Cullin 4A (CUL4A), A Direct Target Of MiR-9 And MiR-137, Promotes Gastric Cancer Proliferation And Invasion By Regulating The Hippo Signaling Pathway

Although Cullin 4A(CUL4A) is mutated or amplified in several human cancer types, its potential role in gastric cancer(GC) and the mechanisms underlying its regulation remain largely uncharacterized. In the present study, we report that CUL4 A was markedly overexpressed in GC cells and in tissues from clinical patients. The expression of CUL4 A significantly correlated with the clinical stage of the tumor and lymph node metastasis, and GC patients with higher levels of CUL4 A had lower survival rates than patients with lower CUL4 A levels. The upregulation of CUL4 A promoted GC cell proliferation, epithelial-mesenchymal transition(EMT), and invasion by downregulating LATS1-Hippo-YAP signaling, a tumor suppressor signaling pathway. Knocking down CUL4 A had the opposite effect in vitro and in vivo. Interestingly, a significant positive correlation between CUL4 A expression and aberrant nuclear YAP distribution were observed in GC tissues. CUL4 A expression was regulated by the microRNAs(miRNAs), miR-9 and miR-137, which directly targeted the 3’-UTR of CUL4 A. Overexpression of miR-9 and miR-137 downregulated the CUL4A-LATS1-Hippo signaling pathway and suppressed GC cell proliferation and invasion in vitro. Taken together, our findings demonstrate that perturbations to miR-9/137-CUL4A-Hippo signaling contribute to gastric tumorigenesis, and suggest potential therapeutic targets for the future treatment of GC.