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1.
Cell Death Dis ; 10(10): 701, 2019 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-31541079

RESUMO

Hepatoblastoma (HB) is the most common hepatic neoplasm in childhood and the therapeutic outcomes remain undesirable due to its recurrence and metastasis. Increasing evidence shows that dipeptidase 1 (DPEP1) has pivotal function in tumorigenesis in multiple tumors. However, the expression pattern, biological function, and underlying mechanism of DPEP1 in HB have not been reported. Here we showed that DPEP1 was significantly upregulated and was associated with poor prognosis in HB patients. In vitro and in vivo assays indicated that silencing DPEP1 significantly suppressed HB cell proliferation, migration, and invasion, while DPEP1 overexpression exhibited the opposite effect. In addition, we identified that DPEP1 was a direct target of microRNA-193a-5p (miR-193a-5p). Functional experiments demonstrated that overexpression of miR-193a-5p significantly inhibited cell proliferation and invasion of HB cells, while the inhibitory effect could be reversed by DPEP1 overexpression. Moreover, miR-193a-5p was decreased in HB tumor tissues and associated with a poor clinical prognosis. Mechanistically, our results indicated that the miR-193a-5p/DPEP1 axis participated to the progression of HB via regulating the PI3K/Akt/mTOR (phosphatidylinositol-3-kinase/Akt/mammalian target of rapamycin) signaling. In conclusion, our findings suggest that the miR-193a-5p /DPEP1 axis might be a good prognostic predictor and therapeutic target in HB.

2.
Cancer Med ; 8(8): 3981-3991, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31150156

RESUMO

Osteosarcoma is the most common type of primary malignant tumor of skeletal with poor prognosis in children and adolescents. Accumulating evidence indicates that CBX2 is overexpressed in multiple human neoplasm and play a critical role in tumorigenesis and progression. However, its functional role and upstream regulation mechanism in osteosarcoma remain unknown. In the present study, tissue microarray (TMA) analysis was performed to determine the association between CBX2 expression and clinical prognosis of osteosarcoma patients by immunohistochemistry. We also investigated the functional role of CBX2 using small interfering RNA (siRNA) in vitro and in vivo. Additionally, we confirmed the direct binding between CBX2 and let-7a via qPCR, western blot and luciferase reporter assay. We found that CBX2 is dramatically upregulated in osteosarcoma tissues and high CBX2 expression was correlated with metastasis, recurrence, and chemotherapy response, as well as unfavorable prognosis in patients with osteosarcoma. Similar results were observed in a sarcoma cohort from The Cancer Genome Atlas (TCGA) dataset. Further experiments revealed that CBX2 knockdown significantly impeded osteosarcoma cell proliferation and invasion ability in vitro, and suppressed the tumor growth in tumor xenografts model. Mechanistically, we confirmed that CBX2 is a functional target of miRNA let-7a. Overexpression of let-7a inhibits osteosarcoma cell proliferation, which was reversed by CBX2 overexpression. Taken together, our study demonstrates that let-7a/CBX2 plays a crucial role in osteosarcoma progression. CBX2 could serve as a promising prognostic biomarker and potential therapeutic target for osteosarcoma patients.

