title: The potential predictive role of nuclear NHERF1 expression in advanced gastric cancer patients treated with epirubicin/oxaliplatin/capecitabine first line chemotherapy.
abstract: Cellular resistance in advanced gastric cancer (GC) might be related to function of multidrug resistance (MDR) proteins. The adaptor protein NHERF1 (Na(+)/H(+) exchanger regulatory factor) is an important player in cancer progression for a number of solid malignancies, even if its role to develop drug resistance remains uncertain. Herein, we aimed to analyze the potential association between NHERF1 expression and P-gp, sorcin and HIF-1α MDR-related proteins in advanced GC patients treated with epirubicin/oxaliplatin/capecitabine (EOX) chemotherapy regimen, and its relation to response. Total number of 28 untreated patients were included into the study. Expression and subcellular localization of all proteins were assessed by immunohistochemistry on formalin-fixed paraffin embedded tumor samples. We did not found significant association between NHERF1 expression and the MDR-related proteins. A trend was observed between positive cytoplasmic NHERF1 (cNHERF1) expression and negative nuclear HIF-1α (nHIF-1α) expression (68.8% versus 31.3% respectively, P = 0.054). However, cytoplasmic P-gp (cP-gp) expression was positively correlated with both cHIF-1α and sorcin expression (P = 0.011; P = 0.002, respectively). Interestingly, nuclear NHERF1 (nNHERF1) staining was statistically associated with clinical response. In detail, 66.7% of patients with high nNHERF1 expression had a disease control rate, while 84.6% of subjects with negative nuclear expression of the protein showed progressive disease (P = 0.009). Multivariate analysis confirmed a significant correlation between nNHERF1 and clinical response (OR 0.06, P = 0.019). These results suggest that nuclear NHERF1 could be related to resistance to the EOX regimen in advanced GC patients, identifying this marker as a possible independent predictive factor.
authors.affiliation: a Functional Biomorphology Laboratory ; National Cancer Research Centre ; Istituto Tumori "Giovanni Paolo II"; Bari , Italy.
authors.forename: Anita
authors.initials: A
authors.lastname: Mangia
authors.forename: Lucia
authors.initials: L
authors.lastname: Caldarola
authors.forename: Stefania
authors.initials: S
authors.lastname: Dell'Endice
authors.forename: Emanuela
authors.initials: E
authors.lastname: Scarpi
authors.forename: Luca
authors.initials: L
authors.lastname: Saragoni
authors.forename: Manlio
authors.initials: M
authors.lastname: Monti
authors.forename: Daniele
authors.initials: D
authors.lastname: Santini
authors.forename: Oronzo
authors.initials: O
authors.lastname: Brunetti
authors.forename: Giovanni
authors.initials: G
authors.lastname: Simone
authors.forename: Nicola
authors.initials: N
authors.lastname: Silvestris
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000069287:Capecitabine / Q000008:administration & dosage; D002467:Cell Nucleus / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D015251:Epirubicin / Q000008:administration & dosage; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D010750:Phosphoproteins / Q000378:metabolism*; D012016:Reference Values; D012189:Retrospective Studies; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009944:Organoplatinum Compounds; D010750:Phosphoproteins; D017923:Sodium-Hydrogen Exchangers; C093376:sodium-hydrogen exchanger regulatory factor; D000077150:Oxaliplatin; D015251:Epirubicin; D000069287:Capecitabine
keywords: Cl, confidence interval; DCR, disease control rate; NHERF1/EBP50; OR, odds ratio; PD, progression disease; cHIF-1α, cytoplasmic HIF-1α; cNHERF1, cytoplasmic NHERF1; cP-gp, cytoplasmic P-gp; cSR1, cytoplasmic SR1; chemotherapy; gastric cancer; immunohistochemistry; mP-gp, membranous P-gp; multi-drug resistance; nHIF-1α, nuclear HIF-1α; nNHERF1, nuclear NHERF1; predictive factor