RESUMEN
TEAD3 acts as a transcription factor in many tumors to promote tumor occurrence and development. But in prostate cancer (PCa), it appears as a tumor suppressor gene. Recent studies have shown that this may be related to subcellular localization and posttranslational modification. We found that TEAD3 was down-expressed in PCa. Immunohistochemistry of clinical PCa specimens confirmed that TEAD3 expression was the highest in benign prostatic hyperplasia (BPH) tissues, followed by primary PCa tissues, and the lowest in metastatic PCa tissues, and its expression level was positively correlated with overall survival. MTT assay, clone formation assay, and scratch assay confirmed that overexpression of TEAD3 could significantly inhibit the proliferation and migration of PCa cells. Next-generation sequencing results indicated that Hedgehog (Hh) signaling pathway was significantly inhibited after overexpression of TEAD3. Rescue assays suggested that ADRBK2 could reverse the proliferation and migration ability caused by overexpression of TEAD3. TEAD3 is downregulated in PCa and associated with poor patient prognosis. Overexpression of TEAD3 inhibits the proliferation and migration ability of PCa cells via restraining the mRNA level of ADRBK2. These results indicate that TEAD3 was down-expressed in PCa patients and was positively correlated with a high Gleason score and poor prognosis. Mechanistically, we found that the upregulation of TEAD3 inhibits the proliferation and metastasis of prostate cancer by inhibiting the expression of ADRBK2.
Asunto(s)
Hiperplasia Prostática , Neoplasias de la Próstata , Masculino , Humanos , Proteínas Hedgehog/metabolismo , Línea Celular Tumoral , Neoplasias de la Próstata/patología , Hiperplasia Prostática/genética , Hiperplasia Prostática/metabolismo , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Movimiento Celular/genética , Factores de Transcripción de Dominio TEARESUMEN
The biochemical mechanisms that regulate the process of cancer metastasis are still poorly understood. Because kinases, and the signaling pathways they comprise, play key roles in regulation of many cellular processes, we used an unbiased RNAi in vitro screen and a focused cDNA in vivo screen against human kinases to identify those with previously undocumented roles in metastasis. We discovered that G-protein-coupled receptor kinase 3 (GRK3; or ß-adrenergic receptor kinase 2) was not only necessary for survival and proliferation of metastatic cells, but also sufficient to promote primary prostate tumor growth and metastasis upon exogenous expression in poorly metastatic cells in mouse xenograft models. Mechanistically, we found that GRK3 stimulated angiogenesis, at least in part through down-regulation of thrombospondin-1 and plasminogen activator inhibitor type 2. Furthermore, GRK3 was found to be overexpressed in human prostate cancers, especially in metastatic tumors. Taken together, these data suggest that GRK3 plays an important role in prostate cancer progression and metastasis.