title: RAN GTPase and Osteopontin in Pancreatic Cancer.
abstract: BACKGROUND
  Pancreatic ductal adenocarcinoma (PDA) has the worst prognosis among cancers, mainly due to the high incidence of early metastases. RAN small GTPase (RAN) is a protein that plays physiological roles in the regulation of nuclear transport and microtubule spindle assembly. RAN was recently shown to mediate the invasive functions of the prometastatic protein osteopontin (OPN) in breast cancer cells. We and others have shown previously that high levels of OPN are present in PDA. In this study, we analyzed the expression and correlation of RAN with OPN in human pancreatic lesions, and explored their regulation in PDA cell lines.
  
  
  METHODS
  Real time PCR was used to analyze RAN and OPN mRNA levels in PDA, adjacent non-malignant, and benign pancreatic tissues. Expression levels were correlated with survival and different clinicopathological parameters using different statistical methods. Transient transfection studies using OPN and RAN plasmids, and knockdown experiments using siRNA were used to examine their mutual regulation.
  
  
  RESULTS
  OPN and RAN levels highly correlated with each other (p<0.0001). OPN or RAN levels did not correlate with venous lymphatic invasion, diabetes, obesity, T stage, BMI, or survival. However, we found a significant association between RAN levels and perineural invasion (HR=0.79, 95% CI 0.59, 1.07; p=0.0378.). OPN and RAN colocalized in PDA tissues and cell lines. Increasing RAN expression in PDA cells induced OPN transcription and RAN silencing reduced total OPN levels. OPN did not have any significant effect on RAN transcription.
  
  
  CONCLUSIONS
  The high levels of RAN in PDA and its correlation with OPN and with perineural invasion suggest that RAN may contribute to PDA metastasis and progression through the induction of OPN. RAN's role in the regulation of OPN in PDA is unique and could provide potential novel therapeutic strategies to combat PDA aggressiveness.
authors.affiliation: Departments of Surgery, Jefferson Pancreatic, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, USA.
authors.forename: Shivam
authors.initials: S
authors.lastname: Saxena
authors.affiliation: Departments of Surgery, Jefferson Pancreatic, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, USA.
authors.forename: Ankit
authors.initials: A
authors.lastname: Gandhi
authors.affiliation: Departments of Surgery, Jefferson Pancreatic, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, USA.
authors.forename: Pei-Wen
authors.initials: PW
authors.lastname: Lim
authors.affiliation: Departments of Surgery, Jefferson Pancreatic, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Relles
authors.affiliation: Departments of Surgery, Jefferson Pancreatic, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, USA.
authors.forename: Konrad
authors.initials: K
authors.lastname: Sarosiek
authors.affiliation: Departments of Surgery, Jefferson Pancreatic, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Kang
authors.affiliation: Departments of Surgery, Jefferson Pancreatic, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, USA.
authors.forename: Galina
authors.initials: G
authors.lastname: Chipitsyna
authors.affiliation: Departments of Surgery, Jefferson Pancreatic, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, USA.
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Sendecki
authors.affiliation: Departments of Surgery, Jefferson Pancreatic, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, USA.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Yeo
authors.affiliation: Departments of Surgery, Jefferson Pancreatic, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, USA.
authors.forename: Hwyda A
authors.initials: HA
authors.lastname: Arafat
keywords: OPN; Pancreatic cancer; RAN
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