microRNAs in hepatocellular carcinoma","volume":"47","author":"Budhu","year":"2008","journal-title":"Hepatology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1016\/S1097-2765(02)00504-X","article-title":"Cyclin G recruits PP2A to dephosphorylate MDM2","volume":"9","author":"Okamoto","year":"2002","journal-title":"Mol. Cell"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1002\/hep.24809","article-title":"Loss of microRNA 122 expression in patients with hepatitis b enhances hepatitis B virus replication through cyclin G(1)-modulated p53 activity","volume":"55","author":"Wang","year":"2012","journal-title":"Hepatology"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1038\/nature04303","article-title":"Silencing of microRNAs in vivo with \u201cantagomirs\u201d","volume":"438","author":"Krutzfeldt","year":"2005","journal-title":"Nature"},{"key":"ref_47","first-page":"878","article-title":"Hcv infection and miravirsen","volume":"369","author":"Janssen","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1056\/NEJMoa1209026","article-title":"Treatment of HCV infection by targeting microRNA","volume":"368","author":"Janssen","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1623","DOI":"10.1002\/hep.28679","article-title":"The liver-specific microRNA-122*, the complementary strand of microRNA-122, acts as a tumor suppressor by modulating the p53\/mouse double minute 2 homolog circuitry","volume":"64","author":"Simerzin","year":"2016","journal-title":"Hepatology"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1038\/nsmb.3050","article-title":"Small-RNA asymmetry is directly driven by mammalian argonautes","volume":"22","author":"Suzuki","year":"2015","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/1476-4598-5-29","article-title":"Identification by real-time PCR of 13 mature microRNAs differentially expressed in colorectal cancer and non-tumoral tissues","volume":"5","author":"Bandres","year":"2006","journal-title":"Mol. Cancer"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"7065","DOI":"10.1158\/0008-5472.CAN-05-1783","article-title":"MicroRNA gene expression deregulation in human breast cancer","volume":"65","author":"Iorio","year":"2005","journal-title":"Cancer Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"8699","DOI":"10.1158\/0008-5472.CAN-07-1936","article-title":"MicroRNA signatures in human ovarian cancer","volume":"67","author":"Iorio","year":"2007","journal-title":"Cancer Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1158\/1078-0432.CCR-08-1355","article-title":"Uncovering growth-suppressive microRNAs in lung cancer","volume":"15","author":"Liu","year":"2009","journal-title":"Clin. Cancer Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1788","DOI":"10.1038\/sj.onc.1210809","article-title":"Widespread deregulation of microRNA expression in human prostate cancer","volume":"27","author":"Ozen","year":"2008","journal-title":"Oncogene"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1038\/onc.2012.28","article-title":"Loss of microRNA-143\/145 disturbs cellular growth and apoptosis of human epithelial cancers by impairing the MDM2-p53 feedback loop","volume":"32","author":"Zhang","year":"2013","journal-title":"Oncogene"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"3207","DOI":"10.1073\/pnas.0808042106","article-title":"P53 represses C-MYC through induction of the tumor suppressor miR-145","volume":"106","author":"Sachdeva","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1038\/cdd.2009.117","article-title":"miR-145 participates with TP53 in a death-promoting regulatory loop and targets estrogen receptor-alpha in human breast cancer cells","volume":"17","author":"Spizzo","year":"2010","journal-title":"Cell Death Differ."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"31361","DOI":"10.18632\/oncotarget.8913","article-title":"Over-Expression of the miR-483-3p overcomes the miR-145\/TP53 pro-apoptotic loop in hepatocellular carcinoma","volume":"7","author":"Lupini","year":"2016","journal-title":"Oncotarget"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"3140","DOI":"10.1158\/0008-5472.CAN-09-4456","article-title":"Oncogenic role of miR-483-3p at the IGF2\/483 locus","volume":"70","author":"Veronese","year":"2010","journal-title":"Cancer Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1351","DOI":"10.1016\/j.bbrc.2005.07.030","article-title":"Extensive modulation of a set of microRNAs in primary glioblastoma","volume":"334","author":"Ciafre","year":"2005","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"19075","DOI":"10.1073\/pnas.0509603102","article-title":"The role of microRNA genes in papillary thyroid carcinoma","volume":"102","author":"He","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1677\/erc.1.01209","article-title":"MicroRNA deregulation in human thyroid papillary carcinomas","volume":"13","author":"Pallante","year":"2006","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"5651","DOI":"10.1038\/onc.2008.178","article-title":"miR-221 controls CDKN1c\/p57 and CDKN1b\/p27 expression in human hepatocellular carcinoma","volume":"27","author":"Fornari","year":"2008","journal-title":"Oncogene"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"23716","DOI":"10.1074\/jbc.M701805200","article-title":"miR-221 and miR-222 expression affects the proliferation potential of human prostate carcinoma cell lines by targeting p27kip1","volume":"282","author":"Galardi","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"3699","DOI":"10.1038\/sj.emboj.7601790","article-title":"Regulation of the p27(Kip1) tumor suppressor by miR-221 and miR-222 promotes cancer cell proliferation","volume":"26","author":"Nagel","year":"2007","journal-title":"EMBO J."},{"key":"ref_67","first-page":"1653","article-title":"Co-suppression of miR-221\/222 cluster suppresses human glioma cell growth by targeting p27Kip1 in vitro and in vivo","volume":"34","author":"Zhang","year":"2009","journal-title":"Int. J. Oncol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"5073","DOI":"10.1158\/1078-0432.CCR-09-0092","article-title":"MicroRNA-221 targets bmf in hepatocellular carcinoma and correlates with tumor multifocality","volume":"15","author":"Gramantieri","year":"2009","journal-title":"Clin. Cancer Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1186\/1476-4598-9-229","article-title":"miR-221 and miR-222 target puma to induce cell survival in glioblastoma","volume":"9","author":"Zhang","year":"2010","journal-title":"Mol. Cancer"},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Li, J., Yao, L., Li, G., Ma, D., Sun, C., Gao, S., Zhang, P., and Gao, F. (2015). miR-221 promotes epithelial-mesenchymal transition through targeting pten and forms a positive feedback loop with \u03b2-catenin\/C-jun signaling pathway in extra-hepatic cholangiocarcinoma. