title: PTPN11/Shp2 overexpression enhances liver cancer progression and predicts poor prognosis of patients.
abstract: OBJECTIVE
  We have previously reported that Shp2, a tyrosine phosphatase previously known as a pro-leukemogenic molecule, suppresses the initiation of hepatocellular carcinoma (HCC). However, the role of Shp2 in HCC progression remains obscure.
  
  
  METHODS
  Shp2 expression was determined in human HCC using real-time PCR, immunoblotting and immunohistochemistry. Clinical significance of Shp2 expression was analyzed in 301 HCC tissues with clinico-pathological characteristics and follow-up information. Short hairpin RNA was utilized to investigate the function of Shp2 in hepatoma cell behavior. Role of Shp2 in HCC progression was monitored through nude mice xenograft assay. Kinase activity assay and co-immunoprecipitation were used for mechanism analysis.
  
  
  RESULTS
  Elevated expression of Shp2 was detected in 65.9% (394/598) of human HCCs, and its levels were even higher in metastasized foci. Overexpression of Shp2 correlated well with the malignant clinico-pathological characteristics of HCC and predicted the poor prognosis of patients. Interference of Shp2 expression suppressed the proliferation of hepatoma cells in vitro and inhibited the growth of HCC xenografts in vivo. Down-regulation of Shp2 attenuated the adhesion and migration of hepatoma cells and diminished metastasized HCC formation in mice. Our data demonstrated that Shp2 promotes HCC growth and metastasis by coordinately activating Ras/Raf/Erk pathway and PI3-K/Akt/mTOR cascade. Moreover, down-regulation of Shp2 enhanced the sensitivity of hepatoma cells upon sorafenib treatment, and patients with low Shp2 expression exhibited superior prognosis to sorafenib.
  
  
  CONCLUSIONS
  Shp2 promotes the progression of HCC and may serve as a prognostic biomarker for patients.
authors: The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200433, China.
authors: Tao
authors: T
authors: Han
authors: The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200433, China.
authors: Dai-Min
authors: DM
authors: Xiang
authors: The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200433, China.
authors: Wen
authors: W
authors: Sun
authors: The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200433, China.
authors: Na
authors: N
authors: Liu
authors: The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200433, China.
authors: Huan-Lin
authors: HL
authors: Sun
authors: The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200433, China.
authors: Wen
authors: W
authors: Wen
authors: The Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, China.
authors: Wei-Feng
authors: WF
authors: Shen
authors: The Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, China.
authors: Ruo-Yu
authors: RY
authors: Wang
authors: The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200433, China.
authors: Cheng
authors: C
authors: Chen
authors: The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200433, China.
authors: Xue
authors: X
authors: Wang
authors: The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200433, China.
authors: Zhuo
authors: Z
authors: Cheng
authors: The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200433, China.
authors: Heng-Yu
authors: HY
authors: Li
authors: The Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, China.
authors: Meng-Chao
authors: MC
authors: Wu
authors: The Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, China.
authors: Wen-Ming
authors: WM
authors: Cong
authors: Department of Pathology, and Division of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA.
authors: Gen-Sheng
authors: GS
authors: Feng
authors: The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200433, China; National Center for Liver Cancer, Shanghai 200433, China. Electronic address: dingjin1103@163.com.
authors: Jin
authors: J
authors: Ding
authors: The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200433, China; National Center for Liver Cancer, Shanghai 200433, China. Electronic address: hywangk@vip.sina.com.
authors: Hong-Yang
authors: HY
authors: Wang
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000401:mortality; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018450:Disease Progression; D006801:Humans; D008113:Liver Neoplasms / Q000209:etiology* / Q000401:mortality; D020935:MAP Kinase Signaling System; D051379:Mice; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D011379:Prognosis; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000502:physiology*; D000077157:Sorafenib; D048490:raf Kinases / Q000502:physiology
chemical_list: D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib; D019869:Phosphatidylinositol 3-Kinases; D048490:raf Kinases; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11
keywords: Hepatocellular carcinoma; Metastasis; Prognosis; Shp2