3.
Cell Prolif ; 51(6): e12510, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30105813

RESUMO

OBJECTIVES: Gallbladder carcinoma (GBC) is the most highly aggressive cancer of biliary tract, but effective therapeutics are lacking. Emerging evidence has unveiled that miR-139-5p is aberrantly downregulated in cancers, including GBC. However, the functions and mechanisms of miR-139-5p in GBC remain unclear. MATERIALS AND METHODS: MiR-139-5p-overexpression was established in GBC cell lines, after which cell proliferation, migration, invasion, colony formation, and glucose metabolism were assayed in vitro. Subsequently, bioinformatics prediction and dual-luciferase reporter were performed to confirm that pyruvate kinase M2 (PKM2) was a direct target of miRNA-139-5p. Xenograft mouse models were applied to investigate the role of miR-139-5p in GBC tumourigenicity in vivo. In situ hybridization and immunohistochemical assays were performed to determine the relationships among miR-139-5p, PKM2 expression and clinical malignancies in GBC samples. RESULTS: We found that miR-139-5p was substantially downregulated in GBC tissues. Low expression of miR-139-5p was significantly associated with poor clinical outcomes. GBC cell proliferation, migration, and invasion could be inhibited by overexpression of miR-139-5p either in vitro or in vivo. In addition, miR-139-5p overexpression could directly inhibit PKM2 expression and lead to suppression of glucose consumption, lactate production, and cellular ATP levels. Moreover, PKM2 was frequently upregulated in GBC and correlated with poor prognosis. Mechanistically, miRNA-139-5p inhibited cell proliferation, migration, and glycolysis in GBC, at least in part, by repressing PKM2. CONCLUSIONS: These results demonstrated a novel role for miR-139-5p/PKM2 in GBC progression and provided potential prognostic predictors for GBC patients.

4.
Oncotarget ; 9(2): 2502-2514, 2018 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-29416787

RESUMO

Osteosarcoma (OS) is the most common primary malignant bone tumor in childhood and adolescence with poor prognosis. The mechanism underlying tumorigenesis and development of OS is largely unknown. ALDH1B1 has been reported to involve in many kinds of human cancers and functions as an oncogene, but the role of ALDH1B1 in OS has not been investigated comprehensively. In the present study, we aimed to examine clinical value and biological function of ALDH1B1 in OS. Firstly, we investigated the roles of ALDH1B1 on an OS tissue microarray (TMA) as well as two OS cohorts from GEO database. We found that ALDH1B1 was significantly up-regulated in OS tissues and was independently associated with poor prognosis. Moreover, ALDH1B1 silencing could suppress the proliferation, migration, invasion in vitro and inhibit the growth of xenograft tumor and of OS cells in vivo. Additional, ALDH1B1 knockdown increased the apoptosis rate and lead to cell cycle arrest in G1 stage of OS cell in vitro. More importantly, the inhibition of ALDH1B1 expression could increase the sensitivity of OS cells to chemotherapy, which suggested that ALDH1B1 might be served as a therapeutic target to reverse drug resistance in chemotherapy in OS patients. Taken together, our founding suggested that ALDH1B1 contributes to OS tumor progression and drug resistance, which may represent a novel prognostic marker and potential therapeutic target for OS patients.

5.
Biomed Pharmacother ; 83: 876-880, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27509223

RESUMO

OBJECTIVES: Adipose tissue derived-mesenchymal stem cells (AMSCs) are one of the most widely used MSCs in the cell therapy for regenerative medicine. In the current study, the role of CXCL13 in AMSCs and its potential signaling pathway were investigated. METHODS: AMSCs were isolated from adipose tissue of healthy subjects. After administrating the cells with CXCL13, the expression levels of miR-23a and runt-related transcription factor 2 (Runx2) were assessed by real-time PCR and western blot. The alterations of phosphoinositide-3 kinase (PI3K)/Akt, stress-activated protein kinase (SAPK)/c-jun kinase (JNK), and extracellular-signal-regulated kinase (ERK1/2) pathways were also evaluated. RESULTS: CXCL13 down-regulated miR-23a and up-regulated Runx2 expression in AMSCs. The inhibitor specific for PI3K/AKT, but not SAPK/JNK and ERK ERK1/2, reversed the effects of CXCL13 on miR-23a and Runx2 expression. CONCLUSION: CXCL13 inhibits miR-23a expression through modulating PI3K/AKT pathway in AMSCs.


Assuntos
Tecido Adiposo/citologia , Quimiocina CXCL13/farmacologia , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Adulto , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Regulação para Baixo/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , MicroRNAs/genética , Transdução de Sinais/genética , Regulação para Cima/genética
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