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[This corrects the article DOI: 10.7150/jca.27748.].
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Database screening indicated that microRNAs (miRNAs) are involved in pathogenesis of endometrial cancer. Among these miRNAs, miR-449a might be involved in tumorigenesis and lower expression of miR-449a was associated with poor prognosis. However, the role of miR-449a and its underlying molecular mechanism in endometrial cancer (EC) has not been investigated. In this study, our analysis found that miR-449a expression is inversely correlated with the stage of EC. Downregulation of miR-449a was correlated with tumor progression and poor prognosis in the EC patients. Results of functional analyses revealed that overexpression of miR-449a in human EC cells alleviated cell proliferation, invasion and metastasis. Conversely, loss of miR-449a in EC cancer cells facilitated all these cellular activities. Moreover, we identified N-myc downstream-regulated gene 1 (NDRG1) as a direct and functional target gene of miR-449a in EC cells, and the expression of NDRG1 in 87â¯EC specimens were inversely correlated with that of miR-449a. Additionally, further studies show that the down-regulation of NDRG1 expression inhibited proliferation and metastasis of EC cells through the PTEN/AKT pathway. Therefore, these results suggest that miR-449a suppresses the growth and metastasis of EC by directly targeting the NDRG1 gene and that the activation of miR-449a may represent an effective therapeutic strategy in EC.
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Proteínas de Ciclo Celular/metabolismo , Neoplasias do Endométrio/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , MicroRNAs/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Animais , Sequência de Bases , Ciclo Celular/genética , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Neoplasias do Endométrio/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Camundongos Nus , MicroRNAs/genética , Pessoa de Meia-Idade , Invasividade Neoplásica , Metástase Neoplásica , Fenótipo , PrognósticoRESUMO
BACKGROUND: High-grade serous ovarian cancer (HGSOC) is the most lethal of all gynecological malignancies. Patients often suffer from chemoresistance. Several studies have reported that Fn14 could regulate migration, invasion, and angiogenesis in cancer cells. However, its functional role in chemoresistance of HGSOC is still unknown. METHODS: The expression of Fn14 in tissue specimens was detected by IHC. CCK-8 assay was performed to determine changes in cell viability. Apoptosis was measured by flow cytometry. The potential molecular mechanism of Fn14-regulated cisplatin resistance in HGSOC was investigated using qRT-PCR, western blotting, and Co-IP assays. The role of Fn14 in HGSOC was also investigated in a xenograft mouse model. RESULTS: In this study, we found that Fn14 was significantly downregulated in patients with cisplatin resistance. Patients with low Fn14 expression were associated with shorter progression-free survival and overall survival. Overexpression of Fn14 suppressed cisplatin resistance in OVCAR-3 cells, whereas knockdown of Fn14 did not affect cisplatin resistance in SKOV-3 cells. Interestingly, Fn14 could exert anti-chemoresistance effect only in OVCAR-3 cells harboring a p53-R248Q mutation, but not in SKOV-3 cells with a p53-null mutation. We isolated and identified primary cells from two patients with the p53-R248Q mutation from HGSOC patients and the anti-chemoresistance effect of Fn14 was observed in both primary cells. Mechanistic studies demonstrated that overexpression of Fn14 could reduce the formation of a Mdm2-p53-R248Q-Hsp90 complex by downregulating Hsp90 expression, indicating that degradation of p53-R248Q was accelerated via Mdm2-mediated ubiquitin-proteasomal pathway. CONCLUSION: Our findings demonstrate for the first time that Fn14 overcomes cisplatin resistance through modulation of the degradation of p53-R248Q and restoration of Fn14 expression might be a novel strategy for the treatment of HGSOC.
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Neoplasias Ovarianas/tratamento farmacológico , Proteínas Proto-Oncogênicas c-mdm2/genética , Receptor de TWEAK/genética , Proteína Supressora de Tumor p53/genética , Animais , Apoptose/genética , Linhagem Celular Tumoral , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas de Choque Térmico HSP90/genética , Humanos , Camundongos , Pessoa de Meia-Idade , Gradação de Tumores , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Intervalo Livre de Progressão , Complexo de Endopeptidases do Proteassoma/genética , Proteólise , Transdução de Sinais/efeitos dos fármacos , Ubiquitinação/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Endometrial cancer represents the leading frequency in gynecological malignancy in developed countries. Even with early detection, metastasis and recurrence remain the main reasons for a high death rate. MicroRNA-449a (miR-449a) has been reported to function as a tumor suppressor, yet the role of miR-449a in endometrial cancer metastasis has not been investigated. The present study identified that miR-449a was downregulated in advanced endometrial cancer. Overexpression of miR-449a decreased the migration and invasion of KLE and AN3CA endometrial cancer cells. Using luciferase reporter assays, we identified that miR-449a directly targeted the steroid receptor coactivator (SRC) by binding to sites in the 3' untranslated regions. Elevated expressions of SRC have been witnessed in advanced endometrial cancer tissues and have promoted tumor metastasis. We also identified that the suppressive effect of miR-449a on metastasis could be mediated by downregulating SRC and that miR-449a could suppress AKT and ERK1/2 pathway activation in endometrial cancer cells. These findings contribute to the current understanding of the function of miR-449a in endometrial cancer.
