Overexpression of NRG1 promotes progression of gastric cancer by regulating the self-renewal of cancer stem cells

• Published in: Journal of gastroenterology 2015-06, Vol.50 (6), p.645-656
• Main Authors: Han, Myoung-Eun, Kim, Hyun-Jung, Shin, Dong Hoon, Hwang, Sun-Hwi, Kang, Chi-Dug, Oh, Sae-Ock
• Format: Article
• Language: English
• Subjects: Abdominal Surgery; Aged; Blotting, Western; Cell Proliferation - physiology; Cell Self Renewal - physiology; Colorectal Surgery; Development and progression; Disease Progression; Female; Fibroblasts - cytology; Gastroenterology; Gene Expression Regulation, Neoplastic; Hepatology; Humans; Immunohistochemistry; Lymphatic Metastasis; Male; Medicine; Medicine & Public Health; Middle Aged; Neoplasm Staging; Neoplastic Stem Cells - cytology; Neuregulin-1 - genetics; NF-kappa B - metabolism; Original Article—Alimentary Tract; Prognosis; Real-Time Polymerase Chain Reaction; Stem cell research; Stem cells; Stomach cancer; Stomach Neoplasms - genetics; Stomach Neoplasms - pathology; Surgical Oncology; Tumor Microenvironment - physiology
• ISSN: 0944-1174; 1435-5922
• DOI: 10.1007/s00535-014-1008-1

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.