Abstract
Growing evidence have shown that the migration and invasion inhibitory protein (MIIP, also known as IIp45) functions as a tumor suppressor and its expression is downregulated in several types of cancer, yet the function of MIIP in prostate cancer (PCa) and the underlying mechanism of action remains largely unknown. Here we demonstrated that MIIP acts as a suppressor of PCa by inhibiting epithelial-mesenchymal transition (EMT) and cell invasion. Overexpressing MIIP repressed cellular invasion of PC3 and DU145 in vitro, accompanied by a decrease of EMT-inducing factors, and an increase of E-cadherin and KLF17. Moreover, a stable MIIP knockdown in PCa cells promoted the tumor growth or bone osteolytic lesions, when xenografted subcutaneously or via tibia injection. Mechanistically, MIIP represses two onco-miRNAs, miR-181a-5p and miR-181b-5p, thus removing the inhibitory effect of these two miRNAs on their target KLF17, which functions as a negative regulator of EMT by directly suppressing the transcription of SNAIL1/2 and TWIST. Finally, by examining the expression of MIIP, miR-181a/b-5p, KLF17, and E-cadherin in paired cancer samples v.s. adjacent normal tissues from a cohort of human prostate cancer patients, we demonstrated that downregulation of MIIP was well associated with downregulation of KLF17 and E-cadherin, but upregulation of miR-181a/b-5p. The positive correlation between MIIP and KLF17 was also confirmed via immunohistochemical staining of a PCa tissue microarray. Taken together, our findings reveal a novel function of MIIP as an EMT inhibitor in PCa and illustrate the underlying molecular mechanisms, providing new insights into the tumor-suppressor role of MIIP.