Network Analysis Reveals Tumor Suppressor lncRNA GAS5 Acts as a Double-edged Sword in Gastric Cancer

The lncRNA GAS5 acts as a tumor suppressor and is downregulated in gastric cancer (GC). In contrast, E2F1, an important transcription factor, and tumor promoter, directly inhibits miR-34c expression in GC cell lines. Furthermore, in the corresponding GC cell lines, lncRNA GAS5 directly targets E2F1. However, lncRNA GAS5 and miR-34c remain to be studied in conjunction with GC. Here, we present a dynamic Boolean network to classify gene regulation between these two non-coding RNAs in GC. This is the first study to show that lncRNA GAS5 can positively regulate miR-34c in GC through a previously unknown molecular pathway coupling lncRNA/miRNA. We compared our network to several in-vivo/in-vitro experiments and obtained an excellent agreement. We revealed that lncRNA GAS5 regulates miR-34c by targeting E2F1. Additionally, we found that lncRNA GAS5, independently of p53, inhibits GC proliferation through the ATM/p38 MAPK signaling pathway. These findings open a new avenue for GC treatment.