title: MUC1 regulates PDGFA expression during pancreatic cancer progression.
abstract: Pancreatic ductal adenocarcinoma (PDA) has one of the worst prognoses of all cancers. Mucin 1 (MUC1), a transmembrane mucin glycoprotein, is a key modulator of several signaling pathways that affect oncogenesis, motility and metastasis. Its expression is known to be associated with poor prognosis in patients. However, the precise mechanism remains elusive. We report a novel association of MUC1 with platelet-derived growth factor-A (PDGFA). PDGFA is one of the many drivers of tumor growth, angiogenesis and metastasis in PDA. Using mouse PDA models as well as human samples, we show clear evidence that MUC1 regulates the expression and secretion of PDGFA. This, in turn, influences proliferation and invasion of pancreatic cancer cells leading to higher tumor burden in vivo. In addition, we reveal that MUC1 overexpressing cells are heavily dependent on PDGFA both for proliferation and invasion, whereas MUC1-null cells are not. Moreover, PDGFA and MUC1 are critical for translocation of β catenin to the nucleus for oncogenesis to ensue. Finally, we elucidate the underlying mechanism by which MUC1 regulates PDGFA expression and secretion in pancreatic cancer cells. We show that MUC1 associates with Hif1-α, a known transcription factor involved in controlling PDGFA expression. Furthermore, MUC1 facilitates Hif1-α translocation to the nucleus. In summary, we have demonstrated that MUC1-induced invasion and proliferation occurs via increased exogenous production of PDGFA. Thus, impeding MUC1 regulation of PDGFA signaling may be therapeutically beneficial for patients with PDA.
authors.affiliation: Department of Biology, University of North Carolina, Charlotte, NC 28223, USA.
authors.forename: M
authors.initials: M
authors.lastname: Sahraei
authors.forename: L D
authors.initials: LD
authors.lastname: Roy
authors.forename: J M
authors.initials: JM
authors.lastname: Curry
authors.forename: T L
authors.initials: TL
authors.lastname: Teresa
authors.forename: S
authors.initials: S
authors.lastname: Nath
authors.forename: D
authors.initials: D
authors.lastname: Besmer
authors.forename: A
authors.initials: A
authors.lastname: Kidiyoor
authors.forename: R
authors.initials: R
authors.lastname: Dalia
authors.forename: S J
authors.initials: SJ
authors.lastname: Gendler
authors.forename: P
authors.initials: P
authors.lastname: Mukherjee
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D018396:Mucin-1 / Q000502:physiology*; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D047368:Tumor Burden; D051176:beta Catenin / Q000378:metabolism
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C060192:MUC1 protein, human; D018396:Mucin-1; D010982:Platelet-Derived Growth Factor; D051176:beta Catenin; C075278:platelet-derived growth factor A