RESUMO
Accumulating evidences have emphasized the essential roles of differentially expressed miRNAs in papillary thyroid cancer (PTC) and follicular thyroid carcinoma (FTC) progression. MiR-128 has been reported to be down-regulated in multiple cancers to restrain tumor growth. However, the role of miR-128 in the development of PTC and FTC and the underlying mechanism remain to be unclear. In this present study, the results indicated that miR-128 expression was markedly down-regulated in PTC and FTC tissues and various thyroid carcinoma cell lines. Functional analysis indicated that over-expression of miR-128 suppressed PTC and FTC cancer cell growth, induced apoptosis and cell cycle arrest in G0/G1 phase. In addition, miR-128 over-expression markedly inhibited cancer cell migration and invasion. However, the processes above were reversed by silencing miR-128 expressions in thyroid tumor cells. Following, we characterized sphingosine kinase-1 (SPHK1) as a direct target of miR-128 that interacted with the 3'-untranslated region (UTR) of SPHK1, and the results were confirmed by using luciferase-reporter assay. We also observed that SPHK1 expression was decreased and negatively correlated with miR-128 expression in PTC and FTC tissues clinically. Importantly, ectopic expression of SPHK1 significantly abrogated the tumor-suppressive effect induced by miR-128, as supported by the reduced apoptosis, while the enhanced proliferation and metastasis. Finally, over-expressing miR-128 apparently reduced the tumor growth rate and tumor weight in vivo using xenograft tumor model, accompanied with a remarkable decrease of SPHK1. Thus, our study illustrated that miR-128 might be a tumor suppressor microRNA that played an essential role in thyroid carcinoma progression.
Assuntos
Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica/genética , MicroRNAs/genética , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Neoplasias da Glândula Tireoide/genética , Regiões 3' não Traduzidas/genética , Animais , Apoptose/genética , Carcinoma Papilar/genética , Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Regulação para Baixo/genética , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Glândula Tireoide/patologiaRESUMO
BACKGROUND MicroRNA-125a (miR-125a) has been involved with many diseases, such as hepatocellular carcinoma and inflammation. In this study, we aimed to investigate the molecular mechanism, including the potential regulator and signaling pathways, of vascular endothelial growth factor (VEGF). MATERIAL AND METHODS We divided the participants into 3 groups by rs12976445 genotype and performed chi-square tests to evaluate the differences between CC and CT+TT groups for sex, age, grading, pT category, metastases, and fludeoxyglucose F18 injection (18FDG) metabolism. RESULTS We found all variables to be statistically significant. We searched the miRNA database online (www.mirdb.org) with the "seed sequence" located within the 3-prime untranslated region (3' UTR) of the target gene and then validated VEGF to be the direct gene via luciferase reporter assay system. We also established the negative regulatory relationship between MiR-125a and VEGF by studying the relative luciferase activity. We conducted real-time polymerase chain reaction and Western blot analysis to study the mRNA and protein expression level of VEGF among different groups (CC=18, CT=8, TT=3) or cells treated with scramble control, miR-125a mimics, VEGF RNA, and MiR-125a inhibitors. CONCLUSIONS We validated the negative regulatory relationship between MiR-125a and VEGF and found that rs12976445 may function as a biomarker to predict metabolism of 18FDG.
