title: PKM2 regulates neural invasion of and predicts poor prognosis for human hilar cholangiocarcinoma.
abstract: BACKGROUND
  The therapeutic and prognostic value of the glycolytic enzymes hexokinase, phosphofructokinase, and pyruvate kinase (PK) has been implicated in a variety of cancers, while their roles in treatment of and prognosis for hilar cholangiocarcinoma (HC) remain unclear. In this study, we determined the expression of PKM2 in and its impact on biology and clinical outcome of human HC.
  
  
  METHODS
  The regulation and function of PKM2 in HC pathogenesis was evaluated using human tissues, molecular and cell biology, and animal models, and its prognostic significance was determined according to its impact on patient survival.
  
  
  RESULTS
  We found that expression of hexokinase 1 and the M2 splice isoform of PK (PKM2) was upregulated in HC tissues and that this expression correlated with tumor recurrence and outcome. PKM2 expression was increased in HC cases with chronic cholangitis as demonstrated by isobaric tags for relative and absolute quantification. High PKM2 expression was highly correlated with high syndecan 2 (SDC2) expression and neural invasion. PKM2 downregulation led to a decrease in SDC2 expression. Treatment with metformin markedly suppressed PKM2 and SDC2 expression at both the transcriptional and posttranscriptional levels and inhibited HC cell proliferation and tumor growth.
  
  
  CONCLUSIONS
  PKM2 regulates neural invasion of HC cells at least in part via regulation of SDC2. Inhibition of PKM2 and SDC2 expression contributes to the therapeutic effect of metformin on HC. Therefore, PKM2 is an independent prognostic factor and potential therapeutic target for human HC.
authors.affiliation: Department of Oncology, East Hospital, Tongji University School of Medicine, Shanghai, 200120, People's Republic of China. qiaoshanqian@aliyun.com.|Department of Gastroenterology, Hepatology and Nutrition, Unit 1466, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA. qiaoshanqian@aliyun.com.
authors.forename: Guanzhen
authors.initials: G
authors.lastname: Yu
authors.affiliation: Department of Surgery, Eastern Hepatobiliary Hospital, Shanghai, People's Republic of China.
authors.forename: Wenlong
authors.initials: W
authors.lastname: Yu
authors.affiliation: Department of Pathology, Eastern Hepatobiliary Hospital, Shanghai, People's Republic of China.
authors.forename: Guangzhi
authors.initials: G
authors.lastname: Jin
authors.affiliation: Department of Oncology, East Hospital, Tongji University School of Medicine, Shanghai, 200120, People's Republic of China.
authors.forename: Dongyun
authors.initials: D
authors.lastname: Xu
authors.affiliation: Department of Pathology, Changhai Hospital, Shanghai, People's Republic of China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Gastroenterology, Changhai Hospital, Shanghai, 200433, People's Republic of China.|Department of Gastroenterology, Hepatology and Nutrition, Unit 1466, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA.
authors.forename: Tian
authors.initials: T
authors.lastname: Xia
authors.affiliation: Department of Gastroenterology, Hepatology and Nutrition, Unit 1466, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA.
authors.forename: Allan
authors.initials: A
authors.lastname: Yu
authors.affiliation: Department of Oncology, East Hospital, Tongji University School of Medicine, Shanghai, 200120, People's Republic of China.
authors.forename: Wenzheng
authors.initials: W
authors.lastname: Fang
authors.affiliation: Department of Pathology, Chinese People's Liberation Army, No 411 Hospital, Shanghai, People's Republic of China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Gastroenterology, Changhai Hospital, Shanghai, 200433, People's Republic of China. zhaoshenli.smmu.edu@hotmail.com.
authors.forename: Zhaosheng
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Gastroenterology, Hepatology and Nutrition, Unit 1466, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA. kepxie@mdanderson.org.
authors.forename: Keping
authors.initials: K
authors.lastname: Xie
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000502:physiology; D006593:Hexokinase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018285:Klatskin Tumor / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D011379:Prognosis; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D053669:Syndecan-2 / Q000235:genetics / Q000378:metabolism; D013963:Thyroid Hormones / Q000235:genetics / Q000378:metabolism*; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D002352:Carrier Proteins; D006593:Hexokinase; D008565:Membrane Proteins; D020033:Protein Isoforms; D053669:Syndecan-2; D013963:Thyroid Hormones; D000097810:Thyroid Hormone-Binding Proteins; C508245:SDC2 protein, human; C472074:HK1 protein, human