PMID- 28894280
OWN - NLM
STAT- MEDLINE
DCOM- 20190613
LR  - 20211204
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 7
IP  - 1
DP  - 2017 Sep 11
TI  - Hypoxia-induced ANGPTL4 sustains tumour growth and anoikis resistance through 
      different mechanisms in scirrhous gastric cancer cell lines.
PG  - 11127
LID - 10.1038/s41598-017-11769-x [doi]
LID - 11127
AB  - Patients with scirrhous gastric cancer (SGC) frequently develop peritoneal 
      dissemination, which leads to poor prognosis. The secreted protein 
      angiopoietin-like-4 (ANGPTL4), which is induced by hypoxia, exerts diverse 
      effects on cancer progression. Here, we aimed to determine the biological 
      function of ANGPTL4 in SGC cells under hypoxia. ANGPTL4 levels were higher in SGC 
      cells under hypoxia than in other types of gastric cancer cells. Hypoxia-induced 
      ANGPTL4 mRNA expression was regulated by hypoxia-inducible factor-1alpha (HIF-1alpha). 
      Under hypoxic conditions, monolayer cultures of ANGPTL4 knockdown (KD) 58As9 SGC 
      (58As9-KD) cells were arrested in the G(1) phase of the cell cycle through 
      downregulation of c-Myc and upregulation of p27, in contrast to control 58As9-SC 
      cells. Moreover, the ability of 58As9-KD xenografts to form tumours in nude mice 
      was strongly suppressed. When 58As9-KD cells were cultured in suspension, hypoxia 
      strongly increased their susceptibility to anoikis through suppression of the 
      FAK/Src/PI3K-Akt/ERK pro-survival pathway, followed by activation of the 
      apoptotic factors caspases-3, -8 and -9. The development of peritoneal 
      dissemination by 58As9-KD cells was completely inhibited compared with that by 
      58As9-SC cells. In conclusion, ANGPTL4 is uniquely induced by hypoxia in cultured 
      SGC cells and is essential for tumour growth and resistance to anoikis through 
      different mechanisms.
FAU - Baba, Koichi
AU  - Baba K
AD  - Department of Surgery, Saga University Faculty of Medicine, 5-1-1, Nabeshima, 
      Saga-shi, Saga, 849-8501, Japan.
FAU - Kitajima, Yoshihiko
AU  - Kitajima Y
AUID- ORCID: 0000-0002-2857-954X
AD  - Department of Surgery, Saga University Faculty of Medicine, 5-1-1, Nabeshima, 
      Saga-shi, Saga, 849-8501, Japan. kitajiy@hosp.go.jp.
AD  - Department of Surgery, National Hospital Organization Higashisaga Hospital, 7324, 
      Ooaza Harakoga, Miyaki-cho, Miyaki-gun, Saga, 849-0101, Japan. 
      kitajiy@hosp.go.jp.
FAU - Miyake, Shuusuke
AU  - Miyake S
AD  - Department of Surgery, Saga University Faculty of Medicine, 5-1-1, Nabeshima, 
      Saga-shi, Saga, 849-8501, Japan.
FAU - Nakamura, Jun
AU  - Nakamura J
AD  - Department of Surgery, Saga University Faculty of Medicine, 5-1-1, Nabeshima, 
      Saga-shi, Saga, 849-8501, Japan.
FAU - Wakiyama, Kota
AU  - Wakiyama K
AD  - Department of Surgery, Saga University Faculty of Medicine, 5-1-1, Nabeshima, 
      Saga-shi, Saga, 849-8501, Japan.
FAU - Sato, Hirofumi
AU  - Sato H
AD  - Department of Surgery, Saga University Faculty of Medicine, 5-1-1, Nabeshima, 
      Saga-shi, Saga, 849-8501, Japan.
FAU - Okuyama, Keiichiro
AU  - Okuyama K
AD  - Department of Surgery, Saga University Faculty of Medicine, 5-1-1, Nabeshima, 
      Saga-shi, Saga, 849-8501, Japan.
FAU - Kitagawa, Hiroshi
AU  - Kitagawa H
AD  - Department of Surgery, Saga University Faculty of Medicine, 5-1-1, Nabeshima, 
      Saga-shi, Saga, 849-8501, Japan.
FAU - Tanaka, Tomokazu
AU  - Tanaka T
AD  - Department of Surgery, Saga University Faculty of Medicine, 5-1-1, Nabeshima, 
      Saga-shi, Saga, 849-8501, Japan.
FAU - Hiraki, Masatsugu
AU  - Hiraki M
AD  - Department of Surgery, Saga-ken Medical Centre Koseikan, 400, Ooaza Nakahara, 
      Kase-machi, Saga-shi, Saga, 840-8571, Japan.
FAU - Yanagihara, Kazuyoshi
AU  - Yanagihara K
AD  - Division of Translational Research, Exploratory Oncology Research & Clinical 
      Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa-shi, Chiba, 
      277-8577, Japan.
FAU - Noshiro, Hirokazu
AU  - Noshiro H
AD  - Department of Surgery, Saga University Faculty of Medicine, 5-1-1, Nabeshima, 
      Saga-shi, Saga, 849-8501, Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20170911
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (ANGPTL4 protein, human)
RN  - 0 (Angiopoietin-Like Protein 4)
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (RNA, Messenger)
SB  - IM
MH  - Angiopoietin-Like Protein 4/genetics/*metabolism
MH  - Animals
MH  - *Anoikis/genetics
MH  - Apoptosis/genetics
MH  - Biomarkers, Tumor
MH  - Cell Hypoxia
MH  - Cell Line, Tumor
MH  - Cell Proliferation
MH  - Disease Models, Animal
MH  - Gene Expression
MH  - Heterografts
MH  - Humans
MH  - Hypoxia/*metabolism
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
MH  - Mice
MH  - Neoplasm Metastasis
MH  - Neoplasm Staging
MH  - RNA, Messenger/genetics
MH  - Signal Transduction
MH  - Stomach Neoplasms/genetics/metabolism/pathology
PMC - PMC5594024
COIS- The authors declare that they have no competing interests.
EDAT- 2017/09/13 06:00
MHDA- 2019/06/14 06:00
PMCR- 2017/09/11
CRDT- 2017/09/13 06:00
PHST- 2016/09/06 00:00 [received]
PHST- 2017/07/18 00:00 [accepted]
PHST- 2017/09/13 06:00 [entrez]
PHST- 2017/09/13 06:00 [pubmed]
PHST- 2019/06/14 06:00 [medline]
PHST- 2017/09/11 00:00 [pmc-release]
AID - 10.1038/s41598-017-11769-x [pii]
AID - 11769 [pii]
AID - 10.1038/s41598-017-11769-x [doi]
PST - epublish
SO  - Sci Rep. 2017 Sep 11;7(1):11127. doi: 10.1038/s41598-017-11769-x.