Overexpression of NRG1 promotes progression of gastric cancer by regulating the self-renewal of cancer stem cells.
BACKGROUND
Gastric cancer stem cells (GCSCs) have been successfully isolated from patients. However, the molecular mechanisms underlying the self-renewal of GCSCs and their relationship with the microenvironment are poorly characterized.


METHODS
GCSCs and cancer-associated fibroblasts (CAFs) were cultured directly from gastric cancer patients. The self-renewal of GCSCs was assayed by sphere formation assay and in vivo tumorigenicity. Expression of neuregulin1 (NRG1) was examined by immunohistochemistry, real-time PCR and western blotting.


RESULTS
CAFs increased the self-renewal of GCSCs by secreting NRG1. NRG1 activated NF-κB signaling and this activation regulated GCSC self-renewal. Moreover, NF-κB-active GCSCs were tumorigenic, however NF-κB-inactive GCSCs were not. The overexpression of NRG1 in stromal cells and cancer cells was observed in the tumor tissues of gastric cancer patients and was associated with clinical stage lymph node metastasis and survival in gastric cancer patients. In addition, we also found that NRG1 can regulate the proliferation and invasion of gastric cancer cells.


CONCLUSIONS
These results indicate that NRG1, which can be secreted by CAFs or cancer cells, promotes progression of gastric cancer by regulating the self-renewal of GCSCs and its overexpression is associated with a prognosis of gastric cancer.
Department of Anatomy, School of Medicine, Pusan National University, Beomeo-Ri, Mulgeum-Eup, Yangsan, 626-870, South Korea.
Myoung-Eun
ME
Han
Hyun-Jung
HJ
Kim
Dong Hoon
DH
Shin
Sun-Hwi
SH
Hwang
Chi-Dug
CD
Kang
Sae-Ock
SO
Oh
D000368:Aged; D015153:Blotting, Western; D049109:Cell Proliferation / Q000502:physiology; D000066673:Cell Self Renewal / Q000502:physiology*; D018450:Disease Progression; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D009367:Neoplasm Staging; D014411:Neoplastic Stem Cells / Q000166:cytology*; D020890:Neuregulin-1 / Q000235:genetics*; D011379:Prognosis; D060888:Real-Time Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000235:genetics / Q000473:pathology*; D059016:Tumor Microenvironment / Q000502:physiology
D016328:NF-kappa B; C094131:NRG1 protein, human; D020890:Neuregulin-1