title: Expression and regulation of nicotine receptor and osteopontin isoforms in human pancreatic ductal adenocarcinoma.
abstract: Osteopontin (OPN) is a secreted phospho-protein that confers on cancer cells a migratory phenotype. We have recently shown that nicotine, a risk factor in pancreatic ductal adenocarcinoma (PDA), induces an alpha7-nicotine acetylcholine receptor (α7-nAChR)-mediated increase of OPN in PDA cells. In this study, we tested nicotine's effect on the expression of OPN splice variants (OPNa, b, c) in PDA cells. We also analyzed the correlation between patients' smoking history with OPN and α7-nAChR levels. RT-PCR and UV-light-illumination of ethidium-bromide staining were used to examine the mRNA expression in tissue and PDA cells treated with or without nicotine (3-300 nM). Localization of total OPN, OPNc and α7-nAChR was analyzed by immunohistochemistry, and their mRNA tissue expression levels were correlated with the patients' smoking history. PDA cells expressed varying levels of OPNa, OPNb, and α7-nAChR. Nicotine treatment selectively induced denovo expression of OPNc and increased α7-nAChR expression levels. In PDA tissue, OPNc was found in 87% of lesions, of which 73% were smokers. OPNc and total OPN levels were correlated in the tissue from patients with invasive PDA. Nicotine receptor was expressed in the invasive and premalignant lesions without clear correlation with smoking history. We show here for the first time that α7-nAChR is expressed in PDA cells and tissues and is regulated by nicotine in PDA cells. This, together with our previous findings that α7-nAChR mediates the metastatic effects of nicotine in PDA, suggest that combined targeting of α7-nAChR and OPNc could be a valid novel therapeutic strategy for invasive PDA, especially in the smoking population.
authors.affiliation: Department of Surgery, Jefferson Pancreatic, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Sullivan
authors.forename: Laurel
authors.initials: L
authors.lastname: Blair
authors.forename: Amer
authors.initials: A
authors.lastname: Alnajar
authors.forename: Tamer
authors.initials: T
authors.lastname: Aziz
authors.forename: Galina
authors.initials: G
authors.lastname: Chipitsyna
authors.forename: Qiaoke
authors.initials: Q
authors.lastname: Gong
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Yeo
authors.forename: Hwyda A
authors.initials: HA
authors.lastname: Arafat
mesh_terms: D001483:Base Sequence; D021441:Carcinoma, Pancreatic Ductal / Q000209:etiology / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D017931:DNA Primers / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D009538:Nicotine / Q000494:pharmacology; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000209:etiology / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects / Q000235:genetics / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C579167:Chrna7 protein, human; D017931:DNA Primers; D020033:Protein Isoforms; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D053495:Osteopontin; D009538:Nicotine