title: Profilin-1 suppresses tumorigenicity in pancreatic cancer through regulation of the SIRT3-HIF1α axis.
abstract: BACKGROUND
  Tumor cells exhibit abnormal actin remodeling profiles, which involve the altered expressions of several important actin-binding proteins. Profilin1 (Pfn1), originally identified as an actin-associated protein, has been linked to several human malignancies. Our recent studies suggested that Pfn1 facilitates apoptosis in pancreatic cancer cells. Here, we investigated the exact role of Profilin1 (Pfn1) in pancreatic adenocarcinoma (PDAC) and the underlying mechanisms.
  
  
  METHODS
  Pfn1 protein expression in PDAC specimens was analyzed by immunohistochemistry using a tissue microarray (TMA) containing PDAC tumor tissue and corresponding normal tissue samples from 72 patients. The effect of Pfn1 expression on cancer proliferation was assessed in cells by up- and down-regulation of Pfn1 in vitro and in vivo. Immunoprecipitation and mass spectrometry were used to identify the Pfn1-associated proteins and potential pathways.
  
  
  RESULTS
  Pfn1 was downregulated in clinical pancreatic adenocarcinoma specimens compared with the surrounding benign tissues. Univariate survival analysis of the PDAC cohorts showed that low expression of Pfn1 was significantly correlated with shortened patient survival (mean 14.2 months versus 20.9 months, P < 0.05). Restoration of Pfn1 in pancreatic cancer cells with low endogenous Pfn1 expression resulted in a nontumorigenic phenotype, suggesting that Pfn1 may be a negative regulator of pancreatic cancer progression. Overexpression of Pfn1 in vivo decreased the tumor volume in orthotopic xenograft nude mice models. Pfn1 upregulated the expression of SIRT3, leading to HIF1α destabilization. This data revealed that aberrant Pfn1 expression contributes to pancreatic cancer progression.
  
  
  CONCLUSIONS
  Our data suggest that Pfn1 is a tumor suppressor in pancreatic cancer that acts via a novel mechanism of regulating the SIRT3-HIF1α axis, independently of its cytoskeleton-related activity.
authors.forename: Wantong
authors.initials: W
authors.lastname: Yao
authors.forename: Shunrong
authors.initials: S
authors.lastname: Ji
authors.forename: Yi
authors.initials: Y
authors.lastname: Qin
authors.forename: Jingxuan
authors.initials: J
authors.lastname: Yang
authors.forename: Jin
authors.initials: J
authors.lastname: Xu
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.forename: Wenyan
authors.initials: W
authors.lastname: Xu
authors.forename: Jiang
authors.initials: J
authors.lastname: Liu
authors.forename: Si
authors.initials: S
authors.lastname: Shi
authors.forename: Liang
authors.initials: L
authors.lastname: Liu
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.forename: Jiang
authors.initials: J
authors.lastname: Long
authors.forename: Quanxing
authors.initials: Q
authors.lastname: Ni
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, 270 DongAn Road, Shanghai 200032, P, R, China. yuxianjun@fudan.edu.cn.
authors.forename: Xianjun
authors.initials: X
authors.lastname: Yu
mesh_terms: D000368:Aged; D000818:Animals; D015153:Blotting, Western; D063646:Carcinogenesis / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D008819:Mice, Nude; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D051304:Profilins / Q000378:metabolism*; D011485:Protein Binding; D025941:Protein Interaction Mapping; D059748:Proteolysis; D056566:Sirtuin 3 / Q000378:metabolism*; D016019:Survival Analysis
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051304:Profilins; C466093:SIRT3 protein, human; D056566:Sirtuin 3
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