The ANXA2P1-hnRNP F-HK2/c-Myc Positive Feedback Loop Promotes Proliferation and Glycolytic Metabolism in Gastric Cancer.

Pseudogene-derived long non-coding RNAs (lncRNAs) contribute to carcinogenesis. However, the role of the pseudogene ANXA2P1 in gastric cancer (GC) growth and glucose metabolism remains unknown. Analysis of microarray and RNA sequencing (RNA-seq) reveals that ANXA2P1 is increased upon glucose starvation in GC cells and displays elevated expression in GC. Moreover, ANXA2P1 overexpression promotes proliferation and metastasis by enhancing aerobic glycolysis in GC. Mechanistically, ANXA2P1 binds to the RNA-binding protein hnRNP F and promotes proximal polyadenylation site usage of HK2, thereby generating a short 3'UTR isoform with enhanced stability. Consequently, elevated HK2 expression accelerates GC proliferation and metabolic reprogramming. Interestingly, HK2 exerts a non-metabolic role by serving as a co-activator of transcription factor c-Myc to collaboratively drive ANXA2P1 expression. Clinically, ANXA2P1, hnRNP F, HK2, and c-Myc were augmented in specimens from GC patients compared to matched normal gastric mucosa. This study illustrates that ANXA2P1 is considered an oncogene, and the ANXA2P1-hnRNP F-HK2/c-Myc positive feedback loop may act as a potential therapeutic target for GC.