PMID- 26467463
OWN - NLM
STAT- MEDLINE
DCOM- 20161020
LR  - 20161230
IS  - 1520-7560 (Electronic)
IS  - 1520-7552 (Linking)
VI  - 31
IP  - 8
DP  - 2015 Nov
TI  - Metformin affects the features of a human hepatocellular cell line (HepG2) by 
      regulating macrophage polarization in a co-culture microenviroment.
PG  - 781-9
LID - 10.1002/dmrr.2761 [doi]
AB  - OBJECTIVE: Accumulating evidence suggests an association between diabetes and 
      cancer. Inflammation is a key event that underlies the pathological processes of 
      the two diseases. Metformin displays anti-cancer effects, but the mechanism is 
      not completely clear. This study investigated whether metformin regulated the 
      microenvironment of macrophage polarization to affect the characteristics of 
      HepG2 cells and the possible role of the Notch-signalling pathway. METHODS: 
      RAW264.7 macrophages were cultured alone or co-cultured with HepG2 cells and 
      treated with metformin. We analysed classical (M1) and alternative (M2) gene 
      expression in RAW264.7 cells using quantitative real-time polymerase chain 
      reaction. Changes in mRNA and protein expressions of Notch signalling in both 
      cell types were also detected using quantitative real-time polymerase chain 
      reaction and Western-blotting analyses. The proliferation, apoptosis and 
      migration of HepG2 cells were detected using Cell Titer 96 AQueous One Solution 
      Cell Proliferation Assay (MTS) (Promega Corporation, Fitchburg, WI, USA), Annexin 
      V-FITC/PI (7SeaPharmTech, Shanghai, China) and the cell scratch assay, 
      respectively. RESULTS: Metformin induced single-cultured RAW264.7 macrophages 
      with an M2 phenotype but attenuated the M2 macrophage differentiation and 
      inhibited monocyte chemoattractant protein-1 (MCP-1) secretion in a co-culture 
      system. The co-cultured group of metformin pretreatment activated Notch 
      signalling in macrophages but repressed it inHepG2 cells. Co-culture also 
      promoted the proliferation and migration of HepG2 cells. However, along with the 
      enhanced apoptosis, the proliferation and the migration of HepG2 cells were 
      remarkably inhibited in another co-culture system with metformin pretreatment. 
      CONCLUSIONS: Metformin can skew RAW264.7 macrophages toward different phenotypes 
      according to changes in the microenvironment, which may affect the inflammatory 
      conditions mediated by macrophages, induce apoptosis and inhibit the 
      proliferation and migration of HepG2 cells. Notch signalling pathway is a 
      potentially important mechanism in the regulation of metformin on macrophage 
      polarization and the subsequent change of hepatoma cells. Copyright (c) 2015 John 
      Wiley & Sons, Ltd.
CI  - Copyright (c) 2015 John Wiley & Sons, Ltd.
FAU - Chen, Miaojiao
AU  - Chen M
AD  - Institute of Metabolism and Endocrinology, the Second Xiangya Hospital of Central 
      South University, Changsha, Hunan, China.
AD  - Diabetes Center of Central South University, Changsha, Hunan, China.
AD  - National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China.
FAU - Zhang, Jingjing
AU  - Zhang J
AD  - Institute of Metabolism and Endocrinology, the Second Xiangya Hospital of Central 
      South University, Changsha, Hunan, China.
AD  - Metabolic Syndrome Research Center, the Second Xiangya Hospital of Central South 
      University, Changsha, Hunan, China.
FAU - Hu, Fang
AU  - Hu F
AD  - Metabolic Syndrome Research Center, the Second Xiangya Hospital of Central South 
      University, Changsha, Hunan, China.
FAU - Liu, Shiping
AU  - Liu S
AD  - Institute of Metabolism and Endocrinology, the Second Xiangya Hospital of Central 
      South University, Changsha, Hunan, China.
AD  - Diabetes Center of Central South University, Changsha, Hunan, China.
AD  - National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China.
FAU - Zhou, Zhiguang
AU  - Zhou Z
AD  - Institute of Metabolism and Endocrinology, the Second Xiangya Hospital of Central 
      South University, Changsha, Hunan, China.
AD  - Diabetes Center of Central South University, Changsha, Hunan, China.
AD  - National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20151120
PL  - England
TA  - Diabetes Metab Res Rev
JT  - Diabetes/metabolism research and reviews
JID - 100883450
RN  - 0 (CCL2 protein, human)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Hypoglycemic Agents)
RN  - 9100L32L2N (Metformin)
SB  - IM
MH  - Apoptosis/drug effects
MH  - Cell Differentiation/drug effects
MH  - Cell Polarity/*drug effects
MH  - Chemokine CCL2/metabolism
MH  - Coculture Techniques
MH  - Hep G2 Cells
MH  - Humans
MH  - Hypoglycemic Agents/*pharmacology
MH  - Macrophages/cytology/*drug effects/metabolism
MH  - Metformin/*pharmacology
MH  - Signal Transduction/*drug effects
OTO - NOTNLM
OT  - Notch
OT  - hepatoma
OT  - inflammation
OT  - macrophage
OT  - metformin
OT  - polarization
EDAT- 2015/10/16 06:00
MHDA- 2016/10/21 06:00
CRDT- 2015/10/16 06:00
PHST- 2015/03/03 00:00 [received]
PHST- 2015/08/28 00:00 [revised]
PHST- 2015/10/09 00:00 [accepted]
PHST- 2015/10/16 06:00 [entrez]
PHST- 2015/10/16 06:00 [pubmed]
PHST- 2016/10/21 06:00 [medline]
AID - 10.1002/dmrr.2761 [doi]
PST - ppublish
SO  - Diabetes Metab Res Rev. 2015 Nov;31(8):781-9. doi: 10.1002/dmrr.2761. Epub 2015 
      Nov 20.