PMID- 31119158
OWN - NLM
STAT- MEDLINE
DCOM- 20191114
LR  - 20220408
IS  - 2314-6141 (Electronic)
IS  - 2314-6133 (Print)
VI  - 2019
DP  - 2019
TI  - The Nutritional Cytokine Leptin Promotes NSCLC by Activating the PI3K/AKT and 
      MAPK/ERK Pathways in NSCLC Cells in a Paracrine Manner.
PG  - 2585743
LID - 10.1155/2019/2585743 [doi]
LID - 2585743
AB  - PURPOSE: Leptin is a nutritional cytokine encoded by the obesity gene whose 
      concentration in the tumor microenvironment is closely related to the occurrence 
      and progression of cancer. However, previous evidence has suggested that there is 
      no clear relationship between serum leptin concentrations and lung cancer 
      progression. Cancer-associated fibroblasts (CAFs), the most abundant component of 
      the tumor microenvironment in a variety of solid tumors, were recently reported 
      to produce leptin. Therefore, it was inferred that leptin is most likely to 
      affect non-small-cell lung cancer (NSCLC) through an autocrine and paracrine 
      mechanism. In the current study, we investigated the paracrine effect and 
      mechanism of leptin produced by CAFs on NSCLC by establishing a novel in vitro 
      cell coculture system. METHODS: A noncontact coculture device was designed and 
      made by 3D printing. CAFs and paired normal lung fibroblasts (NLFs) from 5 
      patients were successfully isolated and cocultured with two NSCLC cell lines in a 
      coculture system. The background expression of leptin was detected by western 
      blot. The in situ expression of leptin and its receptor (Ob-R) in NSCLC tissues 
      and paired normal lung tissues was analyzed by immunohistochemistry. Furthermore, 
      we downregulated the expression of leptin in CAFs and assessed changes in its 
      promotion on NSCLC cells in the coculture system. Finally, changes in the 
      phosphorylation of ERK1/2 and AKT were examined to investigate the molecular 
      mechanisms responsible for the paracrine promotion of NSCLC cells by leptin. 
      RESULTS: Leptin was overexpressed in nearly all five primary CAF lines compared 
      with its expression in paired NLFs. IHC staining showed that the expression of 
      leptin was high in NSCLC cells, slightly lower in CAF, and negative in normal 
      lung tissue. Ob-R was strongly expressed in NSCLC cells. The ability of A549 and 
      H1299 cells to proliferate and migrate was enhanced by high leptin levels in both 
      the cocultured fibroblasts and the culture medium. Furthermore, western blot 
      assays suggested that the MAPK/ERK1/2 and PI3K/AKT signaling pathways were 
      activated by leptin produced by CAFs, which demonstrated that the functions of 
      paracrine leptin in NSCLC are as those of the serum leptin to other cancers. 
      CONCLUSION: Leptin produced by CAF promotes proliferation and migration of NSCLC 
      cells probably via PI3K/AKT and MAPK/ERK1/2 signaling pathways in a paracrine 
      manner.
FAU - Li, Fengzhou
AU  - Li F
AUID- ORCID: 0000-0002-4902-2820
AD  - Department of Thoracic Surgery, The First Affiliated Hospital of Dalian Medical 
      University, Dalian, Liaoning 116011, China.
AD  - Lung Cancer Diagnosis and Treatment Center, Dalian 116011, Liaoning, China.
FAU - Zhao, Shilei
AU  - Zhao S
AD  - Department of Thoracic Surgery, The First Affiliated Hospital of Dalian Medical 
      University, Dalian, Liaoning 116011, China.
AD  - Lung Cancer Diagnosis and Treatment Center, Dalian 116011, Liaoning, China.
FAU - Guo, Tao
AU  - Guo T
AD  - Department of Thoracic Surgery, The First Affiliated Hospital of Dalian Medical 
      University, Dalian, Liaoning 116011, China.
AD  - Lung Cancer Diagnosis and Treatment Center, Dalian 116011, Liaoning, China.
FAU - Li, Jinxiu
AU  - Li J
AUID- ORCID: 0000-0001-7303-1498
AD  - Lung Cancer Diagnosis and Treatment Center, Dalian 116011, Liaoning, China.
FAU - Gu, Chundong
AU  - Gu C
AUID- ORCID: 0000-0002-2981-6578
AD  - Department of Thoracic Surgery, The First Affiliated Hospital of Dalian Medical 
      University, Dalian, Liaoning 116011, China.
AD  - Lung Cancer Diagnosis and Treatment Center, Dalian 116011, Liaoning, China.
LA  - eng
PT  - Journal Article
DEP - 20190418
PL  - United States
TA  - Biomed Res Int
JT  - BioMed research international
JID - 101600173
RN  - 0 (Leptin)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
SB  - IM
MH  - Cancer-Associated Fibroblasts/drug effects/metabolism
MH  - Carcinoma, Non-Small-Cell Lung/*diet therapy/genetics/pathology
MH  - Cell Line, Tumor
MH  - Cell Movement/drug effects
MH  - Cell Proliferation/*drug effects
MH  - Coculture Techniques
MH  - Humans
MH  - Leptin/genetics/metabolism/*pharmacology
MH  - MAP Kinase Signaling System/drug effects
MH  - Paracrine Communication/*drug effects/genetics
MH  - Phosphatidylinositol 3-Kinases/genetics
MH  - Proto-Oncogene Proteins c-akt/genetics
MH  - Tumor Microenvironment/drug effects
PMC - PMC6500706
EDAT- 2019/05/24 06:00
MHDA- 2019/11/15 06:00
PMCR- 2019/04/18
CRDT- 2019/05/24 06:00
PHST- 2019/01/28 00:00 [received]
PHST- 2019/03/26 00:00 [revised]
PHST- 2019/04/08 00:00 [accepted]
PHST- 2019/05/24 06:00 [entrez]
PHST- 2019/05/24 06:00 [pubmed]
PHST- 2019/11/15 06:00 [medline]
PHST- 2019/04/18 00:00 [pmc-release]
AID - 10.1155/2019/2585743 [doi]
PST - epublish
SO  - Biomed Res Int. 2019 Apr 18;2019:2585743. doi: 10.1155/2019/2585743. eCollection 
      2019.