GREM2 maintains stem cell-like phenotypes in gastric cancer cells by regulating the JNK signaling pathway.

Gastric cancer (GC) is one of the major malignancies worldwide. This study was conducted to explore the mechanism by which GREM2 maintains biological properties of GC stem cells (GCSCs), and proved that GREM2 could potentially regulate the proliferation, apoptosis, invasion, migration and tumorigenic ability of GCSCs through the regulation of the JNK signaling pathway. In silico analysis was utilized to retrieve expression microarray related to GC, and differential analysis was conducted. The cell line with the highest GREM2 expression was overexpressed with GREM2 mimic, silencing GREM2 by siRNA, or treated with activator or inhibitor of the JNK signaling pathway. Subsequently, expression of GREM2, JNK signaling pathway-, apoptosis- or migration and invasion-associated factors were determined. Proliferation, migration, invasion, apoptosis of GCSCs in vitro and tumorigenic ability and lymph node metastasis of GCSCs in vivo were determined. Based on the in silico analysis of GSE49051, GREM2 was determined to be overexpressed in GC and its expression was the highest in the MKN-45 cell line, which was selected for the subsequent experiments. Silencing of GREM2 or inhibition of the JNK signaling pathway suppressed the proliferation, migration and invasion, while promoting apoptosis of GCSCs in vitro as well as inhibiting tumorigenesis and lymph node metastasis in vivo. In conclusion, the aforementioned findings suggest that the silencing of GREM2 suppresses the activation of the JNK signaling pathway, thereby inhibiting tumor progression. Therefore, GREM2-mediated JNK signaling pathway was expected to be a new therapeutic strategy for GC.