Phosphodiesterase 12 facilitates the growth and metastatic capabilities of gastric cancer cells by activating the TCAF2/JAK2/STAT3 axis
Phosphodiesterase 12 (PDE12), also known as 2-PDE, is a key molecule in the 2-5A antiviral system and a member of the endonuclease-exonuclease-phosphatase (EEP) superfamily of deadenylases. Current research on PDE12 mainly focuses on mitochondrial mRNA degradation, mitochondrial protein translation, and the related human diseases caused by mitochondrial oxidative phosphorylation disruption. However, the biological role and molecular mechanisms of PDE12 in human cancers remains unclear. Overall design: In the present study, we found that PDE12 was highly expressed in gastric cancer tissues and cell lines. Gain- and loss-of-function experiments confirmed that PDE12 promoted the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of gastric cancer cells. PDE12 knockdown also caused gastric cancer cell cycle arrest in G0/G1 phase by regulating the expression of G1 phase-specific Cyclins and CDKs. Our further studies indicated that PDE12 positively regulated the expression of TRPM8 channel-associated factor 2 (TCAF2), which functioned as an oncogene in gastric cancer. TCAF2 knockdown significantly suppressed gastric cancer cell proliferation, migration and invasion, and also reversed the promoting effect of PDE12 overexpression on the growth and metastasis of gastric cancer cells. Furthermore, our findings revealed a novel mechanism by which PDE12/TCAF2 axis promoted gastric cancer progression by activating the JAK2/STAT3 signaling pathway. Taken together, our data strongly indicate that PDE12 exerts an oncogenic function in gastric cancer progression at least partly via activating the TCAF2/JAK2/STAT3 signaling axis. These observations provide new insights into the tumorigenesis and metastasis of gastric cancer, and suggest that PDE12 may serve as a novel therapeutic target for gastric cancer.