PMID- 25619838
OWN - NLM
STAT- MEDLINE
DCOM- 20160108
LR  - 20170717
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Linking)
VI  - 34
IP  - 41
DP  - 2015 Oct 8
TI  - SHP-1 is a negative regulator of epithelial-mesenchymal transition in
      hepatocellular carcinoma.
PG  - 5252-63
LID - 10.1038/onc.2014.445 [doi]
AB  - Epithelial-to-mesenchymal transition (EMT) is well known to involve in tumor
      invasion and metastasis. Src homology region 2 domain-containing phosphatase 1
      (SHP-1) functions as a potent tumor suppressor and also acts as a negative
      regulator of p-STAT3(Tyr705) oncogenic signaling. However, little is known about 
      the molecular mechanism(s) through which SHP-1 regulates EMT during
      hepatocellular carcinoma (HCC) progression. Here we first reported that
      endogenous SHP-1 protein levels were significantly downregulated in cells with
      mesenchymal characteristics and negatively correlated with p-STAT3(Tyr705) and
      vimentin but positively correlated with E-cadherin. SHP-1 overexpression
      abolished transforming growth factor-beta1 (TGF-beta1)-induced p-STAT3(Tyr705)
      and EMT, as well inhibited migration and invasion but further rescued by signal
      transducer and activator of transcription factor 3 (STAT3) overexpression.
      Depletion of SHP-1 could induce a more increase in TGF-beta1-induced
      p-STAT3(Tyr-705) and EMT characteristics, further supporting the mechanism that
      suppression of TGF-beta1-induced EMT is dependent on SHP-1-mediated STAT3
      inactivation. Constitutively overexpressed SHP-1 tyrosine phosphatase activity by
      D61A-mutated SHP-1 markedly reduced TGF-beta1-induced p-STAT3(Tyr705) and EMT
      features but was not altered by C453S catalytic-dead mutant SHP-1. Consequently, 
      SHP-1 acted as a powerful suppressor in preventing EMT by exerting its tyrosine
      phosphatase activity that directly downregulated p-STAT3(Tyr705). Most notably,
      we discovered a novel SHP-1 agonist SC-43 better than sorafenib to exert more
      potent anti-EMT effects in vitro as well as anti-metastatic growth in vivo. In
      conclusion, SHP-1 is a potent suppressor of HCC EMT and metastasis, thus
      highlighting that SC-43-SHP-1 axis may serve as a potential therapeutic target
      that antagonized p-STAT3(Tyr705) and thereby prevented HCC EMT and metastasis.
FAU - Fan, L-C
AU  - Fan LC
AD  - Department of Medical Research, National Taiwan University Hospital, Taipei,
      Taiwan.
AD  - National Center of Excellence for Clinical Trial and Research, National Taiwan
      University Hospital, Taipei, Taiwan.
FAU - Shiau, C-W
AU  - Shiau CW
AD  - Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei,
      Taiwan.
FAU - Tai, W-T
AU  - Tai WT
AD  - Department of Medical Research, National Taiwan University Hospital, Taipei,
      Taiwan.
AD  - National Center of Excellence for Clinical Trial and Research, National Taiwan
      University Hospital, Taipei, Taiwan.
FAU - Hung, M-H
AU  - Hung MH
AD  - Division of Hematology and Oncology, Department of Medicine, Taipei Veterans
      General Hospital, Taipei, Taiwan.
AD  - Program in Molecular Medicine, School of Life Sciences, National Yang-Ming
      University, Taipei, Taiwan.
FAU - Chu, P-Y
AU  - Chu PY
AD  - Department of Pathology, Show Chwan Memorial Hospital, Changhua City, Taiwan.
AD  - School of Medicine, College of Medicine, Fu Jen Catholic University, Xinzhuang
      Dist., New Taipei City, Taiwan.
FAU - Hsieh, F-S
AU  - Hsieh FS
AD  - Department of Medical Research, National Taiwan University Hospital, Taipei,
      Taiwan.
AD  - National Center of Excellence for Clinical Trial and Research, National Taiwan
      University Hospital, Taipei, Taiwan.
FAU - Lin, H
AU  - Lin H
AD  - Department of Medical Research, National Taiwan University Hospital, Taipei,
      Taiwan.
AD  - National Center of Excellence for Clinical Trial and Research, National Taiwan
      University Hospital, Taipei, Taiwan.
FAU - Yu, H-C
AU  - Yu HC
AD  - Department of Medical Research, National Taiwan University Hospital, Taipei,
      Taiwan.
AD  - National Center of Excellence for Clinical Trial and Research, National Taiwan
      University Hospital, Taipei, Taiwan.
FAU - Chen, K-F
AU  - Chen KF
AD  - Department of Medical Research, National Taiwan University Hospital, Taipei,
      Taiwan.
AD  - National Center of Excellence for Clinical Trial and Research, National Taiwan
      University Hospital, Taipei, Taiwan.
LA  - eng
SI  - GEO/GSE25097
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150126
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (STAT3 Transcription Factor)
RN  - 0 (STAT3 protein, human)
RN  - EC 3.1.3.48 (PTPN6 protein, human)
RN  - EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 6)
SB  - IM
EIN - Oncogene. 2017 Jul 17;:. PMID: 28714962
MH  - Animals
MH  - Carcinoma, Hepatocellular/*enzymology/secondary
MH  - Cell Line, Tumor
MH  - *Epithelial-Mesenchymal Transition
MH  - Humans
MH  - Liver Neoplasms/*enzymology/pathology
MH  - Lung Neoplasms/*enzymology/secondary
MH  - Mice, Nude
MH  - Neoplasm Transplantation
MH  - Protein Tyrosine Phosphatase, Non-Receptor Type 6/*physiology
MH  - STAT3 Transcription Factor/metabolism
EDAT- 2015/01/27 06:00
MHDA- 2016/01/09 06:00
CRDT- 2015/01/27 06:00
PHST- 2014/07/28 00:00 [received]
PHST- 2014/11/24 00:00 [revised]
PHST- 2014/12/05 00:00 [accepted]
PHST- 2015/01/27 06:00 [entrez]
PHST- 2015/01/27 06:00 [pubmed]
PHST- 2016/01/09 06:00 [medline]
AID - onc2014445 [pii]
AID - 10.1038/onc.2014.445 [doi]
PST - ppublish
SO  - Oncogene. 2015 Oct 8;34(41):5252-63. doi: 10.1038/onc.2014.445. Epub 2015 Jan 26.