title: p85α is a microRNA target and affects chemosensitivity in pancreatic cancer.
abstract: BACKGROUND
  We previously identified a correlation between increased expression of the phosphoinositide 3-kinase (PI3K) regulatory subunit p85α and improved survival in human pancreatic ductal adenocarcinoma (PDAC). The purpose of this study was to investigate the impact of changes in p85α expression on response to chemotherapy and the regulation of p85α by microRNA-21 (miR-21).
  
  
  METHODS
  PDAC tumor cells overexpressing p85α were generated by viral transduction, and the effect of p85α overexpression on sensitivity to gemcitabine was tested by MTT assay. Primary human PDAC tumors were stained for p85α and miR-21 via immunohistochemistry and in situ hybridization, respectively. Additionally, PDAC cells were treated with miR-21 mimic, and changes in p85α and phospho-AKT were assessed by Western blot. Finally, a luciferase reporter assay system was used to test direct regulation of p85α by miR-21.
  
  
  RESULTS
  Higher p85α expression resulted in increased sensitivity to gemcitabine (P < 0.01), which correlated with decreased PI3K-AKT activation. Human tumors demonstrated an inverse correlation between miR-21 and p85α expression levels (r = -0.353, P < 0.001). In vitro, overexpression of miR-21 resulted in decreased levels of p85α and increased phosphorylation of AKT. Luciferase reporter assays confirmed the direct regulation of p85α by miR-21 (P < 0.01).
  
  
  CONCLUSIONS
  Our results demonstrate that p85α expression is a determinant of chemosensitivity in PDAC. Additionally, we provide novel evidence that miR-21 can influence PI3K-AKT signaling via its direct regulation of p85α. These data provide insight into potential mechanisms for the known relationship between increased p85α expression and improved survival in PDAC.
authors.affiliation: Department of Surgery, Division of General Surgery, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, CA, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Toste
authors.affiliation: Department of Surgery, Division of General Surgery, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, CA, USA.
authors.forename: Luyi
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Surgery, Division of General Surgery, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, CA, USA.
authors.forename: Brian E
authors.initials: BE
authors.lastname: Kadera
authors.affiliation: Department of Surgery, Division of General Surgery, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, CA, USA.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Nguyen
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, CA, USA.
authors.forename: Linh M
authors.initials: LM
authors.lastname: Tran
authors.affiliation: Department of Surgery, Division of General Surgery, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, CA, USA.
authors.forename: Nanping
authors.initials: N
authors.lastname: Wu
authors.affiliation: Department of Surgery, Division of General Surgery, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, CA, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Madnick
authors.affiliation: Department of Surgery, Division of General Surgery, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, CA, USA.
authors.forename: Sanjeet G
authors.initials: SG
authors.lastname: Patel
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, CA, USA.|Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, CA, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Dawson
authors.affiliation: Department of Surgery, Division of General Surgery, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, CA, USA.|Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, CA, USA.|Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, CA, USA.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Donahue
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D057809:HEK293 Cells; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D003841:Deoxycytidine; D019869:Phosphatidylinositol 3-Kinases; D058543:Class Ia Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D000093542:Gemcitabine
keywords: Chemoresistance; PIK3R1; Pancreatic cancer; miR-21; p85α
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