A negative feedback loop between long noncoding RNA NBAT1 and Sox9 inhibits the malignant progression of gastric cancer cells

Abstract

Long noncoding RNAs (lncRNAs) play critical roles in carcinogenesis and progression, and act as important gene expression modulators. Recent evidence indicates that lncRNA neuroblastoma associated transcript 1 (NBAT1) functions as a tumor suppressor in some types of human cancers. However, its functional role in the development of gastric cancer (GC) remains unknown. The aim of this research was to investigate the clinical significance and biological functions of NBAT1 in GC. NBAT1 was found to be significantly down-regulated in GC tissue. Decreased NBAT1 expression was correlated with poor differentiation, higher tumor stage and lymph node metastasis, and poor prognosis. Functional assays showed that NBAT1 inhibited GC proliferation, migration, and invasion. NBAT1 also suppressed proliferation, migration, and capillary tube formation of human umbilical vein endothelial cells (HUVECs). Mechanistically, NBAT1 interacted with Sox9, and reduced its protein stability by promoting it from polyubiquitination and proteasome-dependent degradation. Moreover, we revealed that Sox9 could occupy the NBAT1 promoter to inactivate its transcription. The negative feedback loop of NBAT1 and Sox9 continuously enhanced the suppressive effects. In conclusion, these findings suggest that feedback regulation of NBAT1 and Sox9 served as a critical effector in GC progression.