Attenuated miR-181a2/181b2 expression predicted a poor prognostic phenotype and advanced clinical stage of cervical cancer. miR-181a2/181b2 prominently dampened cell-cycle progression, suppressed cell growth, and promoted apoptosis of tumor cells in vitro They also effectively impeded tumor formation and growth in vivo miR-181a2/181b2 exert the tumor suppressor ability by depressing the direct target PIK3R3 (p55γ) and consequently modulating the PIK3R3/Akt/FoxO signaling pathway.
Our study shows that the p53/miR-148b/p55PIK axis has an important role in cell proliferation and tumor growth, and may represent a novel therapeutic target for treating cancers containing p53 mutations or losses.
p55PIK, regulatory subunit of class IA phosphatidylinositol 3-kinase (PI3K), plays a crucial role in cell cycle progression by interaction with tumor repressor retinoblastoma (Rb) protein.
Moreover, a cell-permeable peptide containing the N-terminal-binding domain of p55PIK (TAT-N24) disrupted the p55PIK-PCNA interaction in cancer cells, and also inhibited the DNA synthesis and tumor growth in cell culture and in vivo.
PIK3R3 was significantly up-regulated in GC specimens (n = 126, p < 0.05), and 9.5 to 15% tumors showed more than 2 fold increase compare to the paired mucosa tissues.
TNF mRNA was found in epithelial tumor cells and infiltrating macrophages, whereas TNF protein localized primarily to a subpopulation of macrophages within and in close proximity to tumor areas. mRNA and protein for the p55 TNF receptor gene localized to the tumor epithelium and tumor, but not to stromal macrophages.