PMID- 32627027
OWN - NLM
STAT- MEDLINE
DCOM- 20210309
LR  - 20211022
IS  - 1791-2431 (Electronic)
IS  - 1021-335X (Linking)
VI  - 44
IP  - 1
DP  - 2020 Jul
TI  - Metformin inhibits TGF‑beta1‑induced epithelial‑mesenchymal transition and liver 
      metastasis of pancreatic cancer cells.
PG  - 371-381
LID - 10.3892/or.2020.7595 [doi]
AB  - Epithelial‑mesenchymal transition (EMT) is considered a crucial event in the 
      development of cancer metastasis. Metformin is a drug used in the treatment of 
      type 2 diabetes. Recently, increasing evidence has indicated that metformin 
      possesses anti‑tumor activities. However, the effects of metformin on EMT and 
      metastases in pancreatic cancer remain unknown. Thus, the present study 
      investigated whether metformin inhibits EMT of human pancreatic cancer cell 
      lines. Pancreatic cancer cells were stimulated with transforming growth factor beta1 
      (TGF‑beta1), an activator of EMT signaling, with or without metformin. After 48 h, 
      the levels of epithelial and mesenchymal markers were evaluated by western blot 
      analysis, immunocytochemistry and RT‑qPCR. Cancer cell migration was evaluated by 
      an in vitro wound healing assay. The cells stimulated with TGF‑beta1 acquired an 
      elongated and fusiform morphology, which was inhibited by metformin. The wound 
      healing assay revealed that metformin significantly suppressed the 
      TGF‑beta1‑stimulated migration of pancreatic cancer cells. Following treatment with 
      metformin, E‑cadherin expression (epithelial marker) was upregulated, and the 
      levels of mesenchymal markers were downregulated, which had been increased by 
      TGF‑beta1 in these cells. Exposure of the cells to TGF‑beta1 activated the Smad2/3 and 
      Akt/mammalian target of rapamycin (mTOR) pathways, and this effect was inhibited 
      by metformin, suggesting that metformin inhibits TGF‑beta1‑induced‑EMT through the 
      down‑regulation of the Smad pathway in PANC‑1 cells and the downregulation of the 
      Akt/mTOR pathway in BxPC‑3 cells. In an animal model of surgical orthotopic 
      implantation, metformin inhibited liver metastasis without a significant 
      reduction in the size of the primary pancreatic tumor. On the whole, the findings 
      of the present study suggest that metformin inhibits EMT and cancer metastasis 
      through the Smad or Akt/mTOR pathway.
FAU - Yoshida, Juichiro
AU  - Yoshida J
AD  - Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural 
      University of Medicine, Kyoto 602‑8566, Japan.
FAU - Ishikawa, Takeshi
AU  - Ishikawa T
AD  - Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural 
      University of Medicine, Kyoto 602‑8566, Japan.
FAU - Endo, Yuki
AU  - Endo Y
AD  - Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural 
      University of Medicine, Kyoto 602‑8566, Japan.
FAU - Matsumura, Shinya
AU  - Matsumura S
AD  - Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural 
      University of Medicine, Kyoto 602‑8566, Japan.
FAU - Ota, Takayuki
AU  - Ota T
AD  - Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural 
      University of Medicine, Kyoto 602‑8566, Japan.
FAU - Mizushima, Katsura
AU  - Mizushima K
AD  - Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural 
      University of Medicine, Kyoto 602‑8566, Japan.
FAU - Hirai, Yasuko
AU  - Hirai Y
AD  - Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural 
      University of Medicine, Kyoto 602‑8566, Japan.
FAU - Oka, Kaname
AU  - Oka K
AD  - Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural 
      University of Medicine, Kyoto 602‑8566, Japan.
FAU - Okayama, Tetsuya
AU  - Okayama T
AD  - Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural 
      University of Medicine, Kyoto 602‑8566, Japan.
FAU - Sakamoto, Naoyuki
AU  - Sakamoto N
AD  - Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural 
      University of Medicine, Kyoto 602‑8566, Japan.
FAU - Inoue, Ken
AU  - Inoue K
AD  - Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural 
      University of Medicine, Kyoto 602‑8566, Japan.
FAU - Kamada, Kazuhiro
AU  - Kamada K
AD  - Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural 
      University of Medicine, Kyoto 602‑8566, Japan.
FAU - Uchiyama, Kazuhiko
AU  - Uchiyama K
AD  - Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural 
      University of Medicine, Kyoto 602‑8566, Japan.
FAU - Takagi, Tomohisa
AU  - Takagi T
AD  - Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural 
      University of Medicine, Kyoto 602‑8566, Japan.
FAU - Naito, Yuji
AU  - Naito Y
AD  - Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural 
      University of Medicine, Kyoto 602‑8566, Japan.
FAU - Itoh, Yoshito
AU  - Itoh Y
AD  - Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural 
      University of Medicine, Kyoto 602‑8566, Japan.
LA  - eng
PT  - Journal Article
DEP - 20200423
PL  - Greece
TA  - Oncol Rep
JT  - Oncology reports
JID - 9422756
RN  - 0 (Antigens, CD)
RN  - 0 (CDH1 protein, human)
RN  - 0 (Cadherins)
RN  - 0 (Transforming Growth Factor beta1)
RN  - 9100L32L2N (Metformin)
SB  - IM
MH  - Animals
MH  - Antigens, CD/*genetics
MH  - Cadherins/*genetics
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Cell Survival/drug effects
MH  - Epithelial-Mesenchymal Transition/drug effects
MH  - Female
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Humans
MH  - Liver Neoplasms/*drug therapy/genetics/metabolism/*secondary
MH  - Metformin/*administration & dosage/pharmacology
MH  - Mice
MH  - Pancreatic Neoplasms/*drug therapy/genetics/metabolism
MH  - Signal Transduction/drug effects
MH  - Transforming Growth Factor beta1/*pharmacology
MH  - Xenograft Model Antitumor Assays
OTO - NOTNLM
OT  - epithelial-mesenchymal transition
OT  - metformin
OT  - pancreatic cancer
OT  - transforming growth factor beta1
OT  - liver metastasis
EDAT- 2020/07/07 06:00
MHDA- 2021/03/10 06:00
CRDT- 2020/07/07 06:00
PHST- 2019/09/15 00:00 [received]
PHST- 2020/03/26 00:00 [accepted]
PHST- 2020/07/07 06:00 [entrez]
PHST- 2020/07/07 06:00 [pubmed]
PHST- 2021/03/10 06:00 [medline]
AID - 10.3892/or.2020.7595 [doi]
PST - ppublish
SO  - Oncol Rep. 2020 Jul;44(1):371-381. doi: 10.3892/or.2020.7595. Epub 2020 Apr 23.