PMID- 27708244
OWN - NLM
STAT- MEDLINE
DCOM- 20180221
LR  - 20231213
IS  - 1949-2553 (Electronic)
IS  - 1949-2553 (Linking)
VI  - 7
IP  - 44
DP  - 2016 Nov 1
TI  - Hypoxia pathway and hypoxia-mediated extensive extramedullary hematopoiesis are 
      involved in ursolic acid's anti-metastatic effect in 4T1 tumor bearing mice.
PG  - 71802-71816
LID - 10.18632/oncotarget.12375 [doi]
AB  - Hypoxic in the tumor mass is leading to the myeloproliferative-like disease 
      (leukemoid reaction) and anemia of body, which characterized by strong extensive 
      extramedullary hematopoiesis (EMH) in spleen. As the key transcription factor of 
      hypoxia, hypoxia-inducible factor-1 (HIF-1) activates the expression of genes 
      essential for EMH processes including enhanced blood cell production and 
      angiogenesis. We found ursolic acid (UA), a natural pentacyclic triterpenoid 
      carboxylic acid, inhibited growth of breast cancer both in vivo and in vitro. The 
      suppression was mediated through the inhibition of multiple cell pathways linked 
      to inflammation, proliferation, angiogenesis, and metastasis. UA also suppressed 
      the leukemoid reaction and the EMH phenomenon of the tumor bearing mice without 
      any significant suppression on body weight (i.p. by 20 mg/kg for 28 days). This 
      is associated with the significant decrease in white blood cells (WBC), platelets 
      (PLT) and spleen weight. During this process, we also detected the 
      down-regulation of cell proliferative genes (PCNA, and beta-catenin), and metastatic 
      genes (VEGF, and HIF-1alpha), as well as the depression of nuclear protein intensity 
      of HIF-1alpha. Furthermore, the expression of E2F1, p53 and MDM2 genes were increased 
      in UA group when the VEGF and HIF-1alpha was over-expressed. Cancer cells were 
      sensitive to UA treating after the silencing of HIF-1alpha and the response of 
      Hypoxic pathway reporter to UA was suppressed when HIF-1alpha was over expressed. 
      Overall, our results from experimental and predictive studies suggest that the 
      anticancer activity of UA may be at least in part caused by suppressing the 
      cancer hypoxia and hypoxia-mediated EMH.
FAU - Gao, Jian-Li
AU  - Gao JL
AD  - Zhejiang Chinese Medical University, Hangzhou, 310053, China.
AD  - Molecular Oncology Laboratory, The University of Chicago Medical Center, Chicago, 
      IL 60637, USA.
FAU - Shui, Yan-Mei
AU  - Shui YM
AD  - Zhejiang Chinese Medical University, Hangzhou, 310053, China.
FAU - Jiang, Wei
AU  - Jiang W
AD  - Molecular Oncology Laboratory, The University of Chicago Medical Center, Chicago, 
      IL 60637, USA.
FAU - Huang, En-Yi
AU  - Huang EY
AD  - Chongqing Medical University, Chongqing 400016, China.
FAU - Shou, Qi-Yang
AU  - Shou QY
AD  - Zhejiang Chinese Medical University, Hangzhou, 310053, China.
FAU - Ji, Xin
AU  - Ji X
AD  - School of Medicine, Zhejiang University, Hangzhou, 310058, China.
FAU - He, Bai-Cheng
AU  - He BC
AD  - Chongqing Medical University, Chongqing 400016, China.
FAU - Lv, Gui-Yuan
AU  - Lv GY
AD  - Zhejiang Chinese Medical University, Hangzhou, 310053, China.
FAU - He, Tong-Chuan
AU  - He TC
AD  - Molecular Oncology Laboratory, The University of Chicago Medical Center, Chicago, 
      IL 60637, USA.
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Oncotarget
JT  - Oncotarget
JID - 101532965
RN  - 0 (Antineoplastic Agents)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Triterpenes)
RN  - EC 2.3.2.27 (Von Hippel-Lindau Tumor Suppressor Protein)
RN  - EC 6.3.2.- (VHL protein, human)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/*pharmacology
MH  - Apoptosis/drug effects
MH  - Cell Hypoxia
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Female
MH  - *Hematopoiesis, Extramedullary/physiology
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/analysis
MH  - Lung Neoplasms/prevention & control/secondary
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Neoplasms, Experimental/blood supply/*drug therapy/pathology
MH  - Neovascularization, Pathologic/prevention & control
MH  - Signal Transduction/drug effects
MH  - Triterpenes/*pharmacology
MH  - Von Hippel-Lindau Tumor Suppressor Protein/genetics
MH  - Ursolic Acid
PMC - PMC5342124
OTO - NOTNLM
OT  - breast cancer
OT  - extensive extramedullary hematopoiesis
OT  - hypoxic pathway
OT  - metastasis
OT  - ursolic acid
COIS- CONFLICTS OF INTEREST The authors declare that there are no conflicts of 
      interest.
EDAT- 2016/10/07 06:00
MHDA- 2018/02/22 06:00
PMCR- 2016/11/01
CRDT- 2016/10/07 06:00
PHST- 2016/03/29 00:00 [received]
PHST- 2016/09/24 00:00 [accepted]
PHST- 2016/10/07 06:00 [pubmed]
PHST- 2018/02/22 06:00 [medline]
PHST- 2016/10/07 06:00 [entrez]
PHST- 2016/11/01 00:00 [pmc-release]
AID - 12375 [pii]
AID - 10.18632/oncotarget.12375 [doi]
PST - ppublish
SO  - Oncotarget. 2016 Nov 1;7(44):71802-71816. doi: 10.18632/oncotarget.12375.