RESUMO
Autophagy is the main degradation pathway to eliminate long-lived and aggregated proteins, aged or malfunctioning organelles, which is essential for the intracellular homeostasis and prevention of malignant transformation. Although the processes of autophagosome biogenesis have been well illuminated, the mechanism of autophagosome transport remains largely unclear. In this study, we demonstrated that the ninein-like protein (Nlp), a well-characterized centrosomal associated protein, was able to modulate autophagosome transport and facilitate autophagy. During autophagy, Nlp colocalized with autophagosomes and physically interacted with autophagosome marker LC3, autophagosome sorting protein Rab7 and its downstream effector FYCO1. Interestingly, Nlp enhanced the interaction between Rab7 and FYCO1, thus accelerated autophagic flux and the formation of autophagolysosomes. Furthermore, compared to the wild-type mice, NLP deficient mice treated with chemical agent DMBA were prone to increased incidence of hepatomegaly and liver cancer, which were tight associated with the hepatic autophagic defect. Taken together, our findings provide a new insight for the first time that the well-known centrosomal protein Nlp is also a new regulator of autophagy, which promotes the interaction of Rab7 and FYCO1 and facilitates the formation of autophagolysosome.
Assuntos
Autofagia/genética , Proteínas Associadas aos Microtúbulos/genética , Proteínas Nucleares/genética , proteínas de unión al GTP Rab7/genética , Animais , Antracenos/farmacologia , Autofagossomos/genética , Centrossomo/metabolismo , Hepatomegalia/genética , Humanos , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas/genética , Camundongos , Piperidinas/farmacologiaRESUMO
Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive cancers in China, but the underlying molecular mechanism of ESCC is still unclear. Involvement of microRNAs has been demonstrated in cancer initiation and progression. Despite the reported function of miR-503 in several human cancers, its detailed anti-oncogenic role and clinical significance in ESCC remain undefined. In this study, we examined miR-503 expression by qPCR and found the downregulation of miR-503 expression in ESCC tissue relative to adjacent normal tissues. Further investigation in the effect of miR-503 on ESCC cell proliferation, migration, and invasion showed that enhanced expression of miR-503 inhibited ESCC aggressive phenotype and overexpression of CCND1 reversed the effect of miR-503-mediated ESCC cell aggressive phenotype. Our study further identified CCND1 as the target gene of miR-503. Thus, miR-503 functions as a tumor suppressor and has an important role in ESCC by targeting CCND1.
Assuntos
Carcinoma de Células Escamosas/patologia , Ciclina D1/metabolismo , Neoplasias Esofágicas/patologia , MicroRNAs/metabolismo , Regiões 3' não Traduzidas , Idoso , Antagomirs/metabolismo , Sequência de Bases , Sítios de Ligação , Carcinoma de Células Escamosas/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Ciclina D1/antagonistas & inibidores , Ciclina D1/genética , Regulação para Baixo , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular , Humanos , Masculino , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Pessoa de Meia-Idade , Fenótipo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Pontos de Checagem da Fase S do Ciclo Celular , Alinhamento de SequênciaRESUMO
Although progress in clinical and basic research has significantly increased our understanding of breast cancer, little is known about the molecular mechanism underlying breast cancer metastasis. Identification of effective therapeutic targets to prevent breast cancer metastasis is urgently needed. The function of miR-503-3p has been investigated in other cancers, but its role in breast cancer remains undefined. Here, we found that miR-503-3p was overexpressed in breast cancer tissue and plasma compared with adjacent normal breast tissue and with plasma from healthy individuals. Moreover, we identified miR-503-3p to be an oncogene of breast cancer cell proliferation, migration and invasion. Upregulation of miR-503-3p in breast cancer cells inhibited expression of epithelial-mesenchymal transition (EMT)-related protein SMAD2 and the epithelial marker protein E-cadherin by directly binding to their mRNA 3' untranslated region, whereas increased expression of mesenchymal marker proteins, including vimentin and N-cadherin. Taken together, our findings support a critical role for miR-503-3p in induction of breast cancer EMT and suggest that plasma miR-503-3p may be a useful diagnostic biomarker for breast cancer.