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0141168"},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Liu, J., Cao, J., and Zhao, X. (2015). miR-221 facilitates the TGF\u03b21-induced epithelial-mesenchymal transition in human bladder cancer cells by targeting stmn1. BMC Urol., 15.","DOI":"10.1186\/s12894-015-0028-3"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Su, A., He, S., Tian, B., Hu, W., and Zhang, Z. (2013). MicroRNA-221 mediates the effects of PDGF-BB on migration, proliferation, and the epithelial-mesenchymal transition in pancreatic cancer cells. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0071309"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Zhang, C.Z., Han, L., Zhang, A.L., Fu, Y.C., Yue, X., Wang, G.X., Jia, Z.F., Pu, P.Y., Zhang, Q.Y., and Kang, C.S. (2010). MicroRNA-221 and microRNA-222 regulate gastric carcinoma cell proliferation and radioresistance by targeting pten. BMC Cancer, 10.","DOI":"10.1186\/1471-2407-10-367"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"3845","DOI":"10.1038\/onc.2008.6","article-title":"MicroRNA signatures of trail resistance in human non-small cell lung cancer","volume":"27","author":"Garofalo","year":"2008","journal-title":"Oncogene"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"42292","DOI":"10.1074\/jbc.M111.270926","article-title":"Anti-MicroRNA-222 (anti-miR-222) and -181b suppress growth of tamoxifen-resistant xenografts in mouse by targeting timp3 protein and modulating mitogenic signal","volume":"286","author":"Lu","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"29897","DOI":"10.1074\/jbc.M804612200","article-title":"MicroRNA-221\/222 confers tamoxifen resistance in breast cancer by targeting p27kip1","volume":"283","author":"Miller","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1158\/1541-7786.MCR-13-0312-T","article-title":"P53\/mdm2 feedback loop sustains miR-221 expression and dictates the response to anticancer treatments in hepatocellular carcinoma","volume":"12","author":"Fornari","year":"2014","journal-title":"Mol. Cancer Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1002\/path.3995","article-title":"In hepatocellular carcinoma miR-519d is up-regulated by p53 and DNA hypomethylation and targets CDKN1a\/p21, PTEN, Akt3 and TIMP2","volume":"227","author":"Fornari","year":"2012","journal-title":"J. Pathol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1038\/bjc.2014.593","article-title":"miR-1228 promotes the proliferation and metastasis of hepatoma cells through a p53 forward feedback loop","volume":"112","author":"Zhang","year":"2015","journal-title":"Br. J. Cancer"},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Fornari, F., Ferracin, M., Trere, D., Milazzo, M., Marinelli, S., Galassi, M., Venerandi, L., Pollutri, D., Patrizi, C., and Borghi, A. (2015). Circulating microRNAs, miR-939, miR-595, miR-519d and miR-494, identify cirrhotic patients with hcc. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0141448"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"2999","DOI":"10.1073\/pnas.0307323101","article-title":"Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers","volume":"101","author":"Calin","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Vrba, L., Jensen, T.J., Garbe, J.C., Heimark, R.L., Cress, A.E., Dickinson, S., Stampfer, M.R., and Futscher, B.W. (2010). Role for DNA methylation in the regulation of miR-200c and miR-141 expression in normal and cancer cells. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0008697"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1038\/nature06783","article-title":"Lna-Mediated microRNA silencing in non-human primates","volume":"452","author":"Elmen","year":"2008","journal-title":"Nature"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.cmet.2006.01.005","article-title":"miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting","volume":"3","author":"Esau","year":"2006","journal-title":"Cell Metab."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.canlet.2015.11.034","article-title":"MicroRNA-122 confers sorafenib resistance to hepatocellular carcinoma cells by targeting IGF-1r to regulate RAS\/RAF\/ERK signaling pathways","volume":"371","author":"Xu","year":"2016","journal-title":"Cancer Lett."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1038\/nrd4140","article-title":"MicroRNAs and other non-coding RNAs as targets for anticancer drug development","volume":"12","author":"Ling","year":"2013","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"6236","DOI":"10.1158\/0008-5472.CAN-14-0855","article-title":"A small-molecule modulator of the tumor-suppressor miR34a inhibits the growth of hepatocellular carcinoma","volume":"74","author":"Xiao","year":"2014","journal-title":"Cancer Res."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1038\/nature03702","article-title":"MicroRNA expression profiles classify human cancers","volume":"435","author":"Lu","year":"2005","journal-title":"Nature"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1002\/hep.25747","article-title":"Liver tumorigenicity promoted by microRNA-221 in a mouse transgenic model","volume":"56","author":"Callegari","year":"2012","journal-title":"Hepatology"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/17\/12\/2029\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T19:27:54Z","timestamp":1760210874000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/17\/12\/2029"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,12,2]]},"references-count":89,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2016,12]]}},"alternative-id":["ijms17122029"],"URL":"https:\/\/doi.org\/10.3390\/ijms17122029","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2016,12,2]]}}}