title: HuR regulates beta-tubulin isotype expression in ovarian cancer.
abstract: The supply of oxygen and nutrients to solid tumors is inefficient because cancer tissues have an inadequate number of microvessels, thus inducing the selective growth of the most aggressive cancer cells. This explains why many of the factors underlying a poor prognosis are induced in hypoxic/hypoglycemic conditions. Among these factors, a prominent role in several solid tumors is played by the class III beta-tubulin gene (TUBB3). The study described here reveals that glucose deprivation enhances TUBB3 expression at both the gene and protein levels in A2780 ovarian cancer cells. In silico analysis of TUBB3 mRNA sequence predicted a putative binding site for the RNA-binding protein Hu antigen (HuR) in the 3' flanking untranslated region. A hypoglycemic-dependent engagement of this site was shown using RNA pull-down and ribonucleoimmunoprecipitation techniques. Thereafter, HuR gene silencing revealed that TUBB3 translation is HuR dependent in hypoglycemia because HuR silencing inhibited the entry of TUBB3 mRNA into cytoskeletal and free polysomes. Finally, the clinical value of this finding was assessed in a clinical cohort of 46 ovarian cancer patients in whom it was found that HuR cytoplasmic staining was associated with high levels of TUBB3 and poor survival.
authors.affiliation: Laboratory of Antineoplastic Pharmacology, Department of Obstetrics and Gynecology, Catholic University of the Sacred Heart, Rome, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Raspaglio
authors.forename: Ilaria
authors.initials: I
authors.lastname: De Maria
authors.forename: Flavia
authors.initials: F
authors.lastname: Filippetti
authors.forename: Enrica
authors.initials: E
authors.lastname: Martinelli
authors.forename: Gian Franco
authors.initials: GF
authors.lastname: Zannoni
authors.forename: Silvia
authors.initials: S
authors.lastname: Prislei
authors.forename: Gabriella
authors.initials: G
authors.lastname: Ferrandina
authors.forename: Shohreh
authors.initials: S
authors.lastname: Shahabi
authors.forename: Giovanni
authors.initials: G
authors.lastname: Scambia
authors.forename: Cristiano
authors.initials: C
authors.lastname: Ferlini
mesh_terms: D020413:3' Untranslated Regions; D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism*; D000954:Antigens, Surface / Q000378:metabolism*; D045744:Cell Line, Tumor; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D005260:Female; D006801:Humans; D007003:Hypoglycemia / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D016601:RNA-Binding Proteins / Q000378:metabolism*; D014404:Tubulin / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; D000954:Antigens, Surface; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C498585:TUBB3 protein, human; D014404:Tubulin