title: Role of miR-27a, miR-181a and miR-20b in gastric cancer hypoxia-induced chemoresistance.
abstract: Despite the search for new therapeutic strategies for gastric cancer (GC), there is much evidence of progression due to resistance to chemotherapy. Multidrug resistance (MDR) is the ability of cancer cells to survive after exposure to chemotherapeutic agents. The involvement of miRNAs in the development of MDR has been well described but miRNAs able to modulate the sensitivity to chemotherapy by regulating hypoxia signaling pathways have not yet been fully addressed in GC. Our aim was to analyze miR-20b, miR-27a and miR-181a expression with respect to (epirubicin/oxaliplatin/capecitabine (EOX)) chemotherapy regimen in a set of GC patients, in order to investigate whether miRNAs deregulation may influence GC MDR also via hypoxia signaling modulation. Cancer biopsy were obtained from 21 untreated HER2 negative advanced GC patients, retrospectively analyzed. All patients received a first-line chemotherapy (EOX) regimen. MirWalk database was used to identify miR-27a, miR-181a and miR-20b target genes. The expression of miRNAs and of HIPK2, HIF1A and MDR1 genes were detected by real-time PCR. HIPK2 localization was assessed by immunohistochemistry. Our data showed the down-regulation of miR-20b, miR-27a, miR-181a concomitantly to higher levels of MDR1, HIF1A and HIPK2 genes in GC patients with a progressive disease respect to those with a disease control rate. Moreover, immunohistochemistry assay highlighted a higher cytoplasmic HIPK2 staining, suggesting a different role for it. We showed that aberrant expression of miR-20b, miR27a and miR-181a was associated with chemotherapeutic response in GC through HIF1A, MDR1 and HIPK2 genes modulation, suggesting a possible novel therapeutic strategy.
authors.affiliation: a Molecular Genetics Laboratory, IRCCS Istituto Tumori "Giovanni Paolo II - Bari , Italy.
authors.forename: Katia
authors.initials: K
authors.lastname: Danza
authors.affiliation: b Medical Oncology Unit, IRCCS Istituto Tumori "Giovanni Paolo II - Bari , Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Silvestris
authors.affiliation: c Pathology Department , IRCCS Istituto Tumori "Giovanni Paolo II - Bari , Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Simone
authors.affiliation: b Medical Oncology Unit, IRCCS Istituto Tumori "Giovanni Paolo II - Bari , Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Signorile
authors.affiliation: d Pathology Unit, Morgagni Pierantoni Hospital , Forlì , Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Saragoni
authors.affiliation: b Medical Oncology Unit, IRCCS Istituto Tumori "Giovanni Paolo II - Bari , Italy.
authors.forename: Oronzo
authors.initials: O
authors.lastname: Brunetti
authors.affiliation: e Department of Medical Oncology , Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), IRCCS Meldola , Italy.
authors.forename: Manlio
authors.initials: M
authors.lastname: Monti
authors.affiliation: f Functional Biomorphology Laboratory, IRCCS Istituto Tumori "Giovanni Paolo II - Bari , Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Mazzotta
authors.affiliation: a Molecular Genetics Laboratory, IRCCS Istituto Tumori "Giovanni Paolo II - Bari , Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: De Summa
authors.affiliation: f Functional Biomorphology Laboratory, IRCCS Istituto Tumori "Giovanni Paolo II - Bari , Italy.
authors.forename: Anita
authors.initials: A
authors.lastname: Mangia
authors.affiliation: a Molecular Genetics Laboratory, IRCCS Istituto Tumori "Giovanni Paolo II - Bari , Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Tommasi
mesh_terms: D015687:Cell Hypoxia / Q000235:genetics*; D018450:Disease Progression; D018432:Drug Resistance, Multiple; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D035683:MicroRNAs
keywords: Gastric cancer; MDR; hypoxia signaling pathways; miR-181a; miR-20b; miR-27a