title: Shp2 promotes liver cancer stem cell expansion by augmenting β-catenin signaling and predicts chemotherapeutic response of patients.
abstract: Src-homology 2 domain-containing phosphatase 2 (Shp2) has been reported to play an important role in the maintenance and self-renewal of embryonic and adult stem cells, but its role in cancer stem cells (CSCs) remains obscure. Herein, we observed high expression of Shp2 in both chemoresistant hepatocellular carcinomas (HCCs) and recurrent HCCs from patients. A remarkable increase of Shp2 was detected in sorted epithelial cell adhesion molecule-positive or cluster of differentiation 133-positive liver CSCs and in CSC-enriched hepatoma spheroids from patients. Up-regulated Shp2 facilitated liver CSC expansion by promoting the dedifferentiation of hepatoma cells and enhancing the self-renewal of liver CSCs. Mechanistically, Shp2 dephosphorylated cell division cycle 73 in the cytosol of hepatoma cells, and the dephosphorylated cell division cycle 73 bound β-catenin and facilitated the nuclear translocation of β-catenin, which promoted the dedifferentiation of hepatoma cells. Shp2 increased β-catenin accumulation by inhibiting glycogen synthase kinase 3β-mediated β-catenin degradation in liver CSCs, thereby enhancing the self-renewal of liver CSCs. Blockage of β-catenin abolished the discrepancy in liver CSC proportion and the self-renewal capacity between Shp2-depleted hepatoma cells and control cells, which further confirmed that β-catenin is required in Shp2-promoted liver CSC expansion. More importantly, HCC patients with low Shp2 levels benefited from transcatheter arterial chemoembolization or sorafenib treatment, but patients with high Shp2 expression did not, indicating the significance of Shp2 in personalized HCC therapy.
  
  
  
  Shp2 could promote HCC cell dedifferentiation and liver CSC expansion by amplifying β-catenin signaling and may be useful in predicting patient response to chemotherapeutics. (Hepatology 2017;65:1566-1580).
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital/Institute, Second Military Medical University, Shanghai, China.|Nelson Institute of Environmental Medicine, New York University School of Medicine, New York, NY.
authors.forename: Daimin
authors.initials: D
authors.lastname: Xiang
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital/Institute, Second Military Medical University, Shanghai, China.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Cheng
authors.affiliation: The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital/Institute, Second Military Medical University, Shanghai, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Wang
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital/Institute, Second Military Medical University, Shanghai, China.|Department of Oncology, General Hospital of Shenyang Military Region, Shenyang, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Han
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital/Institute, Second Military Medical University, Shanghai, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Sun
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital/Institute, Second Military Medical University, Shanghai, China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Li
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital/Institute, Second Military Medical University, Shanghai, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Yang
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital/Institute, Second Military Medical University, Shanghai, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Chen
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital/Institute, Second Military Medical University, Shanghai, China.
authors.forename: Mingyang
authors.initials: M
authors.lastname: Xia
authors.affiliation: Department of Hepatobiliary Medicine, Eastern Hepatobiliary Surgery Hospital/Institute, Second Military Medical University, Shanghai, China.
authors.forename: Na
authors.initials: N
authors.lastname: Liu
authors.affiliation: Department of General Surgery, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Shengyong
authors.initials: S
authors.lastname: Yin
authors.affiliation: Department of Pathology, Eastern Hepatobiliary Surgery Hospital/Institute, Second Military Medical University, Shanghai, China.
authors.forename: Guangzhi
authors.initials: G
authors.lastname: Jin
authors.affiliation: Department of Pathology, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Terence
authors.initials: T
authors.lastname: Lee
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital/Institute, Second Military Medical University, Shanghai, China.
authors.forename: Liwei
authors.initials: L
authors.lastname: Dong
authors.affiliation: Department of Hepatobiliary Medicine, Eastern Hepatobiliary Surgery Hospital/Institute, Second Military Medical University, Shanghai, China.
authors.forename: Heping
authors.initials: H
authors.lastname: Hu
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital/Institute, Second Military Medical University, Shanghai, China.|National Center for Liver Cancer, Shanghai, China.
authors.forename: Hongyang
authors.initials: H
authors.lastname: Wang
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital/Institute, Second Military Medical University, Shanghai, China.|National Center for Liver Cancer, Shanghai, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Ding
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism*; D054337:Cell Dedifferentiation; D045744:Cell Line, Tumor; D002648:Child; D019008:Drug Resistance, Neoplasm; D005260:Female; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism*; D051381:Rats; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D055815:Young Adult; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D015415:Biomarkers; C454900:CDC73 protein, human; D025521:Tumor Suppressor Proteins; D051176:beta Catenin; D000071679:Glycogen Synthase Kinase 3 beta; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11