Downregulation of microRNA-224-3p hampers retinoblastoma progression via activation of the Hippo-YAP signaling pathway by increasing LATS2

Abstract

PURPOSE. The pivotal role of microRNAs (miRNAs or miRs) has been proved in the pathogenesis of retinoblastoma. miR-224-3p is demonstrated to be involved in several tumors. However, the underlying mechanism of miR-224-3p in retinoblastoma is yet to be investigated. Therefore, this study was designed to identify the regulation of miR-224-3p in human retinoblastoma. METHODS. The expression pattern of miR-224-3p and large tumor suppressor 2 (LATS2) in retinoblastoma was measured by reverse transcription quantitative polymerase chain reaction. Afterward, the interaction between miR-224-3p and LATS2 was identified using a dual luciferase reporter gene assay. Next, gain-of-function and loss-of-function approaches were employed to examine the effects of miR-224-3p and LATS2 as well as their interaction on cell apoptosis, proliferation and angiogenesis abilities, and tumorigenesis. Whether the Hippo-YAP signaling pathway was involved in tumorigenesis was analyzed by determining downstream genes. RESULTS. LATS2 was downregulated in retinoblastoma, and its overexpression promoted apoptosis and suppressed proliferation of retinoblastoma cells. miR-224-3p, highly expressed in retinoblastoma, inhibited the expression of its target gene LATS2, which inhibited activation of the Hippo-YAP signaling pathway. Suppression of miR-224-3p promoted apoptosis while suppressing the proliferation of retinoblastoma cells and angiogenesis. Tumor progression induced by upregulation of miR-224-3p was diminished by restoration of LATS2. It was observed that tumor growth and angiogenesis were reduced by depleted miR-224-3p in the animal experiments. CONCLUSIONS. The present study suggests that miR-224-3p targets LATS2 and blocks the Hippo-YAP signaling pathway activation, thus preventing the progression of retinoblastoma, which could be a new therapeutic target for retinoblastoma.