Abstract
The general mechanism for microRNAs to play biological function is through their inhibition on the expression of their target genes. In cancer, microRNAs may accelerate cell senescence, block angiogenesis, decrease energy supplies, repress tumor cell cycle and promote apoptosis to function as the tumor repressors. On the other hand, microRNAs can modulate tumor suppressor molecules to activate oncogene relevant signaling pathway to initiate tumorigenesis and promote tumor progression. By targeting different genes, miR-22 can function as either a tumor suppressor or a tumor promoter in different types of cancer. In liver cancer, miR-22 mainly functions as a tumor suppressor via its regulation on different genes. In this study, we demonstrated that miR-22 indirectly regulates SPRY2 by inhibiting CBL, an E3 ligase for SPRY2 that has been confirmed. As one of the modulators of the MAPK (mitogen-activated protein kinase)/ERK (extracellular signal-regulated kinase) signaling pathway, SPRY2 plays important roles in many developmental and physiological processes, and its deregulation has been reported in different types of cancer and shown to affect cancer development, progression, and metastasis. By inhibiting the expression of CBL, which stabilizes SPRY2, miR-22 indirectly upregulates SPRY2, thereby suppressing the epithelial-mesenchymal transition (EMT), cell migration, and invasion and decreasing the expression of liver cancer stem cell (CSC) marker genes. The inhibitory effects of miR-22 on EMT, cell migration, and invasion can be blocked by the knockdown of SPRY2 expression in miR-22 overexpressing cells. Additionally, we demonstrated that miR-22 expression inhibits the ERK signaling pathway and that this effect is due to its upregulation of SPRY2. Overall, our study revealed a novel miR-22-3p/CBL/SPRY2/ERK axis that plays an important role in EMT, cell migration, and invasion of liver cancer cells